Butylene Glycol:

Skin-Conditioning Agent – Miscellaneous; Solvent; Viscosity Decreasing Agent; HUMECTANT; MASKING; SKIN CONDITIONING; VISCOSITY CONTROLLING

Firstly, butylene glycol is added to skin care products to increase penetration of other ingredients in the formulation.

Secondly, butylene glycol is sometimes included in formulations to give creams a thinner consistency.

By thinning the cream formula, butylene glycol can make the product more enjoyable to use and reduce the amount of time needed for a thick coat of cream to dissipate.

Thirdly, butylene glycol can also act as a solvent, and makes it easier for other ingredients in the formula to mix. This quality helps create a more homogenous cream texture.

Lastly, this chemical also has humectant properties. By drawing moisture to the skin from the surrounding atmosphere, butylene glycol can add needed hydration to skin cells and can even play a role in easing the appearance of wrinkles.

Causes skin irritation in people with sensitive skin and inflamed skin

Propanediol:

Propanediol 1,3 (referred to as Propanediol hereafter) is a natural, green, propylene glycol alternative derived from corn sugar, used as a humectant, hair and skin conditioner, preservative booster, and solvent with a light, non-sticky, slightly dry skin feel.

Propanediol increases hydration when used in hair and body products, and at 5%, performs better than propylene glycol and butylene glycol. When combined with glycerin, Propanediol shows a synergistic effect that reduces the tackiness of glycerin, while offering the benefits of increased levels of hydration. At levels up to 75%, it shows low potential to irritate or sensitize skin.

In surfactant systems, Propanediol increases the clarity of surfactant systems and viscosity while decreasing the amount of salt necessary to thicken a product. It improves flash foam, and produces more elegant systems with creamier lather and denser foam.

In hair care products, such as shampoo, conditioner, leave on conditioners, or styling aids, it offers a cleaner feeling after rinsing while increasing moisturization, improving detangling, reducing static, and improving wet and dry combing.

In all products, it decreases the freezing point and increases stability in freeze/thaw and heated tests.

Propanediol may boost the efficacy of preservatives. Its efficacy was demonstrated when combined with preservatives containing phenoxyethanol against yeast, gram-positive, and gram-negative organisms, as well as mold.

Ethylhexyl Olivate:

Natural emollient made from olive oil as an alternative to silicones including dimethicone and cyclopentasiloxane, cyclohaxasiloxane. Contain nourishing phytocompounds to support healthy skin. It softens hair and skin, creates a protective film, and reduces greasiness and tackiness. Light like oil with a dry after feel. Colorless and odorless liquid. Saponification value 125-150. Not water-soluble, oil-soluble. Improves spreading of creams & lotions and provides an even protective film to hair. It is a colorless liquid that is poorly soluble in water but soluble in most organic solvents. It is produced on a massive scale (>2,000,000,000 kg/y) for use in numerous applications such as solvents, flavors, and fragrances and especially as a precursor for production of other chemicals such as emollients and plasticizers. It is encountered in natural plant fragrances, and the odor has been reported as “heavy, earthy, and slightly floral” for the R enantiomer and “a light, sweet floral fragrance” for the S enantiomer

Cetearyl Alcohol:

Composed of fatty alcohols, 70:30 ratio. C18 weight % stearyl alcohol 66-76 and C16 weight % cetyl alcohol 22-32. HLB 15.5 (creates oil-in-water emulsions but only to a limited degree). White flakes or pastilles, mild characteristic odor. Not soluble in water. Partially soluble in alcohol.

Fatty alcohol that is a mixture of gentle cetyl and stearyl alcohols. It’s used as an emollient, texture enhancer, foam stabilizer, and carrying agent for other ingredients. Can be derived naturally, as in coconut fatty alcohol, or made synthetically. It is almost always combined with similar-feeling ingredients to create a product’s texture and influence its slip when applied to skin.

Cosmetic products labeled “alcohol free” are allowed to contain cetearyl alcohol, whose effects are quite different from skin-aggravating forms of alcohol. We repeat: fatty alcohols like cetearyl alcohol do not pose a risk of sensitizing skin.

Non-gelling thickener, viscosity & consistency enhancer (also in waterless products like lipsticks). At concentrations under 2% also used as co-emulsifier. Also emollient, moisturizing, and foam boosting properties.

Chlorogenic Acids:

Tetrahexyldecyl Ascorbate

Ergothioneine:

Ergothioneine is a component of white button mushrooms that is considered as an antioxidant with cancer chemopreventive properties. Its antioxidant properties appear to be related to at least four molecular activities:

The ability to scavenge free radicals which can be proposed to arise from the easy one-electron oxidation of its mercapto group to a disulfide

Chelating properties toward divalent metallic cations (see Section 1 of Chapter 4), which is due to its α-amino acid moiety.

3

Activation of antioxidant enzymes such as glutathione peroxidase (Se-GPx) and Mn superoxide dismutase (SOD) and inhibition of superoxide-generating enzymes such as NADPH-cytochrome c reductase.

4

Its ability to affect the oxidation of various hemoproteins such as hemoglobin and myoglobin.

Benzylidene Dimethoxy Dimethylindanone:

AhR in keratinocytes is not only activated by anthropogenic chemicals but also by UVB irradiation, which leads to the intracellular formation of the tryptophan photoproduct and high-affinity AhR ligand 6-formylindolo[3,2-b]carbazole. Because (i) overexpression of a constitutively active AhR causes inflammatory skin lesions, (ii) an increase in CYP activity leads to reactive oxygen species formation, (iii) CYP1 enzymes are critical for chemical-induced skin carcinogenesis, and (iv) COX-2 is involved in UV-induced inflammation and carcinogenesis, it was postulated that a transient inhibition of AhR may protect human skin against the detrimental effects of UVB irradiation

Arabidopsis Thaliana Extract: antioxidant.

Carnosine:

It has been proven to scavenge reactive oxygen species (ROS), as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acidsduring oxidative stress.

Carnosine can increase the Hayflick limit in human fibroblasts,[6] as well as appearing to reduce the telomere shortening rate

Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetesatherosclerosischronic renal failure, and Alzheimer’s disease[9]), and ultimately reducing development of atherosclerotic plaque build-up.[5][10][11]Chronic glycolysis is speculated to accelerate aging, making carnosine a candidate for therapeutic potential.

Vitis Vinifera Seed Extract

Peak Proposed Compound RT (min) [M − H] Measured [M − H] Calculated Error (ppm) mSigma Fragmentation Pattern Molecular Formula
1 Sucrose 5.5 341.108 341.109 2.7 18.0 Not fragmented C12H22O11
2 Procyanidin C (isomer 1) 11.6 865.199 865.198 0.9 42.5 577.114; 289.076 C45H38O18
3 Gallic acid 12.6 169.013 169.014 6.7 3.8 125.024 C7H6O5
4 Procyanidin C (isomer 2) 14 865.197 865.198 1.4 20.8 577.134; 432.093 C45H38O18
5 Procyanidin B (isomer 1) 14.4 577.136 577.135 2.2 46.1 451.124; 289.076 C30H26O12
6 Procyanidin B (isomer 2) 14.6 577.136 577.135 1.3 53.1 425.075; 289.074 C30H26O12
7 Procyanidin B (isomer 3) 15 577.133 577.135 3.6 38.0 289.076 C30H26O12
8 Procyanidin C (isomer 3) 15.6 865.198 865.198 1.0 18.1 577.114; 451.123; 433.072; 289.065 C45H38O18
9 Procyanidin B (isomer 4) 16.4 577.136 577.135 1.9 48.5 425.088; 289.074 C30H26O12
10 Procyanidin B (isomer 5) 17.1 577.133 577.135 4.0 41.7 425.087; 289.073 C30H26O12
11 Galloyl(epi)catechin-(epi)catechin (isomer 1) 17.5 729.146 729.146 0.3 35.7 577.121; 289.074; 169.015 C37H30O16
12 (-)-Epicatechin 18.2 289.072 289.072 2.5 24.5 245.083 C15H14O6
13 Galloyl(epi)catechin-(epi)catechin (isomer 2) 18.7 729.148 729.146 2.5 54.4 577.132; 432.094 C37H30O16
14 Galloyl(epi)catechin-(epi)catechin (isomer 3) 19.2 729.147 729.146 1.0 50.7 577.131; 432.094; 169.014 C37H30O16
15 Procyanidin C (isomer 4) 19.8 865.200 865.198 1.8 22.3 432.094 C45H38O18
16 Procyanidin B (isomer 6) 20.3 577.134 577.135 1.8 49.2 432.092; 289.070 C30H26O12
17 Galloyl(epi)catechin-(epi)gallocatechin 20.9 743.125 743.125 0.0 28.7 591.170 C37H28O17
18 (+)-Catechin 23.1 289.072 289.072 3.4 23.1 245.083 C15H14O6
19 Procyanidin B (isomer 7) 24.3 577.133 577.135 4.4 16.5 407.076; 289.075; 245.044; 125.025 C30H26O12
20 Galloyl(epi)catechin-(epi)catechin (isomer 4) 25.2 729.144 729.146 2.1 19.6 577.131; 451.122 C37H30O16
21 Galloyl(epi)catechin-(epi)catechin (isomer 5) 25.4 729.144 729.146 3.2 14.1 577.131; 289.072 C37H30O16
22 (Epi)catechin gallate (isomer 1) 26.7 441.084 441.083 2.2 25.4 289.072; 169.015; 125.025 C22H18O10
23 Procyanidin B (isomer 8) 28 577.134 577.135 1.3 45.4 425.088; 289.073; 125.025 C30H26O12
24 (Epi)catechin gallate (isomer 2) 28.6 441.082 441.083 1.5 13.6 289.073; 169.015; 125.025 C22H18O10
25 Galloyl(epi)catechin-(epi)catechin (isomer 6) 30.6 729.145 729.146 0.9 35.2 577.117; 407.079; 289.071; 125.023 C37H30O16
26 Quercetin hexoside (isomer 1) 32.6 463.086 463.088 3.9 29.5 300.023 C21H20O12
27 Secoisolariciresinol glucoside 33.7 523.217 523.219 3.1 5.1 361.180 C26H36O11
28 Quercetin rhamnoside 34.9 447.034 447.093 0.3 31.2 300.028 C21H20O11
29 Phloretin xyloglucoside 35.5 567.169 567.172 4.9 33.1 273.073 C26H32O14
30 Quercetin glucuronide 36.1 477.067 477.067 1.5 7.9 300.028 C21H18O13
31 Quercetin hexoside (isomer 2) 36.7 463.071 463.067 1.7 10.5 300.027 C21H20O12
32 Amurenisin 37.1 439.066 439.067 3.1 5.3 Not fragmented C22H16O10
33 Phloretin glucoside 38.4 435.129 435.130 0.6 7.2 273.072 C21H24O10
34 Ellagic acid 39 301.000 300.999 4.3 25.9 Not fragmented C14H6O8
35 Quercetin 46 301.036 301.035 1.5 11.8 Not fragmented C15H10O7
36 Phloretin 47.2 273.077 273.077 0.1 37.0 Not fragmented C15H14O5

Tannins:

Tannins (comprising hydrolysable and condensed tannins) are one of the major groups of polyphenols which are found in our diets. Proanthocyanidins (belonging condensed tannins) have been identified in several agricultural byproducts, seeds, fruits and vegetables and their biological metabolism and pharmacokinetics have been extensively reviewed. In addition to the free radical scavenging and antioxidant activity, proanthocyanidins also exhibit vasodilatory, anti-carcinogenic, anti-allergic, anti-inflammatory, anti-bacterial, cardio-protective, immune-stimulating, anti-viral and estrogenic activities, as well as are inhibitors of the enzymes phospholipase A2 , cyclooxygenase and lipooxygenase . The anti-inflammatory activity of proanthocyanidins is one of the most widely studied . Mechanisms of action include modulation of the arachidonic acid and nuclear factor-κB (NF-κB) pathways, inhibition of eicosanoid generating enzymes, inflammatory mediator secretion and the mitogen-activated protein kinase pathway.

Euterpe Oleracea Fruit Extract

UV-A radiations are known to induce cellular oxidative stress, leading to premature skin aging. Consumption of açai fruit (Euterpe oleracea Martius) is known to have many health benefits due to its high level of antioxidants. Herein, we analyzed the ability of phenolic compounds extracted from this fruit to attenuate UV-A-induced oxidative stress in immortalized fibroblast. A methanol/water açai extract was fractionated by HPLC and each fraction tested for anti-oxidant stress activity. Immortalized fibroblasts were pre-incubated with açai fractions and then exposed to UV-A radiations. Açai extract was found to be able to strongly protect cells from oxidative stress. In particular, reactive oxygen species (ROS) production, GSH depletion, lipid peroxidation and no increase in the phosphorylation levels of proteins involved in the oxidative stress pathway was observed in cells pre-incubated with the extract and then irradiated by UV-A. Mass spectrometry analyses of HPLC fractionated extract led us to the identification of malvidin and cyanidin derivatives as the most active molecules able to counteract the negative effects induced by UV-A irradiation. Our results indicate, for the first time, that açai fruit is a valuable natural source for malvidin and cyanidin to be used as anti-stress molecules and represent good candidates for dietary intervention in the prevention of age related skin damage

Glycyrrhiza Glabra (Licorice) Root Extract,

\it has skin-lightening or to say it another way depigmenting properties. The most active part is called glabridin. The topical application (meaning when you put it on your face) of 0.5% glabridin was shown to inhibit UVB caused pigmentation of guinea pigs. Another study even suggested that licorice is more effective than the gold standard skin-lightening agent hydroquinone. All in all, licorice is considered to be one of the safest skin lightening agents with the fewest side effects.

There is just one catch regarding glabridin and licorice: the amount of glabridin in commercial licorice extracts can vary a lot. We have seen extracts with only 4% glabridin as well as 40% glabridin. The latter one is a very-very expensive ingredient, so if you are after the depigmenting properties try to choose a product that boasts its high-quality licorice extract.

licorice is a potent anti-inflammatory. Glabridin has also some soothing properties but the main active anti-inflammatory component is glycyrrhizin. It’s used to treat several skin diseases that are connected to inflammation including atopic dermatitis, rosacea or eczema. Licorice root/glycyrrhizic acid. Glycyrrhetinic acid, the active principle of licorice root, has been elucidated to have anti-inflammatory properties. Licorice root also offers pigment lightening as it contains liquiritin and isoliquertin, which disperse melanin, and glabridin, which inhibits tyrosinase. Licorice root is effective in treating the hyperpigmentation associated with photoaging.

Theobroma Cacao Seed Extract

Curcuma Longa Root Extract

Polyphenols play an important role in the maintenance of health and prevention of diseases. Polyphenols in the human diet are derived mainly from vegetables, fruits and spices. Drinks and beverages such as coffee, green and black tea, as well as chocolate, red wine, olive oil, nuts, etc., are also good sources of polyphenols. Many of these polyphenol-rich natural resources have been traditionally used as medicines for the prevention of diseases, as well as maintenance of youth and longevity. The recent line of studies has confirmed that these traditionally used natural remedies are strong anti-oxidant and anti-inflammatory agents. In addition, many of them play important roles in regulating the immune system and are now being investigated as chemopreventive, neuroprotective, cardioprotective and hepatoprotective agents, either acting alone or in combinations [1,2]. In particular, turmeric, a typical example of polyphenol-rich natural remedies, has been used for centuries in Indian traditional medicine (Ayurveda) and Traditional Chinese Medicine (TCM) [2]. Moreover turmeric, a popular curry spice, is also used as a food additive and preservative agent worldwide. Turmeric products have been characterized as safe by the Food and Drug Administration (FDA) in the USA, the Natural Health Products Directorate of Canada, and the Joint Expert Committee of the Food and Agriculture Organization/World Health Organization (FAO/WHO) [3]. Curcumin, a principal polyphenol component of turmeric, is available as an over-the-counter (OTC) supplement worldwide. Turmeric was introduced to Europe in the 13th century by Marco Polo and perhaps surprisingly, apart from an early study published in The Lancet in 1937, curcumin/turmeric has only entered extensive preclinical studies and scientific phase I and II/III clinical trial levels in the last 10–15 years

Oxidative damage and inflammation have been pointed out in preclinical studies as the root cause of cancer and other chronic diseases such as diabetes, hypertension, Alzheimer’s disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore, curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic outcome in past clinical trials, largely due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on the anti-inflammatory potential of curcumin and recent developments in dosage form and nanoparticulate delivery systems with the possibilities of therapeutic application of curcumin for the prevention and/or treatment of cancer

Olea Europaea (Olive) Fruit Extract

There is a plethora of lipophilic or amphiphilic microconstituents present in virgin olive oil, among them, phytosterols, squalene, tocopherols, phenolic compounds, terpenic acid derivatives, etc. [26,27,28]. Phenolic compounds occur in the form of: phenolic acids or alcohols, oleuropein derivatives, lignans, and flavonoids. In olive oil, the content of polyphenols ranges from 50 to 1000 mg/kg. As a matter of fact, it depends on the agronomic factors, the ripeness of olives, as well as extraction technology, along with storage or packaging processes [29,30,31,32,33].

The flesh of healthy olives contains about 2–3% of phenolic substances in the form of glucosides and esters. Virgin olive oil contains about 500 mg/L of polyphenols. The quantity and quality of polyphenols in olive oil is closely related to the process of olive milling and further processing. Therefore, virgin olive oils have substantially higher amounts of polyphenols than refined olive oils [30,33]. The phenolic compounds in olive oil are mostly glycides (e.g., oleuropein), alcohols and phenols (tyrosol, hydroxytyrosol), and also flavonoids [26,28,34]. Phenolic compounds are mainly responsible for the characteristic gustatory property of virgin olive oil, namely the bitter taste. Some micro constituents of olive oil are soluble in water, and thus, the content of phenolic compounds that are present in olive oil depends to a large extent on the extraction process

Euterpe Oleracea Fruit Extract

The profile of phenolic acids in juçara fruit consists in gallic acid, protocatechuic, p-hydroxybenzoic, vanillic, chlorogenic, caffeic, syringic, p-coumaric, sinapinic, and ferulic acids Inada et al. [11] were the first to identify the phenolic acids m-coumaric, transcinnamic, 4-hydroxyphenylacetic, and 3,4-dihydroxyphenylacetic in juçara pulp.

The amount of phenolic acids varies during the ripening stage in juçara fruits. The majority phenolic acid in all ripening stages of juçara fruit was protocatechuic acid [19]. Other authors reported that the ripening of the fruit and the geographic location may interfere in the phenolic compounds of the fruits of palm juçara [8], [10].

The main constituents of the phenolic compounds in juçara pulp are the ACNs [8], [9], [10]. The ACNs found in greater amounts in juçara fruits are cyanidin-3-rutinoside followed by cyanidin-3-glucoside. However, De Brito et al. identified a greatest amount of cyanidin-3-glucoside (53%) and cyanidin-3-rutinoside (46%).

Others subtypes of ACNs were identified in the samples of juçara by several authors: cyanidin-3-sambunoside pelargonidin-3-glucoside pelargonidin-3-rutinoside peonidin-3-rutinoside peonidin-3-glucoside [10], and delphinidin-3-glucoside [16], [17].

In addition, the study performed by Peron et al. [28] reported that ACNs from juçara degraded more slowly than from grapes (Italy type) after temperature effect (50 and 90 °C). Although phenolic compounds still found after temperature effect, the 90 °C decreased the antioxidant activity of the extracts. However, in spite of these results, it is emphasized that the ingestion of juçara is preferably in its fresh form, after processing the fruits with addition of water.

A recent research investigated the major ACNs and non-ACN phenolic compounds in juçara extracts using ultra performance liquid chromatography-mass spectrometry. This study found high amounts of ACN, about 26 mg/g dwb from a total of 31 mg/g dwb of phenolic compounds. Cyanidin-3-O-rutinoside was the most abundant ACN (73% of the total phenolic compounds content). Other phenolic compounds found in the extract were cyanidin-3-O-glucoside, pelargonidin-3-O-glucoside, quercetin, rutin, myricetin, kaempferol, kaempferol-3-O-rutinoside, luteolin, apigenin, catechin, ellagic acid, and 4,5-dicaffeoylquinic acid. The authors considered juçara a promising source of polyphenolics, mainly ACNs [29].

