Friday 4 April 2014

Herbal Calendula and Atherosclerosis

Calendula is also known as pot marigold, a annual or perennial herbaceous plants of about 12–20 species of genus Calendula, belonging to the family Asteraceae, native to Southern Europe. It has been used in herbal medicine as spasmolytic, spasmogenic, inflammatory effects and to treat abdominal cramps, wound healing, skin diseases, colitis, constipation, etc.
Edema is a condition of accumulation of fluid in the interstitial spaces, causes of swelling in the feet, ankles and legs.

Ingredients
Beside major chemical constituents of triterpenoids, flavonoids, coumarines, quinones, volatile oil,carotenoids and amino acids, the herb also contains loliolide (calendin), calendulin and n-paraffins.
Atherosclerosis is a condition of thickening of an artery wall as a result of the accumulation of cholesterol and triglyceride.
The study of natural products including botanicals for both therapy of clinical manifestations of atherosclerosis and reduction of atherosclerosis risk, showed a positive effects of herbal Caendula in reduced risk of atherosclerosis and progression of the disease(1). Inflaminat, a composition of (calendula, elder, and violet), which possesses anti-cytokine activity, showed to cause the regression of carotid atherosclerosis(2). Other composition, including calendula, elder, and pansy showed to enhanced maximum antiinflammatory activity. Thus can be used for pathogenetic therapy of various inflammatory diseases, including atherosclerosis(3).



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References

(1) Anti-atherosclerotic therapy based on botanicals by Orekhov AN1, Sobenin IA, Korneev NV, Kirichenko TV, Myasoedova VA, Melnichenko AA, Balcells M, Edelman ER, Bobryshev YV.(PubMed)
(2) Direct anti-atherosclerotic therapy; development of natural anti-atherosclerotic drugs preventing cellular cholesterol retention by Orekhov AN(PubMed)
(3) Use of natural products in anticytokine therapy by Gorchakova TV1, Suprun IV, Sobenin IA, Orekhov AN(PubMed)

Phytochemical allicin and pancreatic cancer

Allicin is phytochemical containing sulfur in the class of organosulfur compound, found abundantly in onion and garlic.
Cancer of pancreas or pancreatic cancer is defined as condition of a malignant neoplasm of the pancreas, as the cells have become cancerous and divided uncontrollably. Most pancreatic cancers start in the ducts (exocrine component of the pancreas) that carry pancreatic juices with cancer of an epithelium that originates in glandular tissue accounts for over 75 - 90% of all cases of exocrine cancers.

The health benefits
Allicin found in garlic and onion has drawn many interest in scientific community in finding a natural potent agent with little and no side effects in preventing and treating cancers. Garlic preparations inhibition of cancer cell-growth has been attributed to a group of structurally-related organosulfur compounds, such as allicin, diallyl disulfide and diallyl trisulfide. Combined treatment with recombinant interleukin-2 (rIL-2) on pancreatic cancer and explored the potential immunological mechanism in mice, showed a significant suppression of cells growth and prolonged survival time in the combined treatment with allicin and rIL-2 group, with increased mature Th cells express the surface protein CD4 and CD8, natural killer cell (NK cell) and Serum levels of interferon-gamma.



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References
(1) Effect of combined treatment with recombinant interleukin-2 and allicin on pancreatic cancer by Wang CJ, Wang C, Han J, Wang YK, Tang L, Shen DW, Zhao Y, Xu RH, Zhang H.(PubMed)
(2) Anti-proliferation activity of synthetic ajoene analogues on cancer cell-lines by Kaschula CH, Hunter R, Hassan HT, Stellenboom N, Cotton J, Zhai XQ, Parker MI.(PubMed)

Phytochemical Piperine and Asthma

Piperine is a phytochemical alkaloid in the class of organosulfur compound, found abundantly in white and black pepper, long pepper, etc.
Asthma is a chronic inflammatory disease affecting the air way of the lung with recurring symptoms, such as wheezing, chest tightness, shortness of breath, and coughing.

