N-retinoyl-D-glucosamine, a new retinoic acid agonist, mediates topical retinoid efficacy with no irritation on photoaged skin.

BACKGROUND: Chronic ultraviolet (UV) radiation from sunlight induces wrinkle formation. Retinoic acid (RA) can markedly improve wrinkles, although RA does have some side-effects, such as skin irritation. As the efficacy and cytotoxicity of RA has been traced to its free carboxylic acid, we synthesized a new molecule, N-retinoyl-D-glucosamine (GRA), in which a glucosamine has been attached to the polar end group of all-trans retinoic acid. OBJECTIVES: To analyse the effect of topical GRA in wrinkle repair and anti-irritation in photoaged mice compared with topical RA, as well as to determine retinoic acid receptor (RAR) and retinoid X receptor (RXR) transactivation activity in vitro. METHODS: Hairless mice were irradiated with 60 mJ cm-2 of UVB for 10 weeks, and then topically treated with 0.05% GRA or 0.05% RA for 8 weeks. An in vitro transcriptional assay was performed and the activity of GRA in 293 cells transfected with RAR-alpha or RXR-alpha expression plasmid and luciferase reporter plasmid then determined. RESULTS: Topical GRA and RA brought about almost complete disappearance of the wrinkles caused by UVB irradiation. The two ligands promoted both a wide repair zone histologically, and the expression of type 1 collagen in the skin. In contrast, topical GRA treatment did not produce irritation such as erythema or roughness, or alteration of transepidermal water loss values, compared with RA. In the in vitro luciferase assay, GRA resulted in significant dose-dependent RAR transactivation activity in a 100 times higher concentration range than RA. GRA did not mediate RXR transactivation activity at all. CONCLUSIONS: Topical GRA appears to be able to repair photoaged skin damage without any of the irritation caused by topical RA, probably via RAR transactivation activity.

Epidermal changes caused by chronic low-dose UV irradiation induce wrinkle formation in hairless mouse.

To investigate the effects of chronic low-dose UV irradiation on the skin, hairless mice were irradiated with a 1/3 minimal erythemal dose (MED) of UV. We examined the relationship between visible changes and skin damage in the dermis and epidermis. Hairless mice were irradiated with UVB (20 mJ/cm2) and UVA (14 J/cm2) three times a week for 10 weeks, followed by a 24-week non-irradiation period. Visible fine wrinkling was present after 4 weeks of irradiation, and the wrinkling progressively worsened throughout the period of irradiation. The wrinkles remained after irradiation was discontinued. In dermal components, no significant histological changes in the collagen fibers and elastic fibers were found, and the amount of hydroxyproline was also not changed. Thus, in the epidermis, there was a significant increase in the number of stratum corneum layers and the terminal-differentiation marker, filaggrin, positive cells. The intensity of staining for the differentiation marker, keratin 1, was reduced. These changes were accompanied by wrinkle formation, and remained after discontinuance of irradiation. These findings suggested that chronic low-dose UV irradiation induces structural and quantitative changes in the epidermis as a result of keratinization impairment, and that this damage in the epidermis is an important causative factor in wrinkle formation.

Coenzyme A stimulates collagen production in cultured fibroblasts; possible mechanisms in enzymatic and gene expression.

Coenzyme A, a cofactor in enzymatic acetyl transfer reactions, stimulates collagen production in cultured fibroblasts. The mechanisms involved in this collagen stimulation were investigated. Enzymatic studies using radiolabeled procollagen as substrate revealed that coenzyme A enhanced prolyl hydroxylase activity. Prolyl hydroxylase is a key enzyme in collagen synthesis acting by hydroxylation of proline residues in procollagen peptide, which is necessary for stabilizing collagen. Northern blot analysis demonstrated that coenzyme A also enhanced mRNA levels of both the alpha subunit of prolyl hydroxylase and the alpha1 chain of type I collagen. The levels of protein production of prolyl hydroxylase and type I collagen were also increased in cultured fibroblasts by coenzyme A, which correlated well with observations from Northern blotting. On the other hand, coenzyme A did not stimulate the activity nor the gene expression of two other processing enzymes: lysyl hydroxylase, which provides the sites for glycosylation and crosslinking between collagen peptides, and lysyl oxidase, a fundamental enzyme in intermolecular crosslinking. These results indicate that coenzyme A stimulates collagen production by at least two separate mechanisms: by enhancing prolyl hydroxylase activity as well as stimulating gene expression of the alpha subunit of this enzyme, and by stimulating gene expression of alpha1 chain of type I collagen.

Eudesmane derivatives from Tessaria integrifolia.

Five eudesmane-type sesquiterpenoids were isolated from the methanol extract of the aerial part of Tessaria integrifolia Ruiz. et Pavon (Compositae). Their structures were elucidated on the basis of spectroscopic analysis is well as chemical evidence.

[Antineoplastic effect of UFT therapy (uracil-FT-207 combination therapy) on experimental pancreatic cancer transplanted in the pancreas and subcutaneous region].

The pancreatic duct cell adenocarcinoma induced by di-isopropanol nitrosamine could be easily and repeatedly transplanted into the subcutaneous or pancreatic tissues of the homologous animals. We established a tumor bearing animal design in which tumor tissues were transplanted simultaneously into subcutaneous and pancreatic tissues. At the first week after the transplantation, the animals were divided into three groups: In FT group FT-207 was given at a dose of 15 mg/kg/day, in UFT group FT-207 and uracil were given at a dose of 3 mg/kg/day and; 6.7 mg/kg/day (molar ratio; 1:4), respectively and in control group a solvent of FT-207 was given. In all groups the drugs were administrated orally for ten days. The size of tumors transplanted in subcutaneous and pancreatic tissues increased more slowly in FT and UFT groups, as compared with that of control group. The inhibitory effect on tumor growth observed in UFT group was more striking than that in FT group. No major side effects were observed in all groups. At the fourth weeks after subcutaneous and intrapancreatic transplantation, the animals were divided into two groups: In FT group FT-207 was given at a dose of 30 mg/kg and in UFT group FT-207 and uracil were given at a dose of 30 mg/kg and 67.2 mg/kg, respectively. In both groups the drugs were given orally, and at one hour after the administration all the animals were killed to determine 5-FU concentration in various tissues. The 5-FU concentrations of subcutaneous and intrapancreatic transplanted tumor tissues were significantly higher in UFT group than those in FT group. UFT therapy, therefore, seems to be hopeful for the treatment of human pancreatic cancer.