Camellia Sinensis Leaf Extract

It has become evident that phenolic compounds from natural products can reduce oxidative stress by indirect antioxidant action. Various flavonoids, which are found naturally in fruits, vegetables, and some beverages, have been demonstrated to exert antioxidant effects through a number of different mechanisms. Tea (Camellia sinensis L.; family Theaceae), the most popular and widely cultivated beverage in Southeast Asia, has received considerable attention among scientists due to its beneficial health effects. The health benefits associated with tea consumption have been attributed in part to the antioxidant activity and free radical-scavenging ability of the most abundant tea catechins [4,5,6]. The principal catechins present in tea leaves are epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), gallocatechin (GC), epicatechin (EC), and catechin. The amount of these compounds, which depends on tea variety, has been regarded as a quality indicator of tea [7]. Various biological functions of green tea, including antioxidant activities [8,9,10], anti-inflammatory activities [11], anti-melanogenic effects [12], and hepatoprotection [13,14,15,16,17], have been reported.

Trifluoroacetyl Tripeptide-2:

TFA-Val-Try-Val-OH

Trifluoroacetyl Tripeptide-2 is a synthetic tripeptide, designed as a matrix metalloproteinase and elastase inhibitor. It can decrease progerin synthesis, increase proteoglycan production and contract collagens. ProgelineTM, is a 3 amino acids peptide biomimetic of Elafin, an enzyme inhibitor that regulates the integrity of the extracellular matrix. ProgelineTM decreases progerin synthesis, a new aging biomarker involved in skin cellular senescence. By acting directly on a senescence marker, ProgelineTM clinically improves the appearance of signs associated with skin maturation: sagging, slackness and wrinkles.

Buddleja Officinalis Flower Extract

The flower buds of Buddleja officinalis Maxim. are used as a folk remedy in traditional Oriental medicine. B. officinalis is a flowering shrub in the family Scrophulariaceae that is widely distributed in America, Africa, and Asia. It is used in China and Korea to treat inflammation, vascular diseases, conjunctivitis, headache, and stroke, as well as enhance liver function [13]. B. officinalis reportedly contains iridoids (e.g., methylcatalpol and 6-O-vanilloyl ajugol), monoterpenoids (e.g., betulalbusides A), flavonoids (e.g., apigenin, isorhoifolin, and linarin), triterpenoids (e.g., acteoside, salidroside, and echinacoside), and phenylethanoids (e.g., buddlejasaponin I and mimengoside B) Several studies have observed the anti-inflammatory activity of B. officinalis flower extract (BFE), including downregulation of extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor- (NF-) κB signaling in BV-2 microglial cells, reduction of intracellular ROS production and NF-κB in human umbilical vein endothelial cells (HUVECs), and inhibition of high glucose-induced matrix metalloproteinase (MMP) activity through the inhibition of oxidative stress in HUVECs [21617]. However, no studies have determined whether BFE can protect hepatocytes from oxidative stress, and the properties of BFE on AMPK have not been evaluated. Therefore, we examined whether BFE protects hepatocytes from severe oxidative stress induced by AA + iron by inhibiting glutathione (GSH) depletion, hydrogen peroxide (H2O2) production, and mitochondrial dysfunction and whether the cytoprotective effects result from AMPK activation. Histomorphometric and histopathological analyses were performed to investigate the possible hepatoprotective effects of BFE against carbon tetrachloride- (CCl4-) induced hepatic damage in mice. The results revealed a molecular basis for the effects of BFE on hepatocyte protection.

Coffea Arabica Leaf Cell Extract

UV is a potent factor in skin photoaging and photocarcinogenesis. Therefore, investigating the inhibiting mechanisms of photoaging would be useful to enable development of agents to slow down the aging process. UV-irradiation increased metalloproteinase (MMP)-1, -3, and -9 and then causes collagen and elastin degradation, leading to the formation of coarse wrinkles and sagging skin. Polyphenols, a group of compounds, possessing a variety of biological activities including inhibition of MMP-1 and elastase, are widely distributed in plants including Coffea arabica. In this study, Coffea arabica leaves extract (CAE), its hydrolysates (CAH), chlororgenic acid and caffeic acid, are studied for their anti-photoaging effect. Coffea arabica leaves were extracted with methanol, and the extract was hydrolyzed with different concentrations of hydrochloric acid. The various concentrations of CAE, CAH, chlororgenic acid and caffeic acid were subject to MMPs and elastase inhibition tests. The fibroblast was used for collagen synthesis and MMP-1, -3, -9 inhibition tests on herbal extracts. The results showed that CAE stimulated type I procollagen expression, inhibited MMP-1, -3, -9 expression and inhibited the phosphorylation of JNK, ERK and p38. The results suggest that CAE can prevent photo-damage in skin through inhibiting MMP expression and MAP kinase pathway

Viscum album (mistletoe) extract

Viscum album (mistletoe) is a hemi parasitic shrub, frequently globular in shape. It grows on the branches of other trees, to which it is attached by a swelling called a haustorium. As a hemi-parasite it depends on its host for water and mineral nutrients but is able to photosynthesize (create its own carbohydrates using sunlight) because it has green leaves and stem10. Two prominent types of V. album, European and American, contain very similar protein constituents but have different medicinal uses. Both species contain lectins (viscumin/agglutinin), protein toxins, alkaloids and polysaccharides. The lectins are structurally similar to to ricin and abrin. According to Franz11 the lectins are cytotoxic glycoproteins, they cause cells to agglutinate and inhibit protein synthesis on the ribosomal level. The lectins are dual chain molecules. Chain A inhibits protein synthesis and chain B activates macrophages and releases lymphokines from lymphocytes. Both chains have been reported to inhibit allergen-induced histamine release from leukocytes and collagen-induced serotonin release from platelets11. According to Bussing and Schietzel12, the amounts and biological activity of V. album lectins are dependent on the host tree, manufacturing process, and time of harvest.

The extract of the leaves of Viscum album has been used for centuries in traditional medicine in many parts of the world13. In some parts of Africa, the plant is used both in the traditional and complementary management of many diseases. In Nigeria, the extract of the leaves of V. album is used in traditional medicine for the treatment of several ailments including hypertension, improve cardio-vascular functions; prevention and management of stroke14,15. A number of biological effects, such as anticancer, antimycobacterial, antiviral, apoptosis-inducing and immunomodulatory activities have been reported for mistletoes16. It has also been reported to be effective in the management of chronic metabolic disorders such as diabetes and free radical scavenging17. Clinical studies reported changes in immune parameters in humans during and after Viscum album application.

Crocus Sativus Leaf Cell Culture Extract

Carotenoids, which include crocin and crocetin, play an important role in health by acting as natural antioxidants. They protect cells and tissues from the detrimental effects of free radicals and reactive oxygen species (ROS). Crocin is the most studied active ingredient with regard to the antioxidant properties of saffron. However, it does not act alone—but thanks to work in synergy with other components such as safranal, dimethylcrocetin and flavonoids [49]. Other studies focused on the negative effects of oxidative stress on our brain since it is the organ most exposed to oxidation, due to the high phospholipid content of neuronal membranes and the existing link with the development of neurodegenerative pathologies such as Alzheimer’s disease, whose treatment with saffron can prevent the aggregation and deposition of amyloid β peptide in the human brain and can, therefore, be useful in Alzheimer’s disease [50 More recently, saffron has attracted a renewed interest for its use in cosmetics. Since ancient times, saffron is used for cosmetic purposes, absorbed in infusion or even in the cutaneous application, mixed with fat or macerated in donkey milk, for its eternal youthful properties. Cleopatra used it in her beauty products. In traditional Iranian medicine, saffron can improve the complexion and can be used to treat erysipelas. In traditional Greek medicine, it can refresh the skin of the face and is used to relieve the liver of the domination of bile and to treat acne, skin diseases and wounds. In addition, the body may look younger and brighter [23,24]. In another category, Hindu women used saffron to make the bindi, the yellow dot on the forehead. It is, in a way, a third eye symbolizing good fortune and conscience [25]. Nowadays, saffron tepals have been studied in several studies as being rich in crocin and kaempferol, thus representing an important source of bioactive compounds for potential cosmetic formulations [26–27]. Besides the antioxidant properties, saffron presents multiple interests for cosmetic applications. The most promising activities are listed hereafter. Cosmetics 2019, 6, 63  4 of 11

4.1. Anti-UV Agent

Prolonged exposure to the sun is extremely harmful because it puts the skin in contact with UV rays, known to cause serious lesions. Saffron is known to have anti-sun effects that can protect the skin from harmful UV rays. Studies show that saffron lotion may be a better sunscreen than homosalate (an organic compound used in some sunscreens). Thus, saffron can be used as a natural UV absorbing agent [28–29]. In addition to the antisolar and moisturizing properties of saffron, the prevention of skin cancers by saffron because of its antioxidant properties is important as well.

Superoxide Dismutases and Superoxide Reductases

Superoxide, O2 •−, is formed in all living organisms that come in contact with air, and, depending upon its biological context, it may act as a signaling agent, a toxic species, or a harmless intermediate that decomposes spontaneously. Its levels are limited in vivo by two different types of enzymes, superoxide reductase (SOR) and superoxide dismutase (SOD). Although superoxide has long been an important factor in evolution, it was not so when life first emerged on Earth at least 3.5 billion years ago. At that time, the early biosphere was highly reducing and lacking in any significant concentrations of dioxygen (O2), very different from what it is today. Consequently, there was little or no O2 •− and therefore no reason for SOR or SOD enzymes to evolve. Instead, the history of biological O2 •− probably commences somewhere around 2.4 billion years ago, when the biosphere started to experience what has been termed the “Great Oxidation Event”, a transformation driven by the increase in O2 levels, formed by cyanobacteria as a product of oxygenic photosynthesis.1 The rise of O2 on Earth caused a reshaping of existing metabolic pathways, and it triggered the development of new ones.2 Its appearance led to the formation of the so-called “reactive oxygen species” (ROS), for example, superoxide, hydrogen peroxide, and hydroxyl radical, and to a need for antioxidant enzymes and other antioxidant systems to protect against the growing levels of oxidative damage to living systems. Dioxygen is a powerful four-electron oxidizing agent, and the product of this reduction is water. + +→ + − O 4H 4e 2H 2 2O (1) When O2 is reduced in four sequential one-electron steps, the intermediates formed are the three major ROS, that is, O2 •−, H2O2, and HO• . + →− •− Oe O 2 2 (2) O 2H e H O 2 22 •− + − + +→ (3) + +→ + +− • H O H e H O HO 22 2 (4) HO H e H • +− + +→ 2O (5) Each of these intermediates is a potent oxidizing agent. The consequences of their presence to early life must have been an enormous evolutionary challenge. In the case of superoxide, we find the SOD and SOR enzymes to be widely distributed throughout current living organisms, both aerobic and anaerobic, suggesting that, from the start of the rise of O2 on Earth, the chemistry of superoxide has been an important factor during evolution.

Ubiquinone

Zingiber Officinate (Ginger) Root Extract

Ubiquinone

  • Ceramide NP,
  • Ceramide AP,
  • Ceramide EOP,
  • Linoleic Acid,
  • Linolenic Acid,
  • Sea Whip Extract,
  • Bisabolol,
  • Tocopherol,
  • Tocopheryl Acetate,
  • Cholesterol,
  • Phytosphingosine,
  • Jojoba Esters,
  • Sodium PCA,
  • Pentylene Glycol,
  • Methyl Gluceth-20,
  • Glycerin,
  • Helianthus Annuus (Sunflower) Seed Wax,
  • Acacia Decurrens Flower Wax,
  • Lecithin,

Sodium Lauroyl Lactylate:

Sodium Lauroyl Lactylate is a salt derived from the lauric acid ester of lactyl lactate (or milk and coconut oil), and is traditionally used as a food emulsifier, although it is seen in cosmetics and personal care products because of its ability, as a lactylate, to penetrate skin easily, providing “residual moisturization, extended fragrance release, and enhanced delivery of actives,” (Lauric acid is known for its moisturizing abilities, and is also recognized as an acne-fighter thanks to its anti-microbial properties.) Sodium Lauroyl Lactylate is used as an ingredient in shampoos, face and body washes, and other foaming cleansers.

Dicetyl Phosphate:

Cetearyl Alcohol & Dicetyl Phosphate and Ceteth-10 Phosphate is a highly effective Oil in water water anionic emulsifier without EO. It is skin compatible, and is used in O/W creams/lotions with a broad spectrum of oils and emollients, especially suitable for stable water-resistant sun-care formulations. It promotes the formation of intimate mixtures of non-miscible liquids by altering the interfacial tension. The surfactant property lowers the surface tension of cosmetic formulations as well as aids the even distribution of the product when used.

Lauryl Lactate

Glycolic Acid and Lactic Acid are naturally occuring organic acids also known as Alpha Hydroxy Acids or AHAs. The salts of Glycolic Acid (Ammonium Glycolate, Sodium Glycolate), the salts of Lactic Acid (Ammonium Lactate, Calcium Lactate, Potassiu Lactate, Sodium Lactate, TEA-Lactate) and the esters of Lactic Acid (Methyl Lactate, Ethyl Lactate, Butyl Lactate, Lauryl Lactate, Myristyl Lactate, Cetyl Lactate) may also be used in cosmetics and personal care products.

  • Skin conditioning agent – emollient – Lauryl Lactate, Myristyl Lactate, Cetyl Lactate.
  • Skin conditioning agent – humectant – Lactic Acid, Ammonium Lactate, Potassium Lactate, Sodium Lactate, TEA-Lactate.

Ceteth-20 Phosphate:

APPEARANCE: White waxy solid with mild fatty odor

DESCRIPTION: The Ceteth ingredients help other ingredients to dissolve in a solvent in which they would not normally dissolve. Ceteths also help to form emulsions by reducing the surface tension of the substances to be emulsified and they clean the skin and hair by helping water to mix with oil and dirt so that they these substances can be rinsed away.

FUNCTION: Ceteth ingredients are used in the formulation of hair dyes and colors, hair conditioners, permanent waves and other hair care products, as well as makeup foundations, cleansing products and other skin care products.

Diisostearyl Malate:

Dermol DISM is a fruit ester made from natural malic acid and highly branched alcohol, which allows it to exhibit an extremely low freeze point. It is an odorless, tasteless ester, that imparts gloss, sheen and lubricity with minimum oiliness. It is recommended as a good binder for pigmented products and is an excellent additive for imparting gloss and sheen in make-ups and lip products.

Xanthan Gum:

 

Xanthan gum was first discovered in the 1950s and is now finding extensive application in the food industry since its introduction in the early 1970s. The gum is obtained from the genus Xanthomonas, notably X. campestris by aerobic fermentation. The xanthan molecules have a (1,4)-β-d-glucopyranose backbone as in cellulose, but in addition have a trisaccharide side chain on every other glucose residue linked through the C3 position. The side chain consists of two mannopyranosyl residues linked on either side to a glucuropyranosyl uronic acid group. The inner mannose residue connected to the backbone may be acetylated while the terminal mannose residue may be pyruvated. The molecular mass of the xanthan molecules is very high (> 3 × 106) and the gum dissolves in water to yield highly viscous solutions. The xanthan molecules are reported to undergo a thermoreversible coil-to-helix transition in solution, which is shifted to higher temperatures by the addition of electrolyte. In the disordered coil form the side chains are envisaged as protruding away from the backbone into solution, while in the ordered form the molecules form a stiff five-fold helical structure with the side chains folded in and associated with the backbone. Most workers now believe that the helix is double-stranded. The stiff xanthan chains tend to associate in solution, giving rise to a very high viscosity at low shear rates, which is sufficient to prevent particles from sedimenting or oil drops from creaming. The associations are readily broken on applying shear, giving rise to a dramatic drop in viscosity and hence the solutions readily flow. Unlike other polyelectrolytes the viscosity of xanthan solutions is relatively insensitive to addition of electrolyte since the electrolyte will promote helix formation. The helices are also stable over a broad range of pH. The high apparent yield stress and pronounced shear thinning characteristics have led to a large increase in the use of this gum, which now finds application in a broad range of food products such as sauces, salad dressings, and mayonnaises.

Hydroxyethylcellulose

 

Carbomer:

Nomenclature: Numerous varieties of crosslinked acrylic acid homo- and copolymers exist, but the term carbomer is typically reserved to describe high molecular weight polymers of acrylic acid that are lightly crosslinked with allyl ethers of polyalcohols Examples of such polyfunctional allyl ethers include tetraallyl pentaerythritol (TAPE) and hexaallyl sucrose. The National Formulary(NF) lists traditional carbomers individually according to their specific chemistry and properties, e.g., solution viscosity, using numbers associated with the trade names of early carbomers, e.g., carbomer 934. For modern carbomers synthesized using benzene-free processes, the NF has adopted the terms carbomer homopolymer, carbomer copolymer, and carbomer interpolymer to describe the various species of carbomers employed as excipients in pharmaceuticals and OTC drug formulations. compendial names carbomers (EU) and carboxyvinyl polymer (JP) refer collectively to the various types of carbomers and carbomer copolymers. In contrast, the INCI Dictionary reserves the term carbomer for crosslinked homopolymers of acrylic acid, and it names crosslinked copolymers of acrylic acid with other comonomers as acrylate crosspolymers, e.g., acrylates/C10–C30 alkyl acrylate crosspolymer.

Acrylates/ C10-30 Acrylate Crosspolymer:

Acrylates/C10-30 Alkyl Acrylate Crosspolymer (AACP) contains both hydrophilic and hydrophobic groups allowing for the polymer to bind to both water and oil, making it useful in combining the two phases to create a single smooth consistency.

It is an excellent thickening and emulsifying agent and is capable of providing flow and clarity to gel systems while improving emulsion stability and smoothness of formula.

Acrylates/C10-30 Alkyl Acrylate Crosspolymer (AACP) is found in many cosmetic products, including facial moisturizers, treatment creams, anti-aging products, tanning lotions and sun creams that have an SPF of 15 or higher.

It appears widely in shampoos, hair coloring and bleaching products, styling gels and lotions, and also in cleaning products and drugs, including chewable, sublingual and effervescent tablets, suppositories and oral

Ethylhexylglycerin:

Ethylhexylglycerin serves as a surfactant and preservant enhancer and acts as a safe preservative in minute amounts. It’s a proven preservative-enhancer and is often used instead of controversial parabens. Its also used as a skin conditioning agent and as deodorizer  

Phenoxyethanol:

Its used as a preservative due to its activity against gram negative bacteria. Should not be used in more than 2% concentration. Not effective against fungi. The Material Safety Data Sheet (MSDS) on phenoxyethanol states that it can cause skin and lung irritation. It’s also toxic to the kidneys, nervous system, and liver, and repeated, long-term exposure can cause organ damage. It notes that toxic effects can occur through inhalation, skin exposure, and ingestion. The toxicity effects listed in the MSDS are based on exposure to the preservative when it’s undiluted, and scientists agree that in high doses phenoxyethanol is toxic.

Carbazole:

Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzenerings fused on either side of a five-membered nitrogen-containing ring. The compound’s structure is based on the indolestructure, but in which a second benzene ring is fused onto the five-membered ring at the 2–3 position of indole (equivalent to the 9a–4a double bond in carbazole, respectively.

Cetyl Alcohol:

A fatty alcohol that’s either produced from the end products of the petroleum industry, or derived from plants (palm oil-palmityl alcohol). It comes in the form of a white, waxy solid. It’s no longer derived from sperm whale oil (where it was originally discovered) seeing how whales are now an endangered species.