The effects
Study of bacterial infections causes of frequent respiratory infections, including bacterial infections provoke asthma attack, showed a positive effect of Piper Longum L. Extract (20% Piperine) in  exhibition of a moderate activity antibacterial activity against selected strains, such as Haemophilus influenzae , Streptococcus pneumoniae , Streptococcus pyrogene and Staphylococcus aureus. In the study of antioxidant defenses of asthma patient, Piper longum extract (20% Piperine) showed a potent antioxidant activiy by scavenging Nitric oxide to  prevent the bronchial inflammation in asthmatic patients.


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References
(1) Effect of selected antiasthmatic plant constituents against micro organism causing upper respiratory tract infection by Nilani P, Duraisamy B, Dhamodaran P, Ravichandran S, Elango K.(PubMed)
(2) Invitro antioxidant activity of selected antiasthmatic herbal constituents by Nilani P, Kasthuribai N, Duraisamy B, Dhamodaran P, Ravichandran S, Ilango K, Suresh B.(PubMed)

Thursday 3 April 2014

Skin aging in Vitamin C points of view

Kyle J. Norton

Skin aging is one of most visible ageing process which occurs constantly in our skin organ. According to the Clinical Centre of Nis, certain plant extracts may have the ability to scavenge free radicals, to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin,  affect skin elasticity and tightness(a). Other suggested that free radicals induced domino effects in production of reactive oxygen species, can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system, leading  injuries damage regulation pathways of skin,  including wrinkles, roughness, appearance of fine lines, lack of elasticity, and de- or hyperpigmentation marks(b).
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support. In skin aging, the vitamin may improve solar radiation protection and epidermal aging(1) through production of collagen due to its antioxidant activity(2)(3).
Epidemiological studies, linking vitamin C in prevention of skin damage and aging have produced some certain results(3a)(3b)(3c), but the large sample size and multi canters studies are necessary to validate it effectiveness.
1. Plasma levels of vitamin C
L-ascorbic acid, was known for its effects on skin-whitening and against anti-oxidation causes of skin aging. During the aging process, levels of vitamin C was found slowly deplete, according to Tokyo Metropolitan Institute of Gerontology in the measurement of plasma and urine of C57BL/6 male mice turnover during 3 to 30 months of aging(4). Therefore, restoration of physiological levels of vitamin C inside the cells might improve  the lysosomal degradation (protection of cell from the degradative enzymes, through protection of the cytosol) in the outflow pathway cells and prevent the pathogenesis of glaucomadegrade proteins(5).
Unfortunately, some researchers suggested that higher levels of circulating vitamin C may not provide protection against incident radiographic knee OA, and be associated with an increased risk of knee OA(6) and the 1Panorama Research Institute and Regenerative Sciences Institute, insisted "careful attention to individual and family medical history and personal genomic data may prove essential to make wise dietary and supplement choices to be combined with exercise(7).

2. The effects
According to the Minghsin University of Science and Technology, in doses dependent manner,  concentration of L-ascorbic acid, induced absorption of the collagen solution in exhibition of smoothing wrinkles and clear up the spots(8). Ascorbic acid (AA) is essential in stimulation  for collagen gene expression. In type 1 and type 4 collagen and SVCT2, the vitamin was found to enhance the expression of type 1 and type 4 collagens and SVCT2 mRNA in cultured human skin fibroblasts at 100 μM AA placed every 24h for 5 days to prevent depletion(9). The Chiang Mai University study also supported the effects of ascorbic acid in anti-aging process through exhibition pro and active MMP-2 inhibitory(10). Other study suggested the combined vitamins, including vitamin C in a single formulation had a slightly lower degradation rate  and more stable formulations as compared to different preparations containing only one of the vitamins(11)(12). Amazingly, in vivo, application of vitamin C showed a significant reduction of oxidative stress in the skin, an improvement of the epidermal-dermal microstructure and a reduction of fine lines and wrinkles in aged skin within a relatively short period of time of product application(13). The  Bruce and Associates study also insisted the effectiveness of vitamin C application over 12 week period as the vitamin enhanced the overall intensity of pigmentation, fine lines and wrinkles, tactile roughness, and laxity with 100% of  satisfied overall appearance of tested subject skin(14).