Works as an emollient, emulsifier, thickener and carrying agent for other ingredients contained in a cosmetic solution. It keeps the oil and water parts of an emulsion from separating, and gives products good spreadability. As a thickening agent and surfactant, it helps alter the viscosity and increase the foaming capacity of non-aqueous (i.e. lotions) and aqueous solutions (i.e. shampoo). It is often misinterpreted as an “alcohol” related to ethyl or rubbing alcohol, both of which can be extremely drying to the skin. The truth, in fact, is quite the opposite, as cetyl alcohol is well known to effectively condition and soften the skin and hair. Because of its multi-functional capabilities, this ingredient is used in a wide range of personal care products such as moisturizer, face cream, shampoo/conditioner, anti-aging treatments.

Cetyl ethylhexanoate:

A synthetic ester of cetyl alcohol and 2-ethylhexanoic acid. Comes in the form of a pale yellow wax/liquid.

Works as an emollient, skin conditioner and thickening agent. It lubricates the surface of the skin/hair, removes the appearance of dry patches and flakes and gives the skin a soft and smooth look. It gives cosmetic products water-repelling properties and an easy spreadabillity. It’s used as a substitute to Spermaceti wax, which comes from whales.

You can find this ingredient in products such as lipstick, foundation, facial moisturizer, lip gloss, anti-aging treatment, lip/eye liner, conditioner and eye shadow.

Isoceteth-20:

is a polyethylene glycol ether formed by the ethoxylation of iso-cetyl alcohol; with the general formula HO(C2H4O)nC16H33 where n has an average value of 20. It is a nonionic surfactant used as an emulsifier in some personal care products.[1] However, as iso-cetyl alcohol is rare in nature isoceteth-20 does not see widespread use.

Ethoxydiglycol:

Also known as diethylene glycol mono ethyl ether, is a cosmetic grade solvent that conforms to the current USP/NF monographs. Ethoxydiglycol is particularly appropriate for skin care preparations where it acts as an excellent solvent and carrier. Its solubility in ethanol, propylene glycol, vegetable oils, water, and butylene glycol makes it a valuable solvent or co-solvent which can be used in hydrophilic or lipophilic phases.

Polysorbates:

Are a class of emulsifiers used in some pharmaceuticals and food preparation. They are often used in cosmetics to solubilize essential oils into water-based products. Polysorbates are oily liquids derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids

Polysorbate 80 is derived from polyethoxylated sorbitan and oleic acid. The hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following polysorbate refers to the lipophilic group, in this case the oleic acid

Polysorbate 20:

(common commercial brand names include Scattics, Alkest TW 20 and Tween 20) is a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan before the addition of lauric acid. Its stability and relative nontoxicity allows it to be used as a detergent and emulsifier in a number of domestic, scientific, and pharmacological applications. As the name implies the ethoxylation process leaves the molecule with 20 repeat units of polyethylene glycol; in practice these are distributed across 4 different chains leading to a commercial product containing a range of chemical species.

Polyacrylate:

Is a synthetic polymer used in cosmetics and personal care products in part because of its ability to absorb as much as 200 to 300 times its mass in water, according to Wikipedia. It is seen as a white powder when dry, but turns into a gel-like substance when wet, and is primarily used as a thickening agent. Sodium Polyacrylate is also used in a variety of formulas because of its other properties, including as an absorbing agent, emulsion stabilizer, film former, emollient, and viscosity increasing agent. Sodium Polyacrylate is also used as a sequestering agent in cleansers and detergents because of its ability to bind to hard water elements like calcium and magnesium, allowing the surfactants to work more effectively.

Fibronectin:

Fibronectin alone binds a plethora of growth factors that are central in tissue repair and fibrosis, including vascular endothelial growth factor (VEGF) , bone morphogenetic protein (BMP)-1 , hepatocyte growth factor (HGF) , fibroblast growth factor (FGF)-2 , platelet-derived growth factor (PDGF) , and latent TGF-β.

 

Palmitoyl tetrapeptide-7

Is a type of synthetic peptide compound which combines several chains of amino acids to reduce skin inflammation and the accompanying skin damage. This peptide compound is also believed to stimulate the regeneration of collagen fibers in the dermis by acting as sort of cellular messenger. Palmitoyl tetrapeptide-7 is also thought to increase the amount of hyaluronic acid in the skin, which can help tighten skin by attracting moisture to the epidermis. Although the chemical is considered to be safe for use in skin care, the ingredient’s ability to break down skin pigment could lead to skin discoloration issues. The higher concentration of this chemical in beauty products may reduce the production of interleukin to up to 40 percent. Interleukin is a chemical often associated with inflammation, as the body creates it in response to damage. For example, skin cells damaged due to the over exposure to the UV rays can cause the production of this chemical, leading to cell deterioration from inflammation. By blocking this chemical, palmitoyl tetrapeptide 7 relieves some of the chemical pressure on the skin, and allows it to heal faster.

 

Hexapeptide-48:

Rubixyl® counteracts the effects of intrinsic (chronological stress ageing) and extrinsic ageing (stress linked to cigarette smoke), by targeting a new category of skin receptor: the Delta Opioid Receptors. Smoothes and refills deep wrinkles in 2 months.
Biological targets: Involucrin, Corneodesmosin, Calmodulin like 5, Occludin, Keratin 10, Acyl-coA synthetase, Sulfotransferase 2B

We have demonstrated that the Rubixyl peptide is a specific agonist of opioid receptor delta. We have demonstrated that opioid receptor delta expression is modulated under inflammatory condition. The agonist Rubixyl was able to block the depletion of opioid receptor delta seen under inflammatory condition in reconstructed human epidermis. Inflammatory conditions lead to the unbalanced gene and protein expressions of markers involved in epidermis integrity and barrier function properties. The treatment of human reconstructed epidermis with the agonist Rubixyl leads to the normalization of unbalanced gene and protein expressions. In vivo study has confirmed the efficiency of the agonist Rubixyl to repair damaged skin by decreasing TEWL, increasing hydration and decreasing wrinkle depth at the periocular and perilabial area.

Tripeptide-1:

The human peptide GHK (glycyl-l-histidyl-l-lysine) has multiple biological actions, all of which, according to our current knowledge, appear to be health positive. It stimulates blood vessel and nerve outgrowth, increases collagen, elastin, and glycosaminoglycan synthesis, as well as supports the function of dermal fibroblasts. GHK’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK has also been found to possess powerful cell protective actions, such as multiple anti-cancer activities and anti-inflammatory actions, lung protection and restoration of chronic obstructive pulmonary disease (COPD) fibroblasts, suppression of molecules thought to accelerate the diseases of aging such as NFκB, anti-anxiety, anti-pain and anti-aggression activities, DNA repair, and activation of cell cleansing via the proteasome system. Recent genetic data may explain such diverse protective and healing actions of one molecule, revealing multiple biochemical pathways regulated by GHK. Tighten loose skin and reverse thinning of aged skin, Repair protective skin barrier proteins , Improve skin firmness, elasticity, and clarity , Reduce fine lines, depth of wrinkles, and improve structure of aged skin , Smooth rough skin, Reduce photodamage, mottled hyperpigmentation, skin spots and lesions, Improve overall skin appearance, Stimulate wound healing, Protect skin cells from UV radiation , Reduce inflammation and free radical damage, Increase hair growth and thickness, enlarge hair follicle size.

  • Dipeptide Diaminobutyroyl Benzylamide Diacetate: Syn®-Ake

Is an anti-wrinkle active compound based on a synthetic tripeptide that mimicsthe effect of Waglerin 1, a peptide that is found in the venom of the Temple Viper, Tropidolaemus wagleri (that lovely little guy pictured above).The Syn®-Ake peptide acts by reducing muscle cell contraction, smoothing mimic wrinkles in a short period, and is reversible. It is useful in anti-aging products and wrinkle treatment products, especially those targeting expression lines.

  • Polyhydroxystearic Acid:

Soft and pliable wax that is naturally derived from castor oil. Acts as a texturing agent, wax, thickener and film former. Ideal for creating creamier textures while increasing the stability of emulsions. Melting point 50-70oC (122-158F). Saponification Value 90-125mg KOH/g. Light tan to brown paste. Water-insoluble, oil soluble.

Properties: Thick pasty thickener, providing consistency and emolliency to lotions and creams but also color cosmetics. Great oil-gelling agent. Acts also as film-former, emulsion stabilizer, sunscreen enhancer, and plasticizer.

 

  • Caprylhydroxamic Acid GG

Description: 100% natural antimicrobial agent for preservative-free and/or paraben-free claims. Approved by Whole Foods Premier Ingredient list. The blend has excellent biostatic & fungistatic activity even at neutral pH where many other antimicrobials fail to be effective. Clear yellow to amber liquid, mild characteristic odor. pH 4-5. Water-soluble.

CAS: 7377-03-9, 26402-26-6, 56-81-5

INCI Name: Caprylhydroxamic acid, glyceryl caprylate, glycerin

Properties: Mild and natural antimicrobial. Compatible with most cosmetic ingredients and can be used in emulsions, anhydrous, and surfactant systems. However, it can interact with residual iron found in some types of clay (e.g. bentonite, silicates) producing a slight orange color.

Use: Add to water phase or at the end of formula. Typical use level 1.0 – 1.2%. Avoid exposure to high temperatures (>90oC / 194F) for more than 2 hours. Store at dry and cool place. Product may solidify or precipitate upon storage. Heat then gently to 35-40oC max (95-104F) and stir until homogeneous, then use. Do not use as a solid, it needs to be liquid and shaken/blended before use. External use only.

Applications: All kinds of skin & hair care products (incl. emulsions, anhydrous & surfactant systems), color cosmetics.

  • Polyglyceryl-4 isostearate:

Polyglyceryl-4 isostearate is an Ester of isostearic acid and polyglycerin4 Polyglyceryl-4 isostearate uses and applications include: Emulsifier in cosmetics; wo emulsifier, lubricant, and antifoam for industrial applications; solubilizer; dispersant in pharmaceutical lotions.

  • Triethanolamine:

Triethanolamine is an amine produced by reacting ethylene oxide (considered highly toxic) with ammonia (another known toxin). It is used as a buffering agent, masking and fragrance ingredient, and surfactant, in addition to its primary use as a pH adjuster. Treithanolamine is used in a variety of cosmetic and personal care products, including eyeliners, mascara, eye shadows, blushers, make-up bases and foundations, as well as in fragrances, hair care products, hair dyes, wave sets, shaving products, sunscreens, and skin care and skin cleansing products. Triethanolamine is also used with in conjunction with fatty acids to convert acid to salt, which in turn becomes the base for a cleanser.  Additionally, it may assist in emulsion formation by reducing surface tension of the substances, enabling water and oil-soluble ingredients to mix.

Triethanolamine is FDA approved as an indirect food additive (aka it can be used in packaging) and CIR approved with concentration limits. The CIR determined that Triethanolamine was “safe for use in cosmetics and personal care products designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of Triethanolamine should not exceed 5%.”

Triethanolamine is considered a moderate hazard ingredient by the Cosmetics Database, which notes as concerns. According to Cosmetic Ingredient Review, Association of Occupational and Environmental Clinics, and the U.S. National Library of Medicine, there is strong evidence that Triethanolamine is a human skin, immune system and respiratory toxicant. One or more animal studies show sense organ effects at very low doses, especially when used around the mouth, eyes and lips, and one or more in vitro tests on mammalian cells show positive mutation results. It has been shown to cause bladder and liver cancer, as well as changes in testicles.

Triethanolamine can cause allergic reactions including eye problems, dryness of hair and skin, and could be toxic if absorbed into the body over a long period of time. It can cause itching, burning, scaling, hives, and blistering of skin, all symptoms which may increase with higher concentrations

Triethanolamine should not be used in products containing N-nitrosating agents to prevent the formation of possibly carcinogenic nitrosamines. N-nitrosating agents include the preservatives Bronopol, Bronidox L, and sodium nitrate.

In order to comply with EU Annex III, it should contain less than 0.5% diethanolamine and less than 50 microgram/kg nitrosamines. Triethanolamine nf is free of diethanolamine. Not all Truth Vitality products mentioned below are formulated with Triethanolamine nf.

  • Triethoxycaprylylsilane:

Is an emulsifier that prevents the oily and liquid parts of a formula from separating. It is also a binding agent. That means that it can bind pigments to form a stable coating. It allows pigments to disperse well on the skin too, ensuring an even coverage

  • Palmitoyl Dipeptide-5 Diaminobutyroyl Hydroxythreonine (PDDH):

This molecule is based upon the palmitoyl chemical species which then has the of the peptides/peptide derivatives lycine, valine, diaminobutyroyl and hydroxythreonine attached to it in sequence. This ingredient also is one of the two active components of Syn-Tacks, which is a patented anti-aging formulation.

It is used as a skin conditioning agent and has biological activity. PDDH has been shown to have active anti-aging properties through in vivo and in vitro studies. It works by stimulating the production of the proteins Laminin V, Collagens IV, VII and XVII and Integrin β. These proteins play a vital role in connecting and maintaining the structure of the dermis and the epidermis of the skin, to produce visible results.

  • Tetradecyl Aminobutyroylvalylaminobutyric Urea Trifluoroacetate:

Loss of skin firmness is one very visible sign of aging. SYN®-HYCAN helps to fight sagging skin by boosting hyaluronan content and increasing the expression of decorin and lumican.

Hyaluronan (HA) plays an important role in the skin. This glucosaminoglycan (GAG) consists of a long sugar chain that can bind up to 1,000 times its weight in water. The excellent moisture-holding property leads to a gel-like framework for collagen, elastin and skin cells. Also important is its ability to act as a filler, which helps provide the skin with mechanical cushioning. SYN®-HYCAN boosts hyaluronan production and allows needle-free HA-based face contour remodeling.

Decorin and lumican are two important proteoglycans of the dermis. Their protein part binds to a collagen fibril while the GAG part acts as a spacer between the fibrils. The result is the formation of thinner collagen fibrils with increased quality and strength.

Both activities of SYN®-HYCAN work nicely together: Fresh hyaluronan and stronger collagen fibrils result in a visible remodeling effect and a firmer skin.

SYN®-HYCAN is a tripeptide which helps to fight skin sagging by boosting hyaluronan production and improving collagen fibrillogenisis. SYN®-HYCAN has a firming and remodeling effect by stimulation of GAG (glycosaminoglycan) biosynthesis. SYN®-HYCAN increases Decorin and Lumican levels for better collagen fibers.

SYN®-HYCAN is a glycerin-based aqueous solution that is both preservative and PEG-free.

Glycereth-26: Gycereth-7, Glycereth-3.

The numbers after Glycereth denote the number of ethoxy units esterified to each OH group on Glycerol. Glycereth-26 is a glyceryl ester and is a multitudinous oil used in cosmetics as an emollient, lubricant, as well as a water-binding and thickening agent (Source). There is not much information on the use of Glycereth-26 specifically, or glyceryl esters in general, although it is clear that its primary function is as a thickener.

Salicylic acid:

Sphingosine:

Nonapeptide-3:

A newish peptide with the promise of mimicking the effects of the skincare superstar, retinol (vitamin A) but without its negative side effects. Similar to retinol, Myristoyl Nonapeptide-3 is claimed to increase cell turnover and to promote the synthesis of collagen but without skin irritation or stinging.

To back up its claim, the German manufacturer did a so-called gene array screening test, where they examined the effect of the molecule on 96 skin-related genes. They did screening for both retinoic acid (the active form of retinol) and our guy Myristoyl Nonapeptide-3. They found that retinoic acid upregulates 21 of the 92 studied genes, and amongst those, 16 genes are also upregulated by Myristoyl Nonapeptide-3. So they trade named the molecule as Retinopeptide 189, as in a peptide that mimics the effects of retinoic acid.

To further prove their point, Symrise (the manufacturer) went ahead the did some ex-vivo testing (meaning testing on human skin explants). They compared a 0.1% retinoic acid solution with 5% and 10% Retinopeptide 189 cream and found that the 10% cream induces a significant increase (43%) in collagen-1 that is comparable to the effect of 0.1% retinoic acid (which performed even better with more than a 50% increase).

They also found that both retinoic acid 0.1% and Retinopeptide 189 5% cream increased epidermal cellular layers in the skin explants showing that both ingredients can increase cell turnover, however retinoic acid did significantly better both in active effects as well as side effects.

Unfortunately, there are currently no in-vivo test results (at least with could not find any), so if you prefer the tried and true, stick with retinol. However, if you are the adventurous type or if your skin is sensitive and cannot tolerate retinoids, Myristoyl Nonapeptide-3 is a promising alternative.

Pentapeptide-17 and Hexapeptide-16:

Significantly improves the look of eyelashes making them appear longer, thicker, and fortified. Noticeably intensifies eye expression. Myristoyl pentapeptide-17 can be combined with myristoyl hexapeptide-16 for best results. Visible effect in 2-4 weeks. Best results at 6 weeks. Hair on the eyelashes and eyebrows have a very short active growth phase of only about 30-45 days which explains why they are shorter than scalp hair. Approximately 60-80% of the eyelashes are in this phase. Entire duration of cycle for the eyelashes is 3-4 months where as the scalp hair cycle is about 3-6 years.

Acetyl Glutamyl Heptapeptide-3 or Acetyl Octapeptide-1 (or -3) (SNAP-8)

Ac-Glu-Glu-Met-Gln-Arg-Arg-Ala-Asp-NH2

Acetyl tetrapeptide-3:

Clinically shown to improve the appearance of hair loss. Improves irritated and sensitive scalp skin. Studies also found positive results on the appearance of eye lashes making them look fuller & thicker.

Palmitoyl Tetrapeptide-3:

GenScript Palmitoyl Tetrapeptide-3 stimulates expression of GCP-2 (Granulocyte Chemotactic Protein), which is a chemotactic protein that can recruit cells involved in the preparation and cleansing of the site, to damaged areas. Palmitoyl Tetrapeptide-3 is also called Rigin. Rigin is a synthetic peptide that is a fragment of immunoglobulin G that has been combined with palmitic acid to make it more lipophillic and thus enhance its affinity towards human skin. Rigin is a peptide that mimics DHEA in the skin.

Acetyl tetrapeptide-2:

Enhances the expression of genes involved in the organization of elastic fibers and dermal cohesion. A novel, multi-functional approach for anti-aging that specifically targets FMLN5 and LOXL-1 signal transduction pathways, Focal Adhesion proteins Zhxin, Integrin, Talin and Actinin and Collagen I, IV, VI and XIV induction.

Creator of functional elastin. It enhances the expression of proteins Fibulin 5 and Lysyl Oxidase-Like 1, up to 2.3-fold and 1.7-fold compared to placebo as shown in vitro, which are key to the organization of elastic fibers.

 More efficient cell support. It upregulates the gene expression of focal adhesions (talin, zyxin, integrins), contributing to the improvement of dermal cohesion.

Increased firmness and dermal structure as tested in vivo with a treatment with 2% Uplevity™ Solution or placebo.
Cosmetic Applications

  • Firming and anti-aging formulations for facial and body care
  • Slimming formulations to avoid flaccidity after losing weight

Formulation Guidelines

  • UplevityTM needs to be incorporated in the water phase of cold gels, lotions or emulsions.
  • In warm emulsions, it should be added once the emulsion is formed and at temperatures below 40°C (104°F).
  • UplevityTM is stable at a pH range between 5.0 and 8.0.

Tetrapeptide-21:

Synthetic Tetrapeptide-21 have shown promise as a skin cream ingredient that can stimulate skin growth and repair. When collagen breaks down, it forms specific Tetrapeptides that signal to your skin that it was damaged and needs to make new collagen. So by applying Tetrapeptides topically, we are trying to trick our skin into thinking that it has lost collagen recently and needs to make more. It activates collagen production and therefore stimulates dermal filling, repair and renewal mechanisms of the skin. In short making skin to work as it was young and helping improve its look.

There are lots of different synthetic Tetrapeptides available in anti-aging skincare products and they have many roles. One of the most important one is Tetrapeptide-21.

Tetrapeptide-21 is a type of synthetic peptide compound which combines several chains of amino acids, which lead to an increased elasticity and a decreased volume of wrinkles and fine lines. Formulations containing 5% Tetrapeptide-21 have shown a 25% improvement in skin roughness and depth of fine and coarse wrinkles.

It also increases the amount of secreted collagen protein in the supernatant of human dermal fibroblast cultures and furthermore enhances the gene expression of important ECM proteins like collagen I and fibronectin and stimulates hyaluronic acid production.

Cell communicating peptide
Tetrapeptide-21 is a cell communicating peptide that prevents damage caused by UV radiation. Moreover, it promotes DNA repair, to provide a complete protection system against intrinsic and extrinsic aging.

Now a days’ tetrapeptide-21 is part of most of the high profile skin care products that help to produce more collagen. As you age, you lose collagen in your face making your skin get loose and saggy. By using these special skin care lines, your body will increase collagen production to give you naturally plump, tight skin and making the skin more youthful and glowing.

Tetrapeptide-30:

It was found that expression of key in- flammation marker genes IL-6 and IL-8, TNF-α and COX-2, as well as expression of genes for tyrosinase and POMC was induced in UVB-irradiated, vehicle-treat- ed skin. This effect was significantly re- duced by treatment with Tetrapeptide- 30.

Tetrapeptide-9:

Dermican™ PW LS 9838 is a synthetic tetrapeptide that provides targeted action on dermal structure via stimulation of lumican and collagen synthesis. It creates a global restructuring of the skin matrix, which is clinically proven to improve skin thickness and firmness. It is a water-soluble powder.

Tetrapeptide-5:

Used for eliminate eye puffiness, promote collagen regeneration, fights water retention enhance skin elasticity.

Tetrapeptide-7:

Gly-Gln-Pro-Arg

Rigin, it turns out, is capable of modulating the production of interleukin-6 (IL-6), a signaling molecule made by T-cells. IL-6 recruits additional immune cells to the site of injury or infection. Sometimes, however, the immune response can become too large and may damage healthy tissue. In the case of skin, this can lead to damage to the ECM and thus breakdown of collagen and elastin. By counteracting the effects of IL-6, rigin is able to reduce the effects of an immune response and protect the skin from damage.

Rigin has also been shown, in animal models, to have activity against matrix metalloproteinases (MMPs). MMPs are a group of enzymes involved in the breakdown of ECM proteins during normal tissue growth. By downregulating the activity of MMPs, rigin can reduce ECM damage and allow cells that restore and maintain the ECM to keep up with the effects of aging [4]. The action of rigin is similar, in some ways, to dehydroepiandosterone, which is sometimes referred to as the “youth hormone.”

Tetrapeptide-22:

increases HSP70 levels in the skin, helping cells to fight stress from extreme weather, pollution, heavy metals, jet-lag and preventing damage from further stress exposure. stimulates HSP70 synthesis and therefore Hsp72, which is the inducible form of the family. An increase in this protein enhances stress tolerance to the skin. Proteotoxic stress can be modulated and cellular damage prevented, especially when the skin is repeatedly challenged or when aging impairs the stress response of the skin.

Tetrapeptide-15:

Tyr-Pro-Phe-Phe-NH2

The tetrapeptide Ac-YPFF-NH (active matter of SkinasensylTM) attenuates the neuronal stimulation via binding on the μ opioid receptor

  • Pure tetrapeptide targeting over-reactive skin by:
    – a decrease of the release of pro-inflammatory neuromediators (CGRP),
    – a reduction of the response of the sensory nerve fibers to external stimuli, via its binding to the μ-opioid receptor on nerve endings.
  • Increase of the skin’s tolerance threshold.
  • Reduction of sensations of pain and discomfort, perceived by the end-users.

Tetrapeptide-2:

Antioxidant amplifier Up-regulates endogenous antioxidants genes: NFE2L2, HMOX1, TRX, GSS, GSTP1, GPX1, CYP2R1
+69% antioxidant activation (HO-1) vs non-treated +23% protection against internal pollution vs non-treated polluted explants Antipollution protection and restoring (anti-inflammaging) -16% AHR activation, protecting against outdoor/indoor pollution +40% cell membrane damage restoring Protection of skin proteins, lipids & DNA With 0.01% Neøclair ProTM active ingredient: -62% AGEs induced by heavy metals, protecting from glycation -22% DNA oxidative damage (8-OHdG) due to synthetic smoke -14% lipid peroxidation (MDA) in presence of synthetic smoke, modulationg inflamation Brightening hyperpigmentation -41% melanin with Neøclair ProTM.

Tetrapeptide-11:

  • Improvement of epidermal cohesion via the stimulation of the synthesis of:
    – syndecan-1, a small proteoglycan involved in the cohesion of epidermal keratinocytes, and – collagen XVII, a fundamental protein of hemidesmosomes.
  • Increase of skin firmness and elasticity.
  • Improvement of epidermal cohesion for a more radiant and uniform skin.

Tetrapeptide-40:

Decreases the appearances of facial redness and telangiectasia caused by an exaggerated inflammatory response. Tetrapeptide that decreases the appearance of facial redness and telangiectasia caused by an exaggerated inflammatory response. telangynTM peptide reduces the release of interleukins (IL-6 and IL-8) induced by 37-amino-acid peptide (LL-37), cathelicidin overexpressed in skin disorders with erythema.

Pentapeptide-3:

-Lys-Thr-Thr-Ser-OH

Matrixyl was discovered through two branches of dermatological research: the search for substances that accelerate healing skin wounds and the study of what causes wrinkles. Similarly to copper peptides, Matrixyl stimulates the lower layers of the skin to heal themselves, thus accelerating the healing of wounds. Cells called fibroblasts are responsible for knitting together wounds of the skin. As you may know, as one ages wounds take longer to heal. This is partially because fibroblasts slowly lose the capacity for collagen production.

Matrixyl stimulates the “matrix” layers in the skin — primarily collagen and fibronectin. When stimulated, the skin produces more collagen. Loss of collagen is what leads to thinning skin and the wrinkling of newly inelastic skin. Matrixyl helps to counteract this natural part of the aging process.

Is Matrixyl (palmitoyl pentapeptide-3) an effective anti wrinkle product?

Yes. In clinical studies, Matrixyl was shown to:
– Increase overall collagen synthesis by up to 117%
– Increase collagen IV synthesis by up to 327%
– Increase hyaluronic acid synthesis by up to 267%

Matrixyl 3000:

Palmitoyl Tripeptide-1 (and) Palmitoyl Tetrapeptide-7

Hexapeptide-33

Which has been shown to have a skin whitening effect and assist in wound healing and wrinkle reduction among other benefits: W3 Peptide.

Pentapeptide-34 trifluoroacetate:

Peptide Q10™ Biofunctional is a novel strategy to counteract the age-related decline of CoQ10 and is a complementary and alternative technology to CoQ10 direct application. By “reinventing CoQ10” with a biological approach, Ashland’s new technology represents a new shift in the anti-aging and antioxidant segment that can be used in conjunction, or not, with topical application of CoQ10.

Coenzyme Q10 (CoQ10) has long been recognized as an effective ingredient that helps consumers stay younger looking. This lipid-soluble component, synthesized naturally in the body and located in mitochondria and cell membranes, is critical to energy generation and acts as a powerful antioxidant to combat premature aging.

Tripeptide-8:

NeutrazenTM is a true neurocosmetic specifically designed to prevent and reverse signs of neurogenic inflammation. NeutrazenTM is an innovative tri-peptide linked to a lipid for optimal penetration and efficacy. NeutrazenTM calms and soothes irritated skin and helps to maintain and restore a normal skin sensitivity threshold.

1- Repetitive Aggressions

– Reduction of the consequences of substance P release.

2- Anti-inflammatory Reactions

– Reduction of pro-inflammatory cytokines.
– Reduction of vasodilation, edema and erythema.

3- Consequences

– Short term: prevention and reduction of irritation.
– Long term: maintenance of a normal skin sensitivity threshold, healthy looking skin.

Tripeptide-31:

  1. Anti‐aging, Anti‐wrinkle Efficacy

Inhibition of MMP‐1 gene transcription and translation Induction of procollagen I protein production
Anti‐aging effect in vivo

  1. Whitening Efficacy

Inhibition of melanin synthesis
Inhibition of tyrosinase activity
Inhibition of melanogenic genes expression Skin‐lightening effect in vivo

  1. Anti‐inflammatory Efficacy

Inhibition of pro‐inflammatory cytokines

Tetrapeptide-20:

Two factors have been identified as the main causes of the hair greying process: the decrease in melanogenesis and the increase in oxidative stress in the hair bulb. Due to its complete mechanism of action, the peptide found in GreyverseTM is able to act simultaneously and efficiently on both factors by stimulating MC1-R (Melanocortin 1 Receptor) Hair follicle cells produce small amounts of hydrogen peroxide (H202) as part of the oxygen cycle. This oxidative substance is naturally degraded by catalase into harmless elements of water and oxygen. With aging, catalase activity decreases leading to an accumulation of H202. This then progressively bleaches the melanin pigments and the hair from the inside out.

Furthermore, a decrease in the anti-oxidant TRP-2 (Tyrosinase Related Protein 2) over time leads to a lack of protection of melanocytes against free radicals.

Tripeptide-5 (Lys-Val-Lys-OH)

Syn-Coll mimics the effects of TSP-1, a naturally occurring molecule that increase TGF-β activity. TGF-β, in turn, causes a persistent increase in the amounts of type I and type III collagen that dermal (skin) fibroblasts produce. In animal studies, Syn-Coll increases collagen production by 2-3 fold over baseline levels. The effects appear to last for about 72 hours before starting to diminish [3].

TSP-1 is an extracellular matrix (ECM) protein, so it is found next to collagen and elastin in the skin. Specific parts of TSP-1 (the parts harvested for use in Syn-Coll) activate latent TGF-β. In animal models and laboratory experiments using human dermal fibroblasts grown in tissue culture, TSP-1 acts locally to improve wound healing. It is also thought to be active in the post-natal development of skin structures [4].

Syn-Coll is also thought to deactivate matrix metalloproteinase 1 and 3 (MMP1 and MMP3), enzymes that are prominent in the destruction of collagen. These enzymes play a role in the natural recycling of collagen as it ages, but can be dramatically upregulated in inflammatory states. This can lead to premature skin damage and the appearance of lines, wrinkles, and more.

Tripeptide-38:

Lysyl-Dioxymethiony-Lysine

Anti-aging peptide derived from the tripeptide KMK naturally found in collagen VI and laminin. In-vitro studies have found a matrikine-like effect that stimulates the synthesis of six major proteins including collagen I, II, IV, fibronectin, hyaluronic acid and laminin 5. Clear liquid, odorless. Water-soluble.

It penetrates deep into the dermis to boost the production of collagen and the synthesis of hyaluronic acid, particularly on the forehead.

Decapeptide-12

(Tyr-Arg-Ser-Aar-Lysd-Tyr-Ser-Ser-Trp-Tyr)

Decapeptide-12 reversibly binds to tyrosinase, an enzyme found in a number of different pigment-producing cells. It prevents tyrosinase from catalyzing the oxidation of phenols, the first step in melanin production. In mammals, tyrosinase is found only in melanosomes, special compartments within pigment-producing cells. Tyrosinase is not preserved across species and, in fact, can differ drastically in structure even among closely-related species. In humans, differences in the efficiency of tyrosinase determine skin color and are the result of slight modifications in the TYR gene found on chromosome 11 [2].

Tripeptide-3:

AHK has been found, in animal and in vitro research, to activate fibroblasts. Fibroblasts are responsible for much of the extracellular matrix (proteins outside of cells) production that occurs in skin and other connective tissues (e.g. bones, muscle, etc.). Fibroblasts are primarily responsible for the production of collagen and elastin. Collage gives skin strength and also acts to attract water, making skin smoother and suppler. Elastin gives skin an ability to stretch and helps to prevent the formation of fine lines and wrinkles. Together, collagen and elastin are heavily involved in preventing skin aging, with both quantity and quality of these proteins falling off as we age. Studies of the effects of AHK on collagen and elastin indicate that it increases collagen type I production by more than 300% [1].

Another effect of AHK is on the production of vascular endothelial growth factor and transforming growth factor beta-1 [2,3]. Endothelial cells line the inside of blood vessels and are responsible for much of the first stages of blood vessel growth. Transforming growth factor beta-1 regulates cell growth, differentiation, and death. By increasing the secretion of endothelial growth factor and decreasing the secretion of transforming growth factor beta-1, AHK can stimulate blood vessel growth, particularly in the skin.

Tripeptide-29:

Gly-Pro-Hyp

Tripeptide-29 is a synthetic mimic of one of the basic building blocks of collagen. Collagen is a long-chain polymer made of short monomeric repeats that are generally made up of three amino acids in sequence. These repeats bond together to create secondary structures, which then combine to form tertiary and even quaternary structures. These complex structures have many emergent properties that the peptide subunits don’t possess. However, changing the nature of the peptide subunits can change the ultimate properties of a quaternary collage compound. Collagen subunits almost always follow the pattern of Gly-Pro-X or Gly-X-Hyp. Tripeptide-29 is a Gly-Pro-Hyp peptide, making it a perfect synthetic analogue of common collage building blocks.

SYN-AKE:  dipeptide diaminobutyroyl benzylamide diacetate

Is a synthetic version of a protein known as Waglerin 1. Waglerin 1, which is 21 amino acids in length, is a protein venom produced by the Malaysian Temple Viper (Tropidolaemus wagleri), a venomous snake found in southeast Asia. The venom of the Temple Viper can paralyze its prey by interfering with signaling between nerves and muscles. Syn-AKE does the same thing but in a controlled form. Syn-AKE is only three amino acids in length, making use of only the active portion of the Waglerin 1 protein. Note the play on the word “snake” in the Syn-AKE (pronounced “Sin ache”) name.

What Does Syn-AKE Do?

Syn-AKE is a competitive antagonist of the muscular nicotinic acetylcholine receptor [3]. Acetylcholine is the neurotransmitter used to send electrical signals from nerves to muscles. Without acetylcholine, muscles do not receive signals to contract and thus remain in a relaxed state. By blocking the acetylcholine receptor, Syn-AKE is able to block normal neuromuscular signaling and prevent muscle contractions. This, in turn, keeps facial muscles relaxed and can reduce the appearance of fine lines and wrinkles. This is the same mechanism that makes Botox successful. The muscle relaxation caused by Syn-AKE is 100% reversible.

Syn-AKE Research on Smoothing Wrinkles

Preparations of Syn-AKE for topical application have been tested in animal models in concentrations that range from 1-4%. These preparations have produced excellent results, smoothing the appearance of mimic wrinkles and expression lines just a short time after the preparation is applied [2]. Research shows that Syn-AKE can reduce the appearance of wrinkles by up to 52% when a 4% topical solution is used [4]. This would make Syn-AKE more effective than Botox [5].

SNAP-8:

Acetyl-Glu-Glu-Met-Gln-Arg-Arg-Ala-Asp-NH2

SNAP-8 is a mimic of the N-terminal end of SNAP-25 which competes with SNAP-25 for a position in the SNARE complex, thereby modulating its formation. If the SNARE complex is slightly destabilized, the vesicle can not release neurotransmitters efficiently and therefore muscle contraction is attenuated, preventing the formation of lines and wrinkles

The Benefits of SNAP-8

– Reduces the depth of wrinkles on the face caused by the contraction of muscles of facial expression, especially in the forehead and around the eyes.

– A safer, cheaper, and milder alternative to Botulinum Toxin, topically targeting the same wrinkle-formation mechanism in a very different way.

– Has been incorporated in cosmetic formulations such as emulsions, gels, sera, etc., where removal of the deep lines or wrinkles in the forehead or around the eyes area is desired.

Dipeptide-3 Norleucine Acetate

Is an amino acid sequence that restores regular exfoliation by competing with desmosomes. Desmosomes (desmoglein and desmocollin) are adhesion proteins that hold skin cells together and contribute to desquamation. This three amino acid chain is recognized at the binding site by desmocollin as being identical to desmoglein but instead of binding cells together, it weakens the cell connections. Skin hydration and smoothness are improved and wrinkle depth is reduced.

Oligopeptide-10

Is an antimicrobial peptide designed for treating acne symptoms. This peptide has been shown to exhibit excellent activity against P-acne bacterium alone but found to be more effective in combinations with low levels of salicylic acid. This allows for an opening of pores to allow oxygen in while enabling oligopeptide-10 into the pores for maximum performance without irritation. A .5 percent combination of Oligopeptide-10 with .5 percent salicylic acid was shown to be 40 percent more effective in reducing comedones, irritation, pustules and papules after 28 days when compared to a leading benzoyl peroxide brand.

Oligopeptide-68

Is a complex combination of TGF-ß agonist peptide that inhibits Microphtalmia-associated transcription factor (MITF). MITF is a major transcriptional regulator of melanogenic enzymes, tyrosinase, TRP-1 and TRP-2. This peptide induces significant skin lightening shown to have a higher activity than Arbutin and vitamin C.

Palmitoyl Dipeptide-5 Diaminobutyloyl Hydroxythreonline and Palmitoyl Dipeptide-6 Diaminohydroxybutyrate

Stimulate the most relevant protein structures in the DEJ (Laminin V, Collagen IV, VII, XVII and Integrin). This gives the skin improved communication and nourishment, which leads to fewer wrinkles and improved firmness. It realigns skin tissues for improved firmness. Syn®-Tacks is a new combination of two peptides that interact with the most relevant protein structures of the dermal-epidermal junction (DEJ).

DEJ provides structural and functional integrity to our skin, but that functionality starts to decline around the age of 30. This decline in functionality proceeds and is even accelerated by external and environmental influences such as UV light, resulting in decreasing skin compactness, elasticity and a lack of skin firmness.

Syn®-Tacks significantly stimulates Laminin V, Collagen type IV, VII and XVII and Intergrin at once. With this broad spectrum activity it is possible to achieve the utmost structural benefit for the skin. By increasing the activity of these proteins the whole structure of the DEJ is improved. This leads to a significantly visible cosmetic benefit.

Functionality:

  • Improved structural integrity
  • Improved epidermal nourishment
  • Improved molecular communication within the skin
  • Improved skin compactness
  • Improved skin tonicity
  • Reduced wrinkles
  • Improved skin firmness

Cosmetic Applications:

  • Antiaging products
  • Skin rejuvenation products
  • Barrier function and skin protecting treatments

Hexapeptide-37

Is a skin hydration peptide that improves water flux from the basal layer of the epidermis to the surface layers through enhancement in aquaporin 3 (AQP3). AQP3 is the most abundant in the epidermis, facilitating transepidermal permeability, increasing water content in the surface and strengthening barrier function. With acetyl hexapeptide-37, skin hydration was enhanced by 131 percent and collagen I synthesis was enhanced by 61 percent.

Tetrapeptide-23

A rejuvenating amino peptide that reduces Advanced Glycation End (AGEs) products. It prevents skin lipid peroxidation, reduces reactive oxygen species and protects cellular membranes from scavenger attacks. Studies showed a visible reduction in wrinkles and an increase in elasticity.

Tripeptide-8

Is a multifunctional neuropeptide that promotes skin homeostasis and helps reduce irritation caused by UV, immune reactions, internal stress and mechanical stress. This neuropeptide reduced inflammatory cytokines up to 64 percent, vasodilation up to 51 percent, and edema up to 60 percent. In a soothing “after-shave” test, in just one week, 90 percent of male volunteers felt more comfortable skin, 83 percent felt irritation was reduced, and 81 percent felt razor burn was soothed.

Pentapeptide-17

Is a keratin stimulating peptide shown to visibly increase eyelash length by 25 percent when used with Myristoyl Hexapeptide-16.

Hexapeptide-16

Is a keratin stimulating peptide shown to visibly increase eyelash length by 25 percent when used with Myristoyl Pentapeptide-17.

Hexapeptide-1

Works as a bio-α-MSH peptide analog. It stimulates hair pigmentation, darkens hair and reverses the gray hair process. It also can help repair DNA damage caused by UV exposure and reduce the skin erythema.

Dipeptide-2

Inhibits the enzyme ACE that causes fluid retention and interferes with lymphatic drainage. Its structure resembles lipids found in the epidermis of the skin that help skin retain moisture.