Taken altogether, vitamin C was found to be effective in slowdown skin aging regardless to the cause, through its antioxidant status, down regulated the expression of Matrix metalloproteinase (MMPs) and enhanced production of collagens. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(15)(16). As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying


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References
(a) Skin ageing: natural weapons and strategies by Binic I1, Lazarevic V, Ljubenovic M, Mojsa J, Sokolovic D.(PubMed)
(b) Phytoconstituents as photoprotective novel cosmetic formulations by Saraf S1, Kaur CD.(PubMed)
(1) Active ingredients against human epidermal aging by Lorencini M1, Brohem CA2, Dieamant GC2, Zanchin NI3, Maibach HI(PubMed)
(2) CAM use in dermatology. Is there a potential role for honey, green tea, and vitamin C? by Barbosa NS1, Kalaaji AN2.(PubMed)
(3) The science behind vitamins by Linder J.(PubMed)
(3a) Split-face study of topical 23.8% L-ascorbic acid serum in treating photo-aged skin by Xu TH1, Chen JZ, Li YH, Wu Y, Luo YJ, Gao XH, Chen HD(PubMed)
(3b) Use of topical ascorbic acid and its effects on photodamaged skin topography by Traikovich SS.(PubMed)
(3c) Formulation and in-vivo evaluation of a cosmetic multiple emulsion containing vitamin C and wheat protein by Akhtar N1, Yazan Y(PubMed)
(4) Ascorbic acid levels in various tissues, plasma and urine of mice during aging by Iwama M1, Amano A, Shimokado K, Maruyama N, Ishigami A.(PubMed)
(5) Ascorbic Acid Modulation of Iron Homeostasis and Lysosomal Function in Trabecular Meshwork Cells by Xu P1, Lin Y, Porter K, Liton PB(PubMed)
(6) High plasma levels of vitamin C and E are associated with incident radiographic knee osteoarthritis by Chaganti RK1, Tolstykh I2, Javaid MK3, Neogi T4, Torner J5, Curtis J6, Jacques P7, Felson D4, Lane NE8, Nevitt MC9; Multicenter Osteoarthritis Study Group (MOST)(PubMed)
(7) Trade-offs between anti-aging dietary supplementation and exercise by Mendelsohn AR1, Larrick JW(PubMed)
(8) [The study of absorption efficiency and restoring effects of collagen and ascorbic acid on aged skin by fluorescence and reflection spectroscopy].[Article in Chinese] by Yang BW1, Lin YM, Wang SY, Yeh DC.(PubMed)
(9) Ascorbic acid enhances the expression of type 1 and type 4 collagen and SVCT2 in cultured human skin fibroblasts by Kishimoto Y1, Saito N, Kurita K, Shimokado K, Maruyama N, Ishigami A.(PubMed)
(10) Nanoscale gelatinase A (MMP-2) inhibition on human skin fibroblasts of Longkong (Lansium domesticum Correa) leaf extracts for anti-aging by Manosroi A1, Kumguan K, Chankhampan C, Manosroi W, Manosroi J.(PubMed)
(11) Benefits of combinations of vitamin A, C and E derivatives in the stability of cosmetic formulations by Gianeti MD1, Gaspar LR, Camargo FB Jr, Campos PM.(PubMed)
(12) Stability of vitamin C derivatives in topical formulations containing lipoic acid, vitamins A and E. by Segall AI1, Moyano MA.(PubMed)
(13) Topical activity of ascorbic acid: from in vitro optimization to in vivo efficacy by Raschke T1, Koop U, Düsing HJ, Filbry A, Sauermann K, Jaspers S, Wenck H, Wittern KP.(PubMed)
(14) Evaluation of a prescription strength 4% hydroquinone/10% L-ascorbic acid treatment system for normal to oily skin by Bruce S1, Watson J(PubMed)
(15) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)

(16) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)

Herbal Calendula and Neuroprotective effects

4. Herbal Calendula and Neuroprotective effects
Calendula is also known as pot marigold, a annual or perennial herbaceous plants of about 12–20 species of genus Calendula, belonging to the family Asteraceae, native to Southern Europe. It has been used in herbal medicine as spasmolytic, spasmogenic, inflammatory effects and to treat abdominal cramps, wound healing, skin diseases, colitis, constipation, etc.
Edema is a condition of accumulation of fluid in the interstitial spaces, causes of swelling in the feet, ankles and legs.