Dipeptide-4

Is a synthetic dipeptide consisting of cysteine and glycine. It is an antioxidant oligopeptide. Dipeptide-4 protects the skin from environmental stress and skin glycosylation, thus it helps maintain skin health and elasticity.

Pentapeptide-18

This is a new peptide and is said to work synergistically with Argirline. It works by mimicking enkephalins, the peptides associated with pain relief. Pentapeptide-18 couples to the enkephalin receptor on the outside of the nerve cells, resulting in a decrease of its “excitability.” In other words, the nerve cell’s activity is turned down and the release of acetylcholine (see Argireline above) is modulated.

Hexapeptide 12

Sequence: Pal-Val-Gly-Val-Ala-Pro-Gly), also known as palmitoyl oligopeptide, is a lipopeptide molecule in biopeptide-EL, and a signal peptide. Unlike water-soluble peptides, palmitoyl Hexapeptide-12 is highly biocompatible with skin’s natural structure. It boosts cell’s natural productivity level and is considered to be one of the most natural powerful antiagers.

Palmitoyl hexapeptide-12 is a signal peptide belonging to the Matrikine series, which is particularly involved in repairing age-related skin damage and promoting dermal fibroblast migration, proliferation, and matrix macromolecular synthesis (eg, elastin, collagen, etc.). It provides support for the skin. It also induces fibroblasts and monocytes to specific locations for wound repair and tissue renewal. Studies have shown that it can reduce the production of interleukin-6 (IL-6) in key skin cells, keratinocytes and fibroblasts. As we all know, IL-6 is a molecule, which can promote the production of inflammation and lead to faster degradation of the skin matrix, resulting in more wrinkles, poor skin firmness and elasticity. Palmitoyl hexapeptide-12 can greatly slow down the degradation of the skin matrix, and may also stimulate its replenishment by reducing the levels of IL-6 and possibly other inflammation mediators.

Hexapeptide-3, hexapeptide-8, argireline:

Argireline NP is a peptide (formerly named acetyl hexapeptide-3, now acetyl hexapeptide-8) that inhibits SNARE complex formation and catecholamine release, resulting in the reduction of the degree of existing facial wrinkles and demonstrated effectiveness against their development with regular use. In clinical studies of twice-a-day treatment, the severity of wrinkles around the eyes decreased up to 17% after 15 days and 27% following 30 days of treatment.

SYN-TC: Tetradecyl Aminobutyroylvalylaminobutyric Urea Trifluoroacetate, Palmitoyl Tripeptide-5, Palmitoyl Dipeptide-5 Diaminobutyroyl Hydroxythreonine

Looking young and beautiful is widely accepted to be a source of professional success and personal happiness. Collagens play a major role in the skin, ensuring proper functionality and thus perfectly smooth, young-looking skin. During the process of aging our body’s natural production of collagen in the skin decreases, and as its functionality is reduced typical signs of aging become visible.

While traditional anti-aging approaches mostly focus on dermal collagen type I, SYN®-TC follows a more holistic approach that focuses on total collagen care. A particular focus is set on collagen type III – the so-called youth collagen – that is known for its skin smoothing properties, especially in young skin. Additional focus is set on the collagens of the dermal-epidermal junction (DEJ), especially on collagen IV, VII and XVI, the so-called anchoring collagens that are essential for skin functionality and support skin firmness.

Key Facts

  • Patented synthetic Tri-and Tetrapeptide technology
  • SYN®-TC significantly increased in vitro the amount of collagens to facilitate their unique contribution to beautiful smooth skin
  • Combines best performance in a tailor made peptide complex

Benefits

  • Skin is smoother with a softer touch and improved overall young looking appearance
  • Skin appears plumper
  • Skin appears firmer
  • Skin elasticity is improved
  • Appearance of fine lines and wrinkles is visibly reduced

Ceteareth:

(where n is a number) refer to polyoxyethylene ethers of a mixture of high molecular mass saturatedfatty alcohols, mainly cetyl alcohol (n = 15) and stearyl alcohol (m = 17). The number n indicates the average number of ethylene oxide residues in the polyoxyethylene chain. These compounds are non-ionic surfactants that work by attracting both water and oil at the same time, frequently used as emulsifiers in soaps and cosmetics.

Sodium laureth sulphate:

Is prepared by ethoxylation of dodecyl alcohol. The resulting ethoxylate is converted to a half ester of sulfuric acid, which is neutralized by conversion to the sodium salt.

Laureth-23:

Laureth-23 is a high HLB emulsifier used in oil-in-water emulsions. Laureth-23 finds use in cosmetic and pharmaceutical products as a surfactant, emulsifier and solubilizer.  It is particularly useful in some formulations in light of its chemical inertness to hydrolytic decomposition.

Laureth-23 is a nonionic surfactant prepared from lauryl alcohol and 23 moles of ethylene oxide. Laureth-23 contains an average of 23 repeating ethylene oxide units.  Small amounts of 1,4-dioxane, a by-product of ethoxylation, may be found in Laureth-23. The potential presence of this material is well known and can be controlled through purification steps to remove it.

Laureth:

laureth-n where n is the average number of ethoxy molecules attached to each molecule of lauryl alcohol. Its formed by ethoxylation of lauryl alcohol. All of these are either emulsifiers or surfactants.

Nitric Oxide:

Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency.

Thrombospondin-1:

Is a secreted protein that modulates vascular cell behavior via several cell surface receptors. In vitro, nanomolarconcentrations of thrombospondin-1 are required to alter endothelial and vascular smooth muscle cell adhesion, proliferation, motility, and survival. Yet, much lower levels of thrombospondin-1 are clearly functional in vivo. This discrepancy was explained with the discovery that the potency of thrombospondin-1 increases more than 100-fold in the presence of physiological levels of nitric oxide (NO). Thrombospondin-1 binding to CD47 inhibits NO signaling by preventing cGMP synthesis and activation of its target cGMP-dependent protein kinase. This potent antagonism of NO signaling allows thrombospondin-1 to acutely constrict blood vessels, accelerate platelet aggregation, and if sustained, inhibit angiogenic responses. Acute antagonism of NO signaling by thrombospondin-1 is important for hemostasis but becomes detrimental for tissue survival of ischemic injuries. New therapeutic approaches targeting thrombospondin-1 or CD47 can improve recovery from ischemic injuries and overcome a deficit in NO-responsiveness in aging.

TNF-α

There are now five approved therapeutics for rheumatologic use, including RA, ankylosing spondylitis, and psoriatic arthritis. Four are mAbs (infliximab, centolizumab, adalimumab, and golimumab), whereas etanercept is a recombinant human TNF receptor (Rc) fused to the Fc portion of IgG that acts as a competitive inhibitor. These therapeutics modify inflammatory joint damage and systemic inflammatory symptoms (16). Optimal outcomes in RA often require combination of conventional methotrexate with anti–TNF-α mAb (17).

Interleukin-6

IL-6 is a pleiotropic cytokine first described as a T- and B-cell growth factor produced by T cells, macrophages, and endothelial cells. It is a potent inducer of local and systemic inflammation where it plays a key role in the acute phase response (e.g., IL-6 binds to cell surface IL-6Rc and signaling is facilitated by glycoprotein 130). Tocilizumab is a mAb targeting IL-6Ra. This mAb attenuates joint inflammation, bone erosion, and systemic inflammation in RA (18). Tocilizumab is also effective in juvenile RA (Still’s disease) and Castleman’s disease (19).

Interleukin-1

IL-1 is an innate cytokine with powerful capacity to activate macrophages and epithelial cells and acts in concert with IL-6 to induce systemic acute phase responses. It has a natural antagonist, IL-1RA. IL-1RA competitively inhibits IL-1Rc binding by IL-1α and IL-1β. Anakinra is a human recombinant form of IL-1RA. Therapeutically, anakinra has been unsuccessful compared with anti–TNF-α therapy for RA, but it is highly effective in modulating the Cryopyrin-associated periodic syndromes, including neonatal onset multisystem inflammatory disease, Muckle–Wells syndrome, acute and chronic gout, and juvenile RA (20).

Interleukin-2

IL-2 is a growth factor for activated T cells. CD28-dependent costimulation of activated T cells induces expression of the high affinity IL-2 (γβ, and δ) receptor (CD25). Basiliximab is a mAb designed to bind and block the IL-2Rc on activated T cells. This mAb is widely used to prevent early kidney transplant rejection.

A Cochrane systematic review shows that basiliximab is effective at reducing rejection 3 and 6 months postrenal transplantation. Because Tregs express high levels of CD25, there is the potential risk that its efficacy may be limited by its potential effect on blocking immunomodulation. A humanized anti–IL-2Rc mAb, daclizumab shows no apparent differences from basiliximab (21) and has been reported to be effective in treating uveitis in eight of ten patients in an open-label study (22).

Interleukin-12/Interleukin-23

These dimeric molecules share one chain in common, p40. Targeting p40 offers the opportunity to attenuate both Th1 (driven by IL-12) and Th17 (enhanced by IL-23) pathways of Th differentiation. Ustekinumab and briakinumab are such inhibitory mAbs. They have been assessed in severe refractory Crohn’s disease but without efficacy (23). Ustekinumab is also effective in psoriasis (24).

Interleukin-15 (IL-15)

Interleukin-15 (IL-15) is a glycoprotein that takes the form of four interconnected α-helices with a mass of 14-15 kDa [129130]. Its action is mainly based on the stimulation of differentiation and proliferation of T cells and NK cells [131]. It is one of the better documented cytokines involved in the pathogenesis of rheumatoid arthritis (RA) [132133]. While analyzing the involvement of IL-15 in the pathogenesis of OA, its increased concentration was found in the synovial fluid in the early stages of the disease [134]. It has also been shown that the increased IL-15 level in the serum correlates with both the sensation of pain and the severity of lesions in the X-ray image [135]. It has also been noted that its presence can stimulate the secretion of certain types of metalloproteinases from the MMPs group [134]

Interleukin-18 (IL-18)

Is another representative of the IL-1F family [9]. It is generated as a precursor form of the pro-IL-18, consisting of 192 amino acid residues, which is transformed into a biologically active form after the activation of Caspase 1 or proteinase 3, comprising 157 amino acid residues [152153]. It has been noted that the level of Caspase 1 is elevated both in the articular cartilage and synovium in OA patients which greatly promotes the formation of IL-1β and IL-18 [154]. The production of IL-18 in the joint is determined by chondrocytes, osteoblasts, FLS, and macrophages [155157]. Its increased concentration is evident in the synovial fluid, synovium, cartilage, and blood serum and shows a positive correlation with the degree of severity of the disease seen in radiographic images [158160]. The effect of IL-18 is mediated by the IL-18Rα receptor, which bears structural and functional similarity to IL-1R. As in the case of IL-1β, efficient signal transmission by IL-18 requires not only the presence of IL-18Rα but also the additional recruitment of the IL-18Rβ (IL-18RAcP) chain [161162]. Intraventricular signal transmission through a heterodimeric receptor complex IL-18 does not show significant differences from the mechanism of signal transduction by the IL-1β receptor complex [163]. Studies have shown that polymorphism of genes encoding both IL-18R and the IL-18 interleukin in some variants may predetermine both the development of OA and lumbar disc degeneration (LDD) [164165]. IL-18 affects chondrocytes by inducing the upregulation of IL-18Rα on their surface and stimulation excess synthesis of metalloproteinases MMP-1, MMP-3, and MMP-13 [166]. In addition to increasing the concentration of cartilage degrading enzymes, there is an inhibition of production of proteoglycans, aggrecan, and type II collagen; moreover, chondrocytes exhibit morphological changes typical of cells entering apoptosis [167169]. IL-18 affects chondrocytes and synovial cells, increasing the production of a range of compounds and enzymes, such as the IL-18 in an autocrine manner, IL-6, iNOS, PGE2, COX-2, and VEGF [155170173].

Interleukin-17A

IL-17A is important in host defense by mobilizing and activating neutrophils, whereas pathologic IL-17A responses lead to the development of autoimmunity. Secukinumb is an inhibitory anti–IL-17A mAb and is effective in psoriasis, psoriatic arthritis, and ankylosing spondylitis (25); however, studies in RA show mixed results and no clear consensus of significant benefit (26). Furthermore, in Crohn’s disease treated with secukinumb, no benefit or disease excerbation was observed (27). In a phase II clinical trial, secukinumab treatment showed promising results in MS (28).

Interleukin-10

This cytokine can attenuate the production of inflammatory cytokines. IL-10 is a prominent participant in human inflammatory diseases (e.g., significant amounts can be measured in the synovium of patients with RA). Administration of IL-10 did not attenuate RA activity (29), but it is beneficial in psoriatic arthritis (30). In ulcerative colitis, IL-10 was ineffective when administered at doses that were not associated with side effects, including anemia (31).

Interleukin-4, Interleukin-13

Interleukin-4 and IL-13 are the signature cytokines of type II inflammatory response. They are key players in the inflammatory response triggered either by an invading parasite or allergen. The cellular sources of IL-4 and IL-13 have been studied extensively and along with CD4 T cells, basophils, eosinophils, mast cells, and NK T cells, appropriately stimulated ILC2 cells have the ability to produce IL-4 and IL-13 (19).

CD4 T helper (Th) cells are the key players during adaptive immune responses12. Almost thirty years ago, it was first recognized by Mossman and Coffman that there are different subsets of Th cells, namely type 1 T helper (Th1) and type 2 T helper (Th2) cells, which are critically involved in distinct types of immune responses35. With the discovery of a third major CD4 T effector cell lineage, Th17 cells that produce interleukin-17 (IL-17), and a regulatory T cell subset (induced regulatory T (iTreg) or peripherally induced regulatory T (pTreg)) that can be differentiated from naive CD4 T cells outside of the thymus, either in vitro or in vivo, the members of CD4 T cell family have expanded269.

Th2 cells are the crucial lymphocytes during adaptive immune responses to the infections of extracellular parasites such as helminths; Th2 cells are also responsible for development of some asthmatic and allergic inflammatory diseases. By secreting IL-4, Th2 cells instruct B cells to produce IgG1 and IgE10; by producing IL-4 and IL-13, Th2 cells induce alternatively activated macrophage11. Th2 cells also recruit eosinophils via IL-5 production12 and directly act on epithelial cells and smooth muscle cells through IL-13 production1315. Therefore, IL-4, IL-5 and IL-13 are the major effector cytokines produced by Th2 cells during type 2 immune responses. All three cytokine genes, Il4Il5 and Il13, are located within a genomic segment, which is subjected to the regulation of locus control region (LCR) in the Rad50 gene1617.

During CD4 T cell activation through T cell receptor (TCR)-mediated signaling and co-stimulation, cytokine signals received by the activated T cells are deterministic in T cell fate commitment. For example, together with TCR ligation, IL-4-mediated activation of the signal transducer and activator of transcription 6 (STAT6) plays an important role during Th2 cell differentiation 1822, although IL-4-independent Th2 cell differentiation may occur in the absence of IL-4 signaling under certain conditions in vivo 2327. Both IL-4-dependent and IL-4-independent Th2 differentiation requires the key transcription factor GATA-3 (Figure 1), which is responsible for epigenetic changes in many Th2-specific gene loci and for direct transcription activation2831. In addition, IL-2-mediated activation of STAT5 is indispensable for the production of Th2 cytokines possibly through chromatin remodeling of the Th2 cytokine locus as well as maintaining GATA3 expression in already differentiated Th2 cells 183234. Therefore, GATA3 up-regulation and STAT5 activation are the two key events for Th2 cell differentiation. Th2 cell differentiation and the induction of Th2 cytokines are also regulated by many other transcription factors including NFAT, NFκb and AP-1 family members. Mechanisms for the reinforcement of Th2 cell differentiation include positive feedbacks, inhibition of other alternative lineage choices and selective growth of differentiated Th2 cells.

Interleukin 12 (IL-12)

Interleukin 12 (IL-12) is the first member of the family described [6]. It is comprised of the IL-12p35 and IL-12p40 subunits and co-expression of both subunits in the same cell is required to secrete the disulfide-linked bioactive IL12p70 cytokine [14]. Although it is secreted by a variety of hematopoietic cell types, the major physiological producers are antigen-presenting cells (APCs), such as DCs and macrophages. Binding of IL-12 to its high-affinity receptor (IL-12Rβ1/IL-12Rβ2) expressed on activated T cells, NK cells and DCs, activates TYK2 (tyrosine kinase 2), JAK2 and STAT pathways (Figure 1) [56]. Although STAT1, STAT3 and STAT4 are activated to varying extents in vitro, physiological responses to IL-12 are mediated mainly through STAT4. IL-12 induces naïve CD4+ T cells to differentiate into Th1 cells, a T-helper subset that is implicated in the etiology of a number of human autoimmune diseases. High levels of IL-12 and Th1 cells are detected in the aqueous humor and vitreous of patients with autoimmune uveitis, suggesting a role for IL-12-induced expansion of Th1 cells in this group of sight-threatening intraocular inflammatory diseases [15]. Multiple sclerosis (MS) is another chronic CNS autoimmune disease which IL-12-induced expansion of Th1 cells is thought to play an important role [1617]. Similar to uveitis and MS, the levels of IL-12 and Th1 cells are elevated in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and are correlated with disease activity [18]. Studies on experimental autoimmune uveoretinitis (EAU) the animal model of human uveitis and experimental autoimmune encephalomyelitis (EAE), the animal model of MS, also showed significant increases in IL-12 and Th1 levels, further underscoring the involvement of IL-12 in the pathogenesis of CNS autoimmune diseases [1920]. Collectively, these and other observations provide strong evidence that IL-12-induced differentiation of Th1 cells might be associated with the development of organ-specific autoimmune diseases. However, IL-12p40-deficient mice are resistant to EAE while IL-12p35−/− mice are susceptible, indicating redundancy of IL-12p40 in the development of autoimmune inflammation and suggesting that IL-23 (IL-12p40/IL-23p19) rather than IL-12, may be more important in developing autoimmune inflammation of the brain [2122]. On the other hand, the levels of IL-17 in the synovial fluid and joints of patients with RA are much higher than the levels of IFN-γ, suggesting that IL-17-producing Th17 cells may play a more important role in RA pathogenesis than IFN-γ-producing Th1 cells [18]. However, studies in the mouse have also shown that either a Th17 or a Th1 effector response can drive autoimmunity and that the dominant effector phenotype may depend on the conditions present during initial exposure to Ag, and/or type of Ag-presenting cells [23]

Interleukin 23 (IL-23)

A decade after the discovery of IL-12, homology search of the human DNA sequence database with a probe specific to the highly conserved “D” helical structure of IL-6-related cytokines led to identification of additional members of the IL-12 family. Interleukin-23 (IL-23) was discovered in 2003 and shares the IL-12p40 subunit with IL-12 but differs from IL-12 because of its unique IL-23p19 subunit [2124]. Similar to IL-12, co-expression of IL-12p40 and IL-23p19 subunits in the same cell is required to secrete the disulfide-linked bioactive IL-23 cytokine. Sharing the IL-12p40 subunit enables IL-12 and IL-23 to interact with the IL-12Rβ1 receptor subunit. The high affinity IL-23 receptor derives from the combination of IL-12Rβ1 with a unique IL-23 receptor subunit (IL-23R) and biologic effects of IL-23 on its target cells are mediated through activation of TYK2, JAK2, STAT3 and STAT4 (Figure 1) [2124]. Many innate immune cells including DCs, macrophages, B cells and endothelial cells produce IL-23 and the high affinity IL-23 receptor is expressed on activated T cells and immune cells including Th17 cells, γδ T cells, natural killer T (NKT) cells and innate lymphoid cells (ILCs) [22]. IL-23 prolongs the expression of type 17 signature cytokines (such as IL-17, IL-22 and GM-CSF) that induce tissue pathology and mediates chronic inflammation by promoting the survival and maintenance of Type 17 cells [2224]. Thus it is notable that during neuroinflammation, IL-23 produced by CNS-resident cells maintains the pathogenic capacity of CNS-invading T cells while resistance of IL-23p19- and p40-deficient mice to EAE correlates with marked reduction of encephalitogenic T cells [2526]. Similarly, IL-23 receptor expression on γδ T cells is implicated in immunopathogenic mechanisms of EAU [27] and it has been suggested that IL-23 plays an important role in birdshot retinochoroidopathy [28]. It is however disappointing that ustekinumab, an IL-12/23 p40 neutralizing antibody, was unsuccessful in a phase II clinical trials of patients with relapsing-remitting MS [29].