Ingredients
Beside major chemical constituents of triterpenoids, flavonoids, coumarines, quinones, volatile oil,carotenoids and amino acids, the herb also contains loliolide (calendin), calendulin and n-paraffins.
Neuro protective effect is defined of a protection against harmful of the brain.
In 3-NP-induced neurotoxicity in rats, Calendula officinalis Linn. flower extract (COE) showed asignificantly attenuated behavioral alterations, oxidative damage and striatal neuronal loss, probably through its antioxidant, anti-inflammatory and estrogenic properties(1). Monosodium glutamate (MSG) a popular flavour enhancer used in food industries may cause neurotoxicity if excess intake.
In neurotoxic mice induced by excess intake of MSG, the similar extract also significantly attenuated behavioral alterations, oxidative stress, and hippocampal damage(2)
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References
(1) Protective effect of Calendula officinalis Linn. flowers against 3-nitropropionic acid induced experimental Huntington's disease in rats by Shivasharan BD1, Nagakannan P, Thippeswamy BS, Veerapur VP, Bansal P, Unnikrishnan MK(PubMed)
(2) Protective Effect of Calendula officinalis L. Flowers Against Monosodium Glutamate Induced Oxidative Stress and Excitotoxic Brain Damage in Rats by Shivasharan BD, Nagakannan P, Thippeswamy BS, Veerapur VP(PubMed)

Phytochemical allicin and Osteosarcoma

Allicin is phytochemical containing sulfur in the class of organosulfur compound, found abundantly in onion and garlic.
Osteosarcoma is a bone cancer found mostly in teenagers and people over age 60.
The health benefits
Phytochemical compounds derived from garlic such as Allicin, diallyl thiosulfinate, have been drawn of interest in cancer treatment research. In the study of the effects of artesunate combined with allicin on osteosarcoma cell lines in vitro and in vivo, found that treatment with artesunate and allicin enhanced the synergistic effects on osteosarcoma cell proliferation and apoptosis. diallyl sulfide (DAS) derived from allicin, in the study of its effect on proliferation of human osteosarcoma MG-63 cells, showed to significantly suppress the growth of MG-63 tumor-bearing tissue. Immunohistochemistry in different concentrations (20 and 40 μg/mL) and decrease microvessel density (MVD) of MG-63 tumor-bearing tissue by suppressing the expression of Vascular endothelial growth factor (VEGF) mRNA.
References
(1) The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo by Jiang W, Huang Y, Wang JP, Yu XY, Zhang LY.(PubMed)
(2) Experimental study on inhibitory effects of diallyl sulfide on growth and invasion of human osteosarcoma MG-63 cells by Hu Y, Chen L, Yi C, Yang F, Chen J.(PubMed)

Wednesday 2 April 2014

Skin aging in Vitamin A points of view

Kyle J.Norton

Skin aging is one of most visible ageing process which occurs constantly in our skin organ. According to the Clinical Centre of Nis, certain plant extracts may have the ability to scavenge free radicals, to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin,  affect skin elasticity and tightness(a). Other suggested that free radicals induced domino effects in production of reactive oxygen species, can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system, leading  injuries damage regulation pathways of skin,  including wrinkles, roughness, appearance of fine lines, lack of elasticity, and de- or hyperpigmentation marks(b).
Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.

1. Retinols
Activation of both all-trans retinoic acid and 9-cis retinoic acid in nuclear retinoic acid receptors (RARα, RARβ, and RARγ), may associate to reduction of skin aging(1). In chronologically aged and photoaged human skin due to alternation of connective tissue collagen, caused by cysteine-rich protein 61(2) (CCN1, a negative regulator of collagen homeostasis). application of all-trans retinoic acid (RA), the major bioactive form of vitamin A in skin, significantly increased type I procollagen and reduced collagenase (matrix metalloproteinases-1, MMP-1)and suppressed recombinant human CCN1(3).
P-Dodecylaminophenol derived from the synthetic retinoid, in the skin of hairless mice study, exhibited the increased cytokeratin 16 expression which is essential in skin healing and maintenance, without causing the desquamation and erythema(4). In a vivo study in assessing major aging signs and performing three-dimensional profilometry and digital imaging during a 9-month double-blind placebo-control involving 48 volunteers, topical application of a ROL-containing product not only improved all major aging signs including wrinkles under the eyes, fine lines and tone evenness, but also promoted keratinocyte proliferation, induced epidermal thickening and alleviated skin aging signs, without any significant adverse reaction(5). Retinyl retinoate 1, another synthetic version of retinols, showed inhibitory activity against c-Jun than retinol and superior effects on collagen synthesis compared to retinol, and may have the potential to be conveniently used as an additive in cosmetics for prevention and improvement of skin aging and medicines for the treatment of skin troubles(6). Some researchers suggested that topical retinol improves fine wrinkles associated with natural aging, through its effects in induction of glycosaminoglycan, increased collagen production are most likely responsible for wrinkle effacement. Retinol-treated aged skin is more likely to withstand skin injury and ulcer formation along with improved appearance(7). Application of a stabilized 0.1% retinol-containing moisturizer showed the improving lines and wrinkles, pigmentation, elasticity, firmness and overall photodamage(8). N-retinoyl-D-glucosamine, a retinoic acid agonist in the study in comparison with retinol acid, showed the same effective of both in complete disappearance of the wrinkles caused by UVB irradiation probably via RAR transactivation activity, but the synthetic agonist showed no adverse effect in causing skin irritation(9).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin) and Retinal
 Carotenoids, plant pigments, converted to vitamin A after intake, though to play an important role in prevention and treatment of some diseases through it antioxidant effects.
Nutrition rich in carotenoids is best known to prevent cell damage, premature skin aging, and skin cancer(10). It has been reported to possess potent anti-oxidant properties and widely used in the skin care industry either as topically applied agents or oral supplements in an attempt to prolong youthful skin appearance(11)(12). Free radicals cause of premature skin aging and lead to immunosuppression and the formation of skin diseases, administration of carotenoids may interact with free radicals to enhance the protection system against that destructive(13). Other study suggested that Stress factors such as illness, UV and IR radiation of the sun, and smoking and alcohol consumption reduce the concentration of the carotenoids in the skin of that lead to deeper and denser of the furrows and wrinkles(14).
The testing of high doses of sun-emitted UV-radiation induce reactive oxygen species (ROS) as major pro-oxidants thus inducing premature skin aging, showed a positive effect of Carotenoid-tablets combined with placebo-cream in induced less carotenoid accumulation than carotenoid-tablets alone(15) of that suggested that In contrast to topical application, the systemically applied carotenoids are stored in the body fat tissue and slowly released onto the skin surface with sweat and sebum. Retinaldehyde (RAL) showed a significant improvement of wrinkles(forehead wrinkles, nasolabial folds, crow's feet and perioral wrinkles)(16). In fact, deficiency of vitamin A may result of induced premature aging. In skin of streptozotocin (STZ)-induced type 1 diabetic rats, showed over expression of matrix metalloproteinase -2 (MMP-2) and hyaluronidase (HAase) but not on vitamin A treated mice, through promoting the production of collagen in dermis and inducing cell growth and inhibition of epidermal differentiation in skin tissues(17).

Taken altogether, vitamin A and its variants are found to be effective in prevention of skin damage and skin aging caused by over expression of type I procollagen and under expression of collagenase (matrix metalloproteinases-1, MMP-1).
Recommended intakes of vitamin A, according to  the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity as causes of dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.