Interleukin 27 (IL-27)

Interleukin 27 (IL-27) was first identified in 1996 from a subtractive hybridization screen of genes expressed in Epstein-Barr virus (EBV) transformed B cell lines [3031]. It is comprised of IL-27p28 and EBV-induced gene 3 (Ebi3). The IL-27p28 subunit was identified by a bioinformatics approach on the basis of its structural homology to α-helical cytokines of the IL-6 family and subsequent studies revealed that it is co-expressed with its heterodimeric partner, Ebi3 [31]. In contrast to IL-12 and IL-23, IL-27p28 and Ebi3 are not secreted as a disulfide-linked dimers and the nature of the association between IL-27p28 and Ebi3 in vivo is uncertain. Thus, co-expression of Ebi3 and IL-27p28 subunits in the same cell may not be required for the production of the bioactive IL-27 cytokine and may instead be secreted independently by various cells types. The IL-27 receptor (IL-27R) is comprised of the ubiquitously expressed gp130 protein and the WSX-1/TCCR and biologic effects of IL-27 are mediated through activation of JAK1, JAK2, TYK2, STAT1 and STAT3 [32]. Studies of Il27ra−/− mice revealed that one of the main functions of IL-27 is to limit the intensity and duration of T cell responses and inhibits Th1, Th2, and Th17 responses by suppressing CD28-mediated IL-2 production through SOCS3 (suppressor of cytokine signaling 3) [3334]. A number of reports have also shown that IL-27 limits autoimmune encephalomyelitis by suppressing the development of Th17 cells and inducing the expansion of a population of IL-10-secreting T cells [3537]. In the immune-privileged ocular tissues, IL-27 produced by retinal cells has also been shown to suppress uveitis and contribute to mechanisms of ocular immune privilege by inducing IL-10 and complement factor H [3840].

In the quest to identify potential pairing partners for the Ebi3 subunit, co-expression of IL-12p35 and Ebi3 led to the discovery of the novel IL-12p35/EbI3 heterodimer now named IL-35 [130]. Initial studies indicated that the secretion of IL-35 is restricted to Foxp3+ Treg and treatment of naive T cells with IL-35 induces a regulatory population, called ‘iTR35 cells’, that mediates T cell suppression via IL-35 [41]. Furthermore, Treg cells also induce iTR35 cells in vivo under inflammatory conditions, which consequently, suppressed Trichuris muris infection and tumors in mice [41]. It is however notable that human Foxp3+ Tregs do not constitutively express IL-35 but can be induced to produce IL-35 by anergic dendritic cells characterized by cell surface expression of B7-H1 (CD274) and sialoadhesin (CD169) [42]. Nonetheless, IL-35 signaling in Tregs is mediated through unconventional receptors comprising IL-12Rβ2/gp130, IL-12Rβ2/IL-12Rβ2 or gp130/gp130. Although it is not clear which of these is the high affinity IL-35 receptor, binding of IL-35 to the receptor preferentially activates JAK1, JAK2, STAT1 and STAT4 [743]. The restricted secretion of IL-35 in regulatory T cells was thought to be peculiar as other members of the IL-12 family are secreted by a variety of myeloid cell types and this led to the suggestion that IL-35 may have divergent functions from IL-12, IL-23 and IL-27. However, recent reports have now identified IL-35-producing regulatory B cells [4445]. Interestingly, the IL-35 receptor identified in B cells comprises of IL-12Rβ2 and IL-27Rα the analysis of IL-35 receptor usage in B cells did not examine whether IL-12Rβ2/IL-12Rβ2 or IL 27Rα/IL-27Rα homodimers are also utilized [45]. The analysis of gp130 utilization in B cells was also based on siRNA-mediated deletion of gp130 or antibody-mediated neutralization of gp130 and incontrovertible proof that IL-35 does not bind to gp130 will await similar analysis B cells from gp130−/− mice. IL-35 has also been shown to induce regulatory B cells that produce IL-10 (Bregs) and/or IL-35 (i35-Bregs), suggesting potential use of autologous regulatory B cells in regulating immune responses in health and disease [4445].

Interleukin-22

Expression and regulation

Another central effector cytokine in the IL-20 family of cytokines is IL-22. Apart from being produced by Th17 cells, IL-22 is also produced by the Th22 cell. Th17 and Th22 cells are closely related, both being CD4+ T helper cells developed under the influence of IL-1β, IL-6, and IL-23 (Figure (Figure2).2). The development of Th17 and Th22 are dependent on different transcription factors, but they also show differences in their expression of surface receptors. While RAR-related orphan receptor gamma (RORγt) is the transcription factor responsible for Th17 induction, the aryl-hydro-carbon receptor (AHR) together with RORγt are the responsible transcription factors for the development of the Th22 phenotype. Th17 cells are identified through expression of CCR6, CCR4, but not CCR10. By contrast, Th22 cells express CCR4, CCR6 and also CCR10 (7980).

IL-22 signals through the heterodimeric receptor complex consisting of the ubiquitously expressed IL-10RB and the more restrictively expressed IL-22RA1 (81). IL-22RA1 is primarily present on epithelial cells and certain monocyte subsets, and very limited IL-22RA1 expression is found on other immune cells (2122). IL-22 functions are further regulated by the presence of IL-22 binding protein (BP), a soluble form of the IL-22RA1 (82). IL-22BP is able to bind IL-22, thereby antagonizing the effector functions of IL-22 (8384).

Function

The effect of IL-22 has been described as protective in some settings, where it promotes increased resistance to bacterial infection in the gut, maintains intestinal barrier functions and promotes the production of antimicrobial peptides (85). Further, T cell differentiation toward an IL-22-producing phenotype may also be favorable in alcoholic hepatitis (86). In contrast, in synovial tissue IL-22 is involved in pro-inflammatory reactions such as FLS proliferation and MCP-1 secretion (87).

In animal models, the IL-23-Th17 axis including IL-22 has been associated with several immune-mediated inflammatory conditions. IL-23 double-knockout mice were resistant to the development of CIA and to CNS inflammation in the experimental allergic encephalopathy (EAE) mouse model (8889). In line with this, IL-22 production was associated with increased joint destruction in the CIA model (Figure (Figure2)2) (90). Recently, IL-23 was shown to act on RORγt+ CD3+CD4-CD8- T cells in order to develop SpA-like disease in mice. The mechanisms involved include IL-22 induced genes associated with new bone formation (Figure (Figure2)2) (91). Animal data further suggest that the IL-22RA1 is the primary driver of disease in the autoinflammatory phenotype. Transgenic mice overexpressing IL-22 develop psoriasis-like disease, which is inhibited after breeding these mice with IL-22RA1 knockout mice (but not with IL-20RA knockout mice) (92). Furthermore, IL-22RA1 transgenic mice develop a systemic inflammatory condition. Eliminating the effect of all three cytokines in the IL-20RB knockout mice attenuates disease in a mouse psoriasis model (93), but upregulates antigen-specific T cell responses (94).

In humans, IL-22 has also been associated with diseases involving the IL-23-Th17 axis such as SpA including psoriatic arthritis (95). Adding to a potential role in these diseases characterized by new bone formation, IL-22 stimulates mineralization by ligament cells in odontologic disease (96). IL-22 has further been shown to be upregulated in RA patients and associated with radiographic progression and disease activity (9798)

Interleukin-26

Expression and regulation

IL-26, also denominated AK155, is a highly cationic charged cytokine initially found in activated T-cells and NK cells as part of the IL-10 cytokine family, and later classified as a Th17 cytokine (102). Recent studies have revealed IL-26 expression in a number of other cell types, including alveolar macrophages (103), bronchial epithelial cells (104), synoviolin+ synovial cells from RA patients (36), and myofibroblasts of spondyloarthritis patients (105) suggesting that IL-26 production occurs in multiple cell types. There is no functional mouse IL-26 gene, which complicates the characterization of this cytokine in preclinical settings.

The IL-26 receptor is a heterodimer composed of IL-10RB and IL-20RA. The IL-10RB monomer is ubiquitously expressed, and shares with IL-10, IL-22, and interferons, while the more sparsely expressed IL-20RA monomer is shared with IL-19, IL-20, and IL-24 (106), and constitutes the limiting factor of the cells ability to respond to IL-26 (106107). Expression of IL-20RA is upregulated in psoriatic skin (40), but also reported present on osteoclasts and osteoblasts (108).

Function

The effector functions of IL-26 are still poorly defined. However, it seems that IL-26 primarily act as part of the anti-microbial response against bacteria by recruiting neutrophils to the site of infection (103). When IL-26 forms complexes with extracellular DNA, bacterial or self-DNA (109110), the IL-26-DNA complexes can be transported into the cytosol of myeloid cells or trigger type 1 interferon production by plasmacytoid dendritic cells and activate monocytes via STimulator of INterferon Genes (STING) and the inflammasome (109110). Elevated levels of IL-26 and IL-26-DNA complexes are seen in a variety of active inflammatory diseases (105).

In immune mediated inflammatory diseases, IL-26 is suggested to be both an important driver of Th17 differentiation and a key Th17 effector cytokine (Figure (Figure2).2). Thus, IL-26 stimulated monocytes are reported to promote Th-17 cell generation from non-Th17-committed memory T-cells in RA (36), However, IL-26 is also produced by Th17 cells in colonic lesions of patients with active inflammatory bowel disease (IBD) (111).

Interleukin-22

Interleukin-22 (IL-22), which was originally named IL-10-related T cell-derived inducible factor (IL-TIF), has generated considerable interest in recent years making it one of the best-studied members of the IL-10 family of cytokines, which also includes IL-10, IL-19, IL-20, IL-24 and IL-26, as well as the lambda-interferons IL-28A, IL-28B and IL-29. Initially described as a TH17 cytokine, as its production has been observed within the same cells that produce IL-17, subsequent evidence has indicated it can be generated independently of IL-17. Unlike most cytokines, which target hematopoietic cells, the main impact of IL-22 is on non-hematopoietic epithelial cells and fibroblasts in tissues as diverse as lung, liver, kidney, thymus, pancreas, breast, gut, skin and the synovium. Although it can have a profound effect on the regeneration of epithelial tissues following injury, largely by promoting survival by inducing proliferation and inhibiting apoptosis of epithelial cells, this same function has also been implicated in pathological states such as malignancy and psoriasis. In addition, a role for IL-22 has also been described in host defense within barrier tissues such as the intestine, oral mucosa, skin and lung. Given this widespread action in regeneration, host defense and pathology, IL-22 is an attractive target for clinical development. In this review, we detail the current state of knowledge about the biology of IL-22 in animals and humans, its sources and targets, and its role in tissue pathology and regeneration

IL-22 has multiple effects on keratinocytes, such as induction of proliferation, migration, tissue remodeling and secretion of anti-microbial peptides and chemokines, as well as delayed differentiation (reviewed in (7)). IL-22 induces keratinocytes to produce anti-microbial proteins, including β-defensin 2, β-defensin 3, S100A7, S100A8, S100A9 and lipocalin 2 (279281). IL-22 also promotes the production of neutrophil-attracting chemokines, such as CXC-chemokine ligand 1 (CXCL1), CXCL2, CXCL5 and CXCL8, and inhibits the expression of CCL22, which attracts Th17 and Th2 (282). IL-22 can also induce the expression of extracellular matrix (ECM)-degrading enzymes matrix metalloproteinases (MMP)-1 and -3, which are required for epithelial migratory capacity during epithelial repair (280). In addition to its role in innate immunity by promoting anti-microbial molecules or attracting neutrophils, IL-22 also inhibits differentiation and maturation of keratinocytes through downregulation of molecules such as keratin 1 (KRT1), KRT10, profilaggrin, involucrin, loricin, kallikrein 7, desmocollin 1 and the late cornified envelope protein 1B (280282).

IL-22 also increases the expression of IL-20, which shares the IL-22R1 chain in its receptor complex (IL-22R1/IL-20R2) and has similar effects as IL-22 on keratinocytes, resulting in a positive feedback loop to amplify the effects of IL-22 (282). IL-22 has major effects on epidermal architecture, resulting in acanthosis (thickening of stratum spinosum in epidermis), parakeratosis (nuclear remnants in stratum corneum due to dysfunctional keratinocyte cornification) and hypogranularity in both 3-D tissue models, as well as IL-22 overexpressing transgenic mice (282283). These architectural changes of the epidermis are similar to those seen in psoriatic plaques. In addition, psoriatic plaques contain neutrophils and increased expression of IL-20 and STAT-3, which could be related to the increased IL-22 levels in the plaques (282284286).

There has been considerable pathology related to IL-22 documented in the skin, where IL-22 is thought to contribute to psoriasis (744). Psoriasis is common chronic skin disease, which affects approximately 2% of the population (287), and shares features with other chronic inflammatory diseases, such as IBD, diabetes mellitus, as well as an associated arthropathy: psoriatic arthritis. The characteristic skin lesions are raised, well-demarcated scaly plaques due to hyperproliferation of the epidermis with premature maturation of keratinocytes and incomplete cornification and retention of nuclei in the stratum corneum (287). The skin lesions contain an inflammatory infiltrate, which consists of dendritic cells, macrophages and T cells in the dermis, as well as neutrophils and T cells in the epidermis. The pathophysiology of psoriasis is multi-factorial with roles for autoimmunity, dysregulation of the innate immune system, proinflammatory cytokines, as well as imbalance of epithelial homeostasis, angiogenesis and genetic and environmental risk factors. However, dendritic and T cells seem to play a predominant role and the primary axis seems to be the production of IL-23 and IL12 by dermal myeloid dendritic cells, which subsequently activates Th1, Th17 and Th22 cells to secrete IL-17, IFN-γ, TNF and IL-22 (288).

Polymorphisms in the IL-22 gene have been associated with psoriasis in a Japanese population (289) and a polymorphism in the promoter region of IL-22 is associated with increased production of IL-22 and increased risk of psoriasis onset in childhood (290). In addition, copy number variation of IL-22 gene exon1 was significantly associated with psoriasis severity (291). Finally, polymorphisms in both IL-23R and IL-12B (coding for common p40 chain) are associated with psoriasis (292).

Initial studies regarding the effects of IL-22 in pathologies of the skin demonstrated that IL-22 levels were increased in T cell dermatoses, such as psoriasis and atopic dermatitis (2353). Consistent with a role in its pathophysiology, psoriasis patients have increased levels of IL-22 in their blood and serum, which has been associated with disease severity (293295). Interestingly, psoriatic plaques also have increased expression of IL-20 and IL-24 which both bind to IL-22R1 and seem to have similar effects as IL-22 on keratinocytes in vitro and in transgenic mice.

Notably, effective therapy for psoriasis results in a decrease in IL-22 levels both in the serum and the psoriatic skin lesions. Studies with IL-23 administration in IL-22-deficient mice demonstrated that IL-22 is required for both acanthosis and neutrophil infiltration (44) and injection of IL-22 into human normal skin xenografts in immunodeficient AGR129 mice resulted in changes similar to psoriasis, including epidermal thickening, expression of the psoriasis-associated marker K16 and increased vascularization (301). In addition, administration of neutralizing antibodies to IL-22 prevented the development of disease, acanthosis, inflammatory infiltrates, and expression of Th17 cytokines in experimental models as well as in human xenografts

  • Interleukin-22 (IL-22) is a cytokine that is produced during inflammation by activated T cells, including T helper 22 (TH22), TH17 and TH1 cells, and by subsets of innate lymphoid cells (ILCs).
  • Via its transmembrane receptor complex composed of IL-22 receptor 1 (IL-22R1) and IL-10R2, IL-22 mainly influences epithelial cells, hepatocytes, pancreatic acinar cells and related stem cells.
  • In many of its target cells, IL-22 enhances the production of antibacterial proteins, inhibits their differentiation and/or increases their proliferation, and protects them against damage. Furthermore, it potentiates the tumour necrosis factor (TNF)- and IL-17-induced production of pro-inflammatory mediators.
  • Therapeutic strengthening of the IL-22–IL-22R system — for example, through the application of recombinant IL-22 or IL-22-inducing small molecules — might have a beneficial impact in liver and pancreas damage, ulcerative colitis, graft-versus-host disease and transplantation of IL-22R1-expressing organs.
  • Conversely, the regenerative and protective effects mediated via IL-22R1 might have a pathogenetic role in, for example, psoriasis and tumorigenesis of IL-22R1-expressing cancers, which suggests that attenuation of the IL22–IL-22R system might be beneficial in such situations.
  • Targeting IL-22R1 (for example, with antibodies) may produce better clinical results than IL-22 neutralization, because two other cytokines — IL-20 and IL-24 — are often co-produced during inflammation and can mediate IL-22-like effects in an IL-22R1-dependent manner.
  • Owing to the lack of IL-22R1 expression on haematopoietic cells, therapeutic modulation of the IL-22–IL-22R1 system is not expected to be accompanied by severe immunological side effects.

Interleukin-7

Common amongst most lymphoid cells, including those that exhibit the capacity to produce IL-22, is their regulation by IL-7 (175). IL-7 is absolutely critical for the generation and development of all lymphoid IL-22 producing cells such as conventional αβ T cells and γδ T cells (176177), however its role in the formation of IL-22-producing NKT cells and ILCs is less clear (175). Although numbers of NKT and ILC3 are reduced in IL-7 or IL-7Rα deficient animals, they are not completely absent suggesting that IL-7 is important for their expansion but not their development (707273130178179). IL-7 signaling appears to be semi-redundant with TSLP, which also signals though IL-7Rα and can rescue ILC numbers in Il7−/− mice (180). The importance of IL-7Rα signaling for LTi expansion is highlighted by the fact that secondary lymphoid organogenesis is abnormal in mice lacking components of the IL-7 pathway (such as Il7−/−Il7ra−/−γc−/− or Jak3−/−) (178179181183), although the effects of IL-7 deficiency are primarily observed in Peyer’s patches. Little decrease in ILCs was observed in the LN of Il7ra−/− mice (81178179). Reduction in ILC number likely plays an important role in the abnormal lymphoid organogenesis noted above. However, the effect of IL-7 deficiency can also be explained by its regulation of LT signaling, which is crucial for secondary lymphoid organ formation (184). Blockade of IL-7 signaling or IL-7Rα deficiency led to reduction in the expression of LTα1β2 by LTi; and incubation with IL-7 led to upregulation of LTα1β2 (88179185186). Although IL-7 has not been shown to directly regulate IL-22 production, it does appear to stabilize RORγt expression (72), itself critical for the differentiation of all IL-22-producing subsets and for optimal IL-22 gene expression (40187). Interestingly, much like other lymphopenic mice such as Rag−/− (138188189), production of IL-22 by ILC3 is actually increased on a per cell basis in Il7−/− and Il7ra−/− mice (138). Thus, it seems that IL-7 is important for the expansion of IL-22 producing cells (in particular NCR+ ILC3), but may not be required for their functional production of IL-22.

The Interleukin (IL)-20 Cytokine Family

The IL-20 subfamily of cytokines represents one of the three subfamily groups comprising the IL-10 family of cytokines. This family also includes the IL-10 cytokine itself and the type III IFN group (with IL-28A, IL-28B, and IL-29 members), categorized according to their biological function (1). They all work together to maintain epithelial tissue homeostasis and integrity, enhancing innate epithelial immunity, and regulating the healing process after infection or inflammatory events (24). The IL-20 subfamily includes IL-19, IL-20, IL-22, IL-24, and IL-26, which all have the common function of communicating leukocytes and epithelial cells in different tissues such as the liver. They play an important role in controlling tissue regeneration following injury, promoting survival as well as inhibiting apoptosis of epithelial cells (5).