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References
(a) Skin ageing: natural weapons and strategies by Binic I1, Lazarevic V, Ljubenovic M, Mojsa J, Sokolovic D.(PubMed)
(b) Phytoconstituents as photoprotective novel cosmetic formulations by Saraf S1, Kaur CD.(PubMed)
(1)  40 years of topical tretinoin use in review by Baldwin HE1, Nighland M, Kendall C, Mays DA, Grossman R, Newburger J.(PubMed)
(2) Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin by Quan T1, He T, Shao Y, Lin L, Kang S, Voorhees JJ, Fisher GJ.(PubMed)
(3) Retinoids suppress cysteine-rich protein 61 (CCN1), a negative regulator of collagen homeostasis, in skin equivalent cultures and aged human skin in vivo by Quan T1, Qin Z, Shao Y, Xu Y, Voorhees JJ, Fisher GJ(PubMed)
(4) Effects of the aminophenol analogue p-Dodecylaminophenol on mouse skin by Takahashi N1, Fujiu Y(PubMed)
(5) Antiaging action of retinol: from molecular to clinical by Bellemère G1, Stamatas GN, Bruère V, Bertin C, Issachar N, Oddos T.(PubMed)
(6) Synthesis and in vitro biological activity of retinyl retinoate, a novel hybrid retinoid derivative by Kim H1, Kim B, Kim H, Um S, Lee J, Ryoo H, Jung H(PubMed)
(7) Improvement of naturally aged skin with vitamin A (retinol) by Kafi R1, Kwak HS, Schumacher WE, Cho S, Hanft VN, Hamilton TA, King AL, Neal JD, Varani J, Fisher GJ, Voorhees JJ, Kang S.(PubMed)
(8) A stabilized 0.1% retinol facial moisturizer improves the appearance of photodamaged skin in an eight-week, double-blind, vehicle-controlled study by Tucker-Samaras S1, Zedayko T, Cole C, Miller D, Wallo W, Leyden JJ.(PubMed)
(9) N-retinoyl-D-glucosamine, a new retinoic acid agonist, mediates topical retinoid efficacy with no irritation on photoaged skin by Kambayashi H1, Odake Y, Takada K, Funasaka Y, Ichihashi M, Kato S(PubMed)
(10) Influence of dietary carotenoids on radical scavenging capacity of the skin and skin lipids by Meinke MC1, Friedrich A, Tscherch K, Haag SF, Darvin ME, Vollert H, Groth N, Lademann J, Rohn S.(PubMed)
(11) Discovering the link between nutrition and skin aging by Schagen SK1, Zampeli VA, Makrantonaki E, Zouboulis CC.(PubMed)
(12) The role of nutraceuticals in anti-aging medicine by Vranesić-Bender D.(PubMed)
(13) Interaction between carotenoids and free radicals in human skin by Lademann J1, Schanzer S, Meinke M, Sterry W, Darvin ME(PubMed)
(14) Carotenoids in human skin by Lademann J1, Meinke MC, Sterry W, Darvin ME(PubMed)

(15) Dermal carotenoid level and kinetics after topical and systemic administration of antioxidants: enrichment strategies in a controlled in vivo study by Darvin ME1, Fluhr JW, Schanzer S, Richter H, Patzelt A, Meinke MC, Zastrow L, Golz K, Doucet O, Sterry W, Lademann J(PubMed)
(16) Retinaldehyde/hyaluronic acid fragments: a synergistic association for the management of skin aging by Cordero A1, Leon-Dorantes G, Pons-Guiraud A, Di Pietro A, Asensi SV, Walkiewicz-Cyraska B, Litvik R, Turlier V, Mery S, Merial-Kieny C(PubMed)
(17) A close relationship between type 1 diabetes and vitamin A-deficiency and matrix metalloproteinase and hyaluronidase activities in skin tissues by Takahashi N1, Takasu S.(PubMed)