The IL-20 subfamily of cytokines is encoded by genes located in different clusters, which all share genomic organization, primary and secondary structures, and receptor complexes (6). IL-19, -20, and -24 genes are confined in chromosome 1q32, close to IL-10 gene location (7), while IL-22 and IL-26 are enclosed in chromosome 12q16 (89) (Figure (Figure1A).1A). Regarding their regulation, different transcription factors have been reported for IL-19 (PE1 and AML-1) (10), IL-20 (NF-κB) (11), and IL-24 (Jak1, Stat3, Stat6, Spcs3, and AP-1) (1213), though only putative regulators have been suggested for IL-22 and IL-26 transcriptional control. Signaling events by IL-20 subfamily members result in receptor dimerization; Janus kinase (Jak) 1, Jak2, and Tyrosine kinase 2 phosphorylation; and final signal transducer and activator of transcription (STAT)1 STAT3, and STAT5 activation (1417) (Figure (Figure1B).1B). The best-studied cytokine signaling pathways are those regulated by IL-10 and IL-22, with the mitogen-activated protein kinases’ final recruitment for anti-apoptotic and mitogenic gene expression in target cells.

Interleukin-26

Expression and regulation

IL-26, also denominated AK155, is a highly cationic charged cytokine initially found in activated T-cells and NK cells as part of the IL-10 cytokine family, and later classified as a Th17 cytokine (102). Recent studies have revealed IL-26 expression in a number of other cell types, including alveolar macrophages (103), bronchial epithelial cells (104), synoviolin+ synovial cells from RA patients (36), and myofibroblasts of spondyloarthritis patients (105) suggesting that IL-26 production occurs in multiple cell types. There is no functional mouse IL-26 gene, which complicates the characterization of this cytokine in preclinical settings.

The IL-26 receptor is a heterodimer composed of IL-10RB and IL-20RA. The IL-10RB monomer is ubiquitously expressed, and shares with IL-10, IL-22, and interferons, while the more sparsely expressed IL-20RA monomer is shared with IL-19, IL-20, and IL-24 (106), and constitutes the limiting factor of the cells ability to respond to IL-26 (106107). Expression of IL-20RA is upregulated in psoriatic skin (40), but also reported present on osteoclasts and osteoblasts (108).

Function

The effector functions of IL-26 are still poorly defined. However, it seems that IL-26 primarily act as part of the anti-microbial response against bacteria by recruiting neutrophils to the site of infection (103). When IL-26 forms complexes with extracellular DNA, bacterial or self-DNA (109110), the IL-26-DNA complexes can be transported into the cytosol of myeloid cells or trigger type 1 interferon production by plasmacytoid dendritic cells and activate monocytes via STimulator of INterferon Genes (STING) and the inflammasome (109110). Elevated levels of IL-26 and IL-26-DNA complexes are seen in a variety of active inflammatory diseases (105).

In immune mediated inflammatory diseases, IL-26 is suggested to be both an important driver of Th17 differentiation and a key Th17 effector cytokine (Figure (Figure2).2). Thus, IL-26 stimulated monocytes are reported to promote Th-17 cell generation from non-Th17-committed memory T-cells in RA (36), However, IL-26 is also produced by Th17 cells in colonic lesions of patients with active inflammatory bowel disease (IBD) (111).

In RA, IL-26 acts as a pro-inflammatory cytokine, which is constitutively expressed by synovial cells and induce cytokine secretion by myeloid cells leading to Th17 cell generation (Figure (Figure2).2). Single-nucleotide polymorphisms (SNPs) associated with RA, as well as other inflammatory disorders, like IBD, have been identified in the IL26 gene (112114).

In SpA, levels of IL-26 are elevated in synovial fluid compared with plasma which suggests that IL-26 is produced locally in the inflamed joint. IL-26 was primarily produced by α-smooth-muscle-actin expressing fibroblasts, called myofibroblasts. This subtype of fibroblast is specifically upregulated in SpA (115) and is a contributor to fibrosis in several immune mediated diseases (116). Osteoblasts treated with IL-26 show increased mineralization and IL-26 could therefore play a pro-fibrotic role in SpA as well as induce inflammation (Figure (Figure2).2). Supporting this association, a fibrotic effect of IL-26 was also reported in graft versus host disease (117).

Interleukin-19, Interleukin-20, and Interleukin-24

Expression and regulation

Cytokine localization

IL-20 and IL-24 have been identified in mononuclear cells in the synovial membrane of RA patients by immunohistochemistry (1516). IL-19 has been found in vimentin+ and CD68+ synovial cells in the hyperplastic lining layers of RA synovial tissues (17). Further, the expression of IL-20 in RA synovial tissue was shown to be particularly associated with macrophages, neutrophil granulocytes and fibroblast-like synovial cells (18). IL-19, IL-20, and IL-24 have all been identified in both synovial fluid and plasma of patients with RA and SpA (15161820).

Cellular sources

All three IL-20R cytokines are expressed by monocytes, fibroblasts and several epithelial cells. Furthermore, IL-19 and IL-24 are expressed by B cells, IL-20 production can be induced in dendritic cells and IL-24 is expressed by Th2 cells (112122). Toll like receptor (TLR)2 and TLR4 agonists and IL-1β increase the production of all three cytokines (2325) (Figure (Figure2).2). The induction of the IL-20R cytokines through activation of TLR2 and TLR4 is interesting because several endogenous TLR2 and TLR4 agonists are produced in RA and SpA (e.g., HMGB1 and hyaluronic acid fragments) (2629). In fact, this pathway may be the primary contributor to the increase in plasma levels of IL-20 and IL-24 in SpA. Myofibroblast pathways are thus activated in SpA, which lead to extracellular matrix turnover and new bone formation (30). In this process, factors from host cells such as fibrinogen, EDA fibronectin, hyaluronic acid, and tenascin C are released. These factors can all function as danger associated molecular patterns (DAMPs) (31). Further, all three cytokines are induced by immune complexes that activate FcγRs in PBMCs. More specifically, citrullinated fibrinogen-containing immune complexes were shown to activate FcγRIIa (Figure (Figure2)2) (32). The association between the IL-20R cytokines and either IgM-RF and anti-CCP antibodies could be important because these autoantibodies and the generation of immune complexes is an ongoing process even in patients in clinical remission (1). In line with this, the concentration of IL-20 and IL-24 remained increased in some patients with early RA at follow-up after 6 months of treatment compared with HCs in this study (32). Thus, some patients have increased levels of IL-20 and IL-24 even when in clinical remission.

Function

The IL-20R axis was first associated with psoriasis (4046), but later also with other immune-mediated inflammatory diseases such as inflammatory bowel disease (4751) and arthritis. The IL-20R subunits have now been identified as risk genes for developing an immune-mediated inflammatory disease in three independent genetic studies (5254).

Most studies have focused on pro-inflammatory roles of IL-20 and IL-24, whereas IL-19 seems to have anti-inflammatory functions. In evidence of this, transgenic mice overexpressing IL-20 (40) and IL-24 (42) develop psoriasis-like skin disease, while IL-19 overexpressing mice have a normal phenotype (13). In contrast, IL-19 knockout mice show increased susceptibility to experimentally induced colitis (47). In line with this, single-nucleotide polymorphisms of the IL-19 gene (but not the IL-20 or IL-24 genes) are protective in psoriasis (41). Likewise, single-nucleotide polymorphisms of the IL-20 and IL-24 genes (but not the IL-19 gene) are associated with juvenile idiopathic arthritis (5556). IL-19 has also been suggested to be protective in human colonic inflammation (57), while the role of IL-20 (4849) and IL-24 (5051) needs further study. Finally, IL-19 has several anti-inflammatory functions in atherosclerotic disease (58). Several studies have found induction of MCP-1 as a pathogenic mechanism of IL-20 and IL-24 function. MCP-1 expression is upregulated in transgenic mice overexpressing IL-24 and IL-20 increases the production of MCP-1 in kidney mesangial cells and intervertebral disc cells (425960).

Supporting the tissue homeostasis function of the IL-20R cytokines, the receptor subunits IL-20RA and IL-22RA1 are found on several epithelial cells of target organs such as keratinocytes and lining cells of the gut and airways (132122). The two cytokines are upregulated in wound healing and regulate tissue repair mechanisms (6163). Supporting tissue homestatic properties in arthritis, IL-20 and IL-24 have been shown to increase osteoblast mineralization and are associated with chronic changes in the lumbar spine in SpA (Figure (Figure2)2) (24). Further, the IL-22RA1 was recently found on osteoclast precursors and osteoclasts. In line with this, IL-20 and IL-24 plasma levels were associated with radiographic progression in early RA patients. Further, IL-20 and IL-24 stimulation led to an increased MCP-1 production in osteoclast cultures (32). MCP-1 is a chemoattractant protein that recruits CCR-2-expressing cells. This receptor is expressed by osteoclast precursors (6466). Hereby, IL-20 and IL-24 could perpetuate bone destruction by stimulating the recruitment of more monocytes and osteoclast precursors to areas of ongoing bone resorption (Figure (Figure2).2). These findings are in line with the identified role of IL-20 in osteoporosis (67) and osteoarthritis (68).

Interleukin-5, Interleukin-I4, Interleukin-13

T helper 2 cells produce a number of cytokines including inteleukin (IL)-5, IL-4 and IL-13. Group 2 innate lymphoid cells (ILC2s) also produce IL-5 under sterile conditions. IL-5 is interdigitating homodimeric glycoprotein and a member of the four α helical bundle motifs conserved among hematopoietic cytokines. IL-5 exerts its effects on target cells via IL-5 receptor (IL-5R), composed of an IL-5R α and βc subunit. The membrane proximal proline-rich motif of the cytoplasmic domain of both IL-5R α and βc subunits is essential for IL-5 signal transduction. Although IL-5 was initially identified by its ability to support the growth and terminal differentiation of mouse B cells into antibody-secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells. For example, IL-5 is now recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Overexpression of IL-5 in mouse significantly increases eosinophil numbers and antibody levels in vivo, while mice lacking a functional gene for IL-5 or IL-5R display developmental and functional impairments in B cell and eosinophil lineages. In mice, the role of the IL-5/IL-5R system in the production and secretion of Immunoglobulin (Ig) M and IgA in mucosal tissues has been reported. Although eosinophils protect against invading pathogens including virus, bacteria and helminthes, they are also involved in the pathogenesis of various diseases, such as food allergy, asthma, and inflammatory bowel diseases. The recent expansion in our understanding in the context of IL-5 and IL-5-producing ILC2s in eosinophil activation and the pathogenesis of eosinophil-dependent inflammatory diseases has led to advances in therapeutic options. A new therapy currently under invetigarion in clinical trials uses humanized monoclonal antibodies against IL-5 or the IL-5R. In this review, we summarize our current understanding of the functions of IL-5 and its receptor, the innate regulation of IL-5-producing cells, and therapeutic potential of anti-IL-5 and anti-eosinophil (IL-5R) antibodies.

Interleukin-8

Chemokines are a family of cytokines that cause the directed migration of leukocytes along a concentration gradient, resulting in the accumulation of the migrating cells at the source of chemokine production. IL-8, also known as CXCL8, is a pro-inflammatory CXC chemokine that was discovered for its role in promoting chemotaxis and degranulation of neutrophils [3]. It signals via binding with the G protein-coupled receptors cysteine-X-cysteine chemokine receptor 1 (CXCR1, IL-8Rα) or CXCR2 (IL-8Rβ). These receptors differ markedly in their chemokine-binding specificity; CXCR1 only binds IL-8 and CXCL6, whereas CXCR2 can bind to multiple cytokines, including IL-8, CXCL1, and CXCL2 [4]. Ligand binding to these receptors leads to the activation of multiple primary downstream signaling pathways, including the phosphatidylinositol-3 kinase (PI3K)/Akt, phospholipase C (PLC)/protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) pathways, as well as activation of focal-adhesion kinase (FAK), Rho-family GTPases, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling [5,6].

In normal physiology, macrophages, endothelial cells, and epithelial cells produce IL-8 in response to infection or tissue injury, where one of the functions of IL-8 is to induce chemotaxis of granulocytes, primarily neutrophils, to the affected site. Once localized to the site of insult, IL-8 can promote resolution of infection by inducing phagocytosis, oxidative burst, and the release of DNA webs known as neutrophil extracellular traps that trap and kill invading microbes [7]. The second function of IL-8 is to activate the angiogenic response. IL-8 signaling in vascular endothelial cells induces cell proliferation, survival, and migration [8], which ultimately culminate in the formation of new blood vessels [9]. In this manner IL-8 serves to both resolve the inflammatory stimulus, and promote healing.

Interleukin-9

What’s unique about Th9 cells? Historically, IL-9 was thought to be a Th2 cytokine and its re-assignment to Th9 cells put Th2 cells and Th9 cells at odds. It remains unclear what the exact relationships are between Th2 cells and Th9 cells. They clearly share certain features. For example, both subsets depend on IL-4 for their induction, and possibly differentiation; transcription factors that are central to Th2 induction (e.g., STAT6, GATA3) are also important for the induction of Th9 cells[9]. However, Th2 and Th9 subsets are also very different, especially the cytokine milieu required for their induction. As mentioned above, TGF-β is critical to Th9 induction, but it inhibits Th2 cells. Functionally, evidence supporting Th9 cells as a distinct subset is strong[13]. Some studies suggest that Th9 cells might be a subset of Th2 cells, derived in a Th2 environment in which IL-4 expression in Th2 cells is turned off [37]. In earlier studies, Th9 cells were found to express other Th2 cytokines also such as IL-10[3637], but in other studies, IL-10 was clearly absent in Th9 cells.

Th9 cells are closely associated with other cell types in the immune system, and their interactions are involved in mounting protective immune responses, as well as induction of immunopathologies. For example, Th9 cells are closely associated with mast cells, type II innate lymph cells (ILC2), and Foxp3+Tregs [33]. Their crosstalks can have profound impact on the outcomes of immune responses, and therefore, attracting much attention recently. The interaction between Th9 cells and mast cells was studied in multiple models. Th9 cells, by producing IL-9, promote the proliferation and survival of mast cells, which play a key role in allergic inflammation[42]. IL-9 is not required for the generation of mast cell precursors, but IL-9 acts as a crucial growth factor of mast cells. Indeed, neutralization of IL-9 or deficiency of IL-9 receptor resulted in defective expansion and recruitment of mast cells in different disease models [4344]. Moreover, IL-9 was shown to induce mast cell to produce multiple other cytokines, including IL-5, IL-6, IL-9, IL-10 and IL-13, which mediate allergic inflammation. IL-9 also facilitates the expansion of Th17 cells in certain models, thus promoting autoimmune inflammation [4546]. Besides Th17 cells, IL-9 also targets Foxp3+Tregs. It has been shown that IL-9 is required for the suppressive function of Tregs, as IL-9 receptor deficient Foxp3+Tregs exhibit impaired ability to suppress effector CD4+ T cells in vitro and in vivo, resulting in much more severe experimental autoimmune encephalomyelitis (EAE) [46].

Another cell type that often associates with Th9 cells is ILC2. ILC2 cells are prominently featured in the pathogenesis of asthma; they produce copious amount of cytokines, especially IL-5 and IL-13, and act as key drivers of type 2 immunity[47]. ILC2 cells also serve as a source of IL-9 in allergic and autoimmune inflammation. In a model of papain-induced lung inflammation, IL-9 from ILC2 cells was clearly involved in lung inflammation [48]. Additionally, IL-9 is required for ILC2 cell functions, as neutralization of IL-9 leads to reduced expression of IL-5 and IL-13 by ILC2 cells [48]. Other studies also showed that reduced IL-9 and Th9 cells were correlated with decreased IL-9+ ILC2 and allergic responses in itk-deficient mice[49]. More recently, Moretti and colleagues reported that in cystic fibrosis, mast cells, ILC2, and Th9 cells form an intricate amplification loop, driving severe lung inflammation [50]. Clearly, Th9 cells, together with the above-mentioned cell types, can form a network that drives productive type 2 immunity, as well as allergic and autoimmune inflammations.

Acetyl Hexapeptide-8:

  • An anti-aging peptide (Argireline) comprised of six amino acids to help with lifting and anti-wrinkle
  • Reduces deep wrinkles associated with facial expressions by relaxing the contractions of facial muscles that cause repeated expression lines (i.e. crow’s feet)

ACETYL GLYCYL BETA-ALANINE:

A skin-whitening peptide that goes by the trade name GenoWhite. The manufacturer claims that it hinders the mechanism of pigmentation in two ways: first, it inhibits melanin generating enzymes like Tyrosinase so that less pigment is formed and then it also hinders the transport of the pigment to the upper layers of the skin where it becomes visible (little organelles called melanosomes carry the pigment upwards).

The in-vivo (made on real people) test of the manufacturer shows great spot-fading results after 56 days using 2% GenoWhite (with the first visible results showing already after 14 days).

Aminoethylphosphinic Acid:

  • A naturally occurring phosphonate in plant and animal membranes
  • Brightening agent by inhibiting melanin (skin pigmentation) production
  • Anti-age spots
  • Humectant
  • Chelating agent: binds to metallic compounds and prevents them from contaminating and adhering to the skin

Biotinoyl Tripeptide-1:

  • Natural herbal compound that improves and helps anchor the hair follicle more firmly into the skin
  • Increases metabolism in the follicles to produce an anti-aging effect within the hair follicle
  • Provides a protective and reparative effect for different structures of the hair follicle
  • Lessens the harmful effect of DHT by increasing blood circulation to the hair follicle and rejuvenating it

Butylene Glycol:

  • An organic molecule with two alcohol groups 
  • Most gentle of glycols 
  • Humectant- moisturizing properties binds moisture and holds water in the skin 

Camellia Sinensis (Green Tea) Leaf Extract:

  • Natural botanical ingredient that contains antioxidant properties that help prevent premature aging and protects against UV damage
  • Cell protecting function- protects skin from damaging effect of free radicals

Caprylyl Glycol:

  • An effective humectant when combined with 1.2-Hexanediol and works synergistically with other preservatives by increasing the antimicrobial activity 
  • Preservative that protects against antimicrobial growth from bacteria and yeast 
  • Skin conditioning agent- moisturizer, emollient, and works on the skin’s surface to give it a soft and smooth texture 
  • Stabilizer and viscosity regulator

Cellulose Gum:

  • Thickener 
  • mulsion stabilizer and viscosity controlling (water retention agent)

CETYL ALCOHOL:

A fatty alcohol that’s either produced from the end products of the petroleum industry, or derived from plants (palm oil-palmityl alcohol). It comes in the form of a white, waxy solid. It’s no longer derived from sperm whale oil (where it was originally discovered) seeing how whales are now an endangered species.

Works as an emollient, emulsifier, thickener and carrying agent for other ingredients contained in a cosmetic solution. It keeps the oil and water parts of an emulsion from separating, and gives products good spreadability. As a thickening agent and surfactant, it helps alter the viscosity and increase the foaming capacity of non-aqueous (i.e. lotions) and aqueous solutions (i.e. shampoo). It is often misinterpreted as an “alcohol” related to ethyl or rubbing alcohol, both of which can be extremely drying to the skin. The truth, in fact, is quite the opposite, as cetyl alcohol is well known to effectively condition and soften the skin and hair. Because of its multi-functional capabilities, this ingredient is used in a wide range of personal care products such as moisturizer, face cream, shampoo/conditioner, anti-aging treatments.

CETYL ETHYLHEXANOATE:

A synthetic ester of cetyl alcohol and 2-ethylhexanoic acid. Comes in the form of a pale yellow wax/liquid.

Works as an emollient, skin conditioner and thickening agent. It lubricates the surface of the skin/hair, removes the appearance of dry patches and flakes and gives the skin a soft and smooth look. It gives cosmetic products water-repelling properties and an easy spreadabillity. It’s used as a substitute to Spermaceti wax, which comes from whales. You can find this ingredient in products such as lipstick, foundation, facial moisturizer, lip gloss, anti-aging treatment, lip/eye liner, conditioner and eye shadow.

Chlorphenesin:

  • Antimicrobial, antifungal, and some antibacterial properties 
  • Preservative- prevents viscosity changes, pH changes, emulsion breakdown, and microorganism growth 

Chrysin:

  • A naturally occurring flavonoid (botanical ingredient) extracted from plants 
  • Combats puffiness and dark circles by helping to eliminate the pigmented bilirubin and iron deposits underneath the skin (dark circles)
  • Skin conditioning agent and anti-inflammatory properties 
  • Antioxidant- provides protection against UV-induced damage

Citrus Aurantium Bergamia (Bergamot) Fruit Oil:

  • Oil from the peel of the bergamot fruit 
  • Natural antibiotic and disinfectant 
  • The antibacterial activity helps reduce acne as it helps to kill the bacteria on the skin before it can react to create blackheads and pimples 
  • Also has an added property of helping to control excess oil production in the skin 
  • Antiseptic and antifungal properties, which help fight infection and aid recovery, therefore, encourages wound healing and skin regeneration-helps the skin heal faster for old acne scars, eczema, psoriasis 
  • Prevent and treat scars and stretch marks as well fade old scars due to helping regulate the distribution of melanin, the skin’s natural pigment, while evening out skin tone 
  • Cooling, refreshing nature- ideally suited to help calm inflamed skin 

Citrus Grandis (Grapefruit) Extract:

  • Natural botanical that has anti-microbial and anti-inflammatory properties
  • Also acts as an antioxidant and as an Alpha-Hydroxy Acid (AHA)- a natural skin moisturizing agent 

Cyclopentasiloxane:

It’s used in skincare and hair care as a lubricant, emollient, delivery agent, conditioner and solvent. When applied to the skin and hair, it gives a silky and slippery feeling to the touch and acts a mild water repellent by forming a protective barrier on the skin. It’s an odorless, volatile liquid at room temp and evaporates after application to the skin.
HIGH concerns: Persistence and bioaccumulation;

MODERATE concerns: Organ system toxicity (non-reproductive) and can cause cancer in lab animals.

LOW concerns: can get absorbed into the skin, Ecotoxicology, Endocrine disruption, Neurotoxicity.

 

The chemical formula for Cyclopentasiloxane:

It gives a wet look and slippery feel to the skin and hair without the need for oily substance and is non comedogenic.

Dimethicone:

It’s a silicone polymer also known as polymethylsiloxone. It is used as emollient, lubricant, skin protectant and conditioner. It gives a wet look and silky feel to skin and hair without the use of oily substances. It very fluid and can be spread in thin layer over the skin giving it shine, forming a protective barrier and a silky slippery feel like oil. Because it can form a thin stable water resistant coat on the skin, it helps with keeping skin hydrated by preventing extra water loss.

The chemical formula for Dimethicone:

 

Dipeptide-2:

  • Natural moisturizing factor- structure resembles lipids found in epidermis of skin that help skin retain moisture 
  • Anti-puffiness- A peptide consisting of two amino acids the improves lymphatic circulation to more effectively remove toxins in the skin 

FLAVANOIDS:

Chemically flavonoids are based upon a fifteen-carbon skeleton consisting of two benzene rings (A and B as shown in (Figure)linked via a heterocyclic pyrane ring (C). They can be divided into a variety of classes such as flavones (e.g., flavone, apigenin, and luteolin), flavonols (e.g., quercetin, kaempferol, myricetin, and fisetin), flavanones (e.g., flavanone, hesperetin, and naringenin), and others. The various classes of flavonoids differ in the level of oxidation and pattern of substitution of the C ring, while individual compounds within a class differ in the pattern of substitution of the A and B rings.

Flavonoids occur as aglycones, glycosides, and methy- lated derivatives. The basic flavonoid structure is aglycone (Figure). Six-member ring condensed with the benzene ring is either a -pyrone (flavonols and flavanones) or its dihydroderivative (flavonols and flavanones). The position of the benzenoid substituent divides the flavonoid class into flavonoids (2-position) and isoflavonoids (3-position). Flavonols differ from flavanones by hydroxyl group at the 3- position and a C2–C3 double bond. Flavonoids are often hydroxylatedinpositions3,5,7,2,3’, 4’and 5’Methylethers and acetyl esters of the alcohol group are known to occur in nature. When glycosides are formed, the glycosidic linkage is normally located in positions 3 or 7 and the carbohydrate can be L-rhamnose, D-glucose, glucorhamnose, galactose, or arabinose.

Glycerin:

  • Naturally occurring alcohol compound that balances the water levels in skin to facilitate moisture 
  • Humectant (moisturizing properties)- absorbs water and helps retain in moisture 
  • Emollient- Helps the skin feeling smoother and soft

Hesperidin Methyl Chalcone:

  • A bioflavonoid that is naturally found in the peel, pulp, and membranes of citrus fruit 
  • Antioxidant properties- helps to combat inflammation and cell damage caused by free radicals
  • Improves the appearance of the characteristic, bluish-black dark circles by helping to strengthen the capillaries under the eyes 
  • Anti-Puffiness 

Human Fibroblast Conditioned Media:

  • Contains Growth Factors (TBF-Beta, GM-CSF, & PDGF) and cytokines which promote cell development and improves extrinsic signs of aging 
  • Stimulates fibroblast growth factor, cell replication, collagen synthesis, matrix remodeling, and tissue repair 
  • Promotes healing and reduces scar coloration 
  • Anti-aging/anti-wrinkle 

Hydroxyethyl Acrylate/ Sodium Acryloyl dimethyl Taurate Copolymer:

  • Antioxidant 
  • Viscosity controlling emulsion agent that thickens and stabilizes the VRS 
  • Provides a sensation of freshness followed by a melting effect on contact with the skin and leaves a feeling of softness 

Integrin alpha2beta1:

  • ligand is collagen
  • upregulates or downregulates TGF
  • Collagen remodelling and contraction, myofibroblast differentiation during wound healing and fibrosis, re-epithelialization during wound healing 

Integrin alfa3beta1:

  • ligand is Laminins
  • Keratinocytes, fibroblasts, carcinoma cells, lung alveolar epithelial cells

  • Re-epithelialization during wound healing, EMT, cancer cell migration and invasion 

Hydroxyethyl Acrylate/ Sodium Acryloyl dimethyl Taurate Copolymer:

  • Antioxidant 
  • Viscosity controlling emulsion agent that thickens and stabilizes the VRS 
  • Provides a sensation of freshness followed by a melting effect on contact with the skin and leaves a feeling of softness 

Integrin alpha1beta1:

  • main ligand is collagen 
  • upregulates TGF
  • collagen remodelling, Collagen remodelling and contraction, myofibroblast differentiation during wound healing and fibrosis

Lactic Acid:

  • Natural Alpha-Hydroxy Acid (AHA) contained in sour milk that is a natural skin-moisturizing agent & has beneficial effects on dry skin
  • Humectant- moisturizing properties; binds moisture and holds water in the skin 
  • Exfoliant- Gently exfoliates by increasing cellular turnover 
  • Increases ceramide levels- one of the main components of the epidermis layer of human skin & creates a water- impermeable, protective organ to prevent excessive water loss due to evaporation 
  • Potent skin lightener for age spots or darkened areas 
  • Reduces acne breakouts 
  • Promotes collagen growth 

Lonicera Caprifolium & L. Japonica (Honeysuckle) Flower Extract:

  • Natural botanical- derived from the Honeysuckle plant, common Asian vine 
  • Antimicrobial properties- used as a natural preservative to keep the product fresh 

Menthyl Lactate:

  • A form of Lactic acid (derived from menthol + lactic acid) 
  • Cooling agent- provides a refreshing booster for the skin when applied topically for skin irrigation, pain, itching, or sunburn 

N-Hydroxysuccinimide:

  • Organic compound 
  • Lessens dark circles under eye by eliminating blood-originated pigments responsible for the color of dark circles and local inflammation 

NONAPEPTIDE-1

Nonapeptide-1 can prevent melanin synthesis and unwanted pigmentation by preventing activation of the tyrosinase, thus allowing for a better control over skin tone.

Oenothera Biennis (Evening Primrose) Seed Extract:

  • Natural botanical extracted from plant 
  • Contains polyphenols which possess antioxidant activities 
  • Riich in omega-6 fatty acids including linoleic acid (LA), and gamma linoleic acid (GLA) which enhance epidermal barrier 
  • Has ability to dilute sebum production and calm inflammation 

OLIGOPEPTIDE-34

Oligopeptide-34 is a small protein molecule (also known as a peptide) consisting of 13 amino acids strung together to create a highly efficient and active molecule that addresses melanin formation. Storage: Common storage 2-8℃, long time storage -20℃. FunctionsOligopeptide-34 decreases melanin synthesis and tyrosinase activity in melanocytes, and it decreases the transfer of melanosomes.

After determining the optimum concentration of Oligopeptide-34, we concluded additional studies that indicated a reduction in Tyrosinase enzyme activity by 65 percent. Studies comparing Oligopeptide-34 to Vitamin C and Arbutin showed Oligopeptide-34 to be superior; Vitamin C and Arbutin reduced pigmentation by 27 percent and 40 percent, respectively, while Oligopeptide-34 reduced pigmentation by 47 percent. Twice daily application on 22 Asian individuals indicated “a statistically significant brightening effect on pigmented spots” as measured by spectrophotometers and subjective appraisal. Eighty-four percent of the panelists rated the product performance after eight weeks as “very good or good.

Palmitoyl Oligopeptide:

    • Blend of several fatty and amino acids that help produce same results of retinoid without the sensitivity 
    • Stimulates collagen/elastin production and glycosaminoglycan synthesis, as well as increase hyaluronic acid levels 
    • Anti-aging properties by reducing fine lines, improving texture, firming the eye skin, and brightening the skin’s tone 

Palmitoyl Tetrapeptide- 7:

  • A peptide compound combining several chains of amino acids which activates the synthesis of the skin’s extracellular matrix and connective tissues 
  • Helps facilitate the appropriate inflammatory response by suppressing the production of excess interleukins from exposure to UV radiation 

Panthenol:

  • Humectant (moisturizing properties)- absorbs water and helps retain in moisture 
  • Improves elasticity to promote cell regeneration 
  • Forms a smooth film on the strand to thicken hair 

Phenoxyethanol:

  • An organic chemical compound, known as glycol ether 
  • Topical antiseptic and anti-microbial preservative that keeps bacteria, yeasts, and mold out of organic ingredients 
  • One of the most widely used safe and effective preservatives in skincare products 

Polysorbate 20:

  • Oil Solubilizer 
  • Surfactant- Emulsifying agent and solubilizing agent 

Polysorbate 60:

  • Oil Solubilizer 
  • Thickening and emulsifying agent- reduce the surface tension of the VRS serum, which aids in the process of emulsifying 

Propylene Glycol:

  • Natural humectant (to retain moisture)- helps to hold the chemical structure of the Growth Factors so there is no break down (protein degradation) & holds structure of the Growth Factor proteins intact
  • Skin-conditioning agent- penetration enhancer for growth factors and active ingredients to further penetrate the skin 
  • Solvent- Solubilizes active ingredients 
  • Emulsifying agent- stabilizing and viscosity controlling 

Rosmarinus Officinalis (Rosemary) Leaf Oil:

  • Botanical ingredient extracted from the flowering tops and leaves of the rosemary plant 
  • Stimulates circulation 
  • Helps healing wounds and reduce skin fragility 
  • Skin conditioning agent antioxidants- helps retard oxidation and inhibits the action of some microorganisms 
  • Tonic, microbial, and astringent properties 

Simmondsia Chinensis (Jojoba) Seed Oil:

  • Botanical ingredient that is extracted from seeds of the shrub
  • Emollient, lubricant- works as a natural moisturizer to improve elasticity and restore the vaginas suppleness, containing tocopherols to minimize oxidation and lipid peroxidation 
  • As a natural moisturizer, it helps keep the intercellular structure of the epidermis intact and effectively keeps bacteria out, facilitates the skin’s healing process, and prevents dermal irritation 
  • Effectively and quickly penetrates the skin easily by resembling natural sebum-like molecules secreted by the human sebaceous glands 
  • Increase moisturizing abilities by not only the skin’s fast absorption but also by forming a lipid layer on the skin that helps retain moisture levels, improves flexibility and elasticity 
  • Light yet hydrating, especially beneficial in treating inflamed and irritated skin conditions 
  • Contains a straight chain molecular composition which gives it superior stability and prevents the serum from oxidizing or deteriorating 
  • Antibacterial, anti-inflammatory, hypoallergenic, non-toxic and contains skin soothing properties for the vaginal wall linings 

Sodium Hyaluronate:

  • Sodium salt of hyaluronic acid, a naturally occurring polysaccharide found in connective tissues 
  • Humectant- contains hydrating properties that helps skin maintain and absorb water more effectively within the extracellular matrix creating an all-around fuller appearance (it retains more water than any other natural substance- up to 1000 times its weight in water)
  • Skin conditioning agent- moisturizes the skin & creates smoother, softer skin 
  • Anti-aging/Anti-wrinkles

Squalane:

  • Naturally occurring lipid that’s used in lubricating serums & creams
  • Emollient- as a strong moisturizer, makes the external layers of the epidermis softer and more pliable, as well as increase water content (hydration) 
  • Has the ability to completely and rapidly penetrate the epidermis at a rate of 2mm per second
  • Antioxidants- promotes cell growth, skin cell regeneration & oxygenation 
  • Increase cell turnover & collagen production 
  • Enhance elasticity and moisture retention of the vagina 
  • Antibacterial 

Steareth- 20:

  • Dispersant- reduce interactive forces between molecules of liquid 
  • Surfactant- Emulsifying & solubilizing agent 

Tetrahexyldecyl Ascorbate:

  • Stable, oil-soluble form of Vitamin C ester (from Ascorbic acid- naturally occurring compound with antioxidant properties) 
  • Antioxidant- protects against cell damage, helps prevent oxidative stress, and repairs UVA/UVB damage 
  • Stimulate collagen synthesis & glycosaminoglycans (a natural moisturizer)
  • Contains whitening agent so clarifies and brightens the skin 
  • Lipid soluble- easily penetrates into the skin 

Tocopheryl Acetate:

  • Natural skin conditioning agent 
  • A form of Vitamin E (combination of acetic acid + tocopherol, Vitamin E) 
  • Antioxidant- protects against cell damage, helps prevent oxidative stress, and repairs UVA/UVB damage 
  • Anti-aging, moisturizing, & anti-inflammatory properties 
  • Fat-soluble vitamin- most readily absorb by the skin 

Xanthan Gum:

  • Polysaccharide
  • Thickener- adds viscosity and texture
  • Emulsion stabilizer- helps to stabilize both oil-soluble & water-soluble ingredients so that separation does not occur

Transforming Growth Factor-a(TGF-a)

  • Polysaccharide
  • Thickener- adds viscosity and texture
  • Emulsion stabilizer- helps to stabilize both oil-soluble & water-soluble ingredients so that separation does not occur

Transforming Growth Factor-a(TGF-a)

  • Secreted By: Macrophages, Keratinocytes, T-Lymphocytes
  • Function: Mitogenic and chemotactic for keratinocyte and fibroblast.
  • Expression of antimicrobial peptides, epithelial and hepatocyte proliferation.
  • May mediate angiogenesis, epidermal regrowth, and formation of granulation tissue.

CELLULAR COMMUNICATION VIA GROWTH FACTORS AND CYTOKINES

Transforming Growth Factor-a(TGF-a)

Secreted By: Macrophages, Keratinocytes, T-Lymphocytes

Function: Mitogenic and chemotactic for keratinocyte and fibroblast. Expression of antimicrobial peptides, epithelial and hepatocyte proliferation. May mediate angiogenesis, epidermal regrowth, and formation of granulation tissue.

Transforming Growth Factor-ß2(TGF-ß2)

Secreted By: Macrophages, Platelets, Endothelial Cells, Monocytes, Keratinocytes, Fibroblasts, T-Cells, Smooth Muscle Cells, Hepatocytes

Function: Macrophage, lymphocyte, fibroblast, granulocyte and smooth muscle chemotaxis. Keratinocyte proliferation. Potent Macrophage deactivator. Angiogenesis, Fibroplasia, Matrix Metallopreteinase production inhibition, TIMP synthesis.

Transforming Growth Factor-ß3(TGF-ß3)

Secreted By: Fibroblasts, Keratinocytes

Function: Controls wound healing by regulating the movements of epidermal and dermal cells in injured skin.Transforming growth factor beta 3(TGF-ß3) is a type of protein known as a cytokine, which is involved in cell differentiation.

Found in high levels in embryo wound healing. It is an antagonist to TGF-ß1 and TGF-ß2.

Tumor Necrosis Factor (TNF-a)

Secreted By:TNF is produced mainly byMacrophages, but also Lymphoid Cells, Mast Cells, Endothelial Cells, Cardiac Myocytes, Adipose Tissue, Fibroblasts, and Neuronal Tissue. Large amounts of TNF are released in response to lipopolysaccharide, other bacterial products, and Interleukin-1 (IL-1).

Function: Regulates the proliferation of macrophages during differentiation. Tumor necrosis factor (TNF, cachexia or cachectic, formally known as tutor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.

The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis and viral replication.

Platelet Derived Growth Factor (PDGF)

Secreted By: Platelets, Macrophages, Keratinocytes, Endothelial Cells, Smooth Muscle Cells

Function: Macrophage, Fibroblast, Granulocyte and smooth muscle chemotaxis. Macrophage, Granulocyte and Macrophage activation. Fibroblast, endothelial cell and smooth muscle proliferation. Angiogenesis. Matrix metalloproteinase, fibronectin and HA production. ECM formation. Wound remodelling. Integrin formation.

Hepatocyte Growth Factor (HGF)

Secreted By: Mesenchymal Cells, Platelets

Function: Epithelial and endothelial cell proliferation. Hepatocyte motility. Mitosis, proteolysis, anti-apoptosis, cell morphogenesis, activation of MAPK activity.

Vascular Endothelial Growth Factor (VEGF)

Secreted By: Mesenchymal Cells, Endothelial Cells, Platelets, Fibroblasts, Keratinocytes, Macrophages

Function: Endothelial cell proliferation and angiogenesis. Increases vascular permeability.

Epidermal Growth Factor (EGF)

Secreted By: Platelets, Macrophages, Keratinocytes

Function: Regulation of cell growth(keratinocyte, fibroblast), proliferation, and differentiation. Stimulates production of non-collagenous proteins, but not production of collagen. Aids with granulation tissue formation. Stimulates collagenase secretion from fibroblasts to degrade the matrix during remodelling.

Fibroblast Growth Factor 1 (FGF-1)

Secreted By: Macrophages, Mast Cells, Endothelial Cells, Fibroblasts, T-Cells

Function: Fibroblast chemotaxis, fibroblast and keratinocyte proliferation, keratinocyte migration, matrix deposit, wound contraction, angiogenesis.

Fibroblast Growth Factor 2 (FGF-2)

Secreted By: Macrophages, Mast Cells, Endothelial Cells, Fibroblasts, T-Cells

Function: Fibroblast chemotaxis, fibroblast and keratinocyte proliferation, keratinocyte migration, matrix deposit, wound contraction, angiogenesis.

Keratinocyte Growth Factor (KGF), Also known as FGF-7

Secreted By: Stromal Cells, fibroblasts

Function: The Keratinocyte Growth Factor (KGF), also known as FGF7, is a growth factor present in the epithelialisation-phase of wound healing. Causes proliferation of keratinocytes. Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family (hence the alternative designation FGF-7).

It is produced by stroll cells, but acts as mitogen for epithelial cells. FGF-7 is known to stimulate keratinocyte expression of VEGF.

Transforming Growth Factor-a(TGF-a)

Secreted By: Macrophages, Keratinocytes, T-Lymphocytes

Function: Mitogenic and chemotactic for keratinocyte and fibroblast. Expression of antimicrobial peptides, epithelial and hepatocyte proliferation. May mediate angiogenesis, epidermal regrowth, and formation of granulation tissue.