Arch Pharm Res
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Aging is a key risk factor for many diseases, understanding the mechanism of which is becoming more important for drug development given the fast-growing aging population. In the course of our continued efforts to discover anti-aging natural products, the active constituent 6-shogaol was isolated from Zingiber officinale Roscoe. The chemical structure of 6-shogaol was identified by comparison of its NMR data with literature values. ⋯ Mechanism of such action was investigated using C. elegans models, suggesting that 6-shogaol is capable of increasing stress tolerances via enzyme induction. The proposed mechanism was further supported by observation of the increase in SOD and HSP expressions upon treatment with 6-shogaol in transgenic strains of C. elegans which contain GFP-based reporters. In addition, the mechanism was elaborated by confirming that the effect observed for 6-shogaol is independent from other aging-related factors that are known to affect the aging process of C. elegans.
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Clinical Trial
Development of a column-switching LC-MS/MS method of tramadol and its metabolites in hair and application to a pharmacogenetic study.
Hair is a valuable specimen for monitoring long-term drug use. Tramadol is an effective opioid analgesic but is associated with risks such as drug dependence and unexpected toxicity arising from genetic differences in metabolism. However, few studies have been performed on the distribution of tramadol and its metabolites in hair. ⋯ The (mean) concentrations of O-desmethyltramadol (ODMT) and N,O-didesmethyltramadol (NODMT) in the CYP2D6*10/*10 and CYP2D6*5/*5 groups were lower than those in the CYP2D6*wt/*wt group, while the (mean) concentrations of N-desmethyltramadol (NDMT) were higher. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT were well correlated with the CYP2D6 genotypes. The developed method was successfully applied to the clinical study, which demonstrated that the concentrations of a drug and its metabolites in hair were dependent on the polymorphism of its metabolizing enzyme.
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Tramadol is a centrally acting synthetic opioid analgesic and has received special attention due to its abuse potential and unexpected responses induced by CYP2D6 polymorphism. Oral fluid is an advantageous biofluid for drug analysis due to non-invasive sampling and high correlation of drug concentrations with plasma. However, few studies have been performed on distribution of tramadol and its metabolites in oral fluid. ⋯ Pharmacokinetic parameters, such as Css,max and AUC0-τ of tramadol, NDMT and NODMT, in the CYP2D6*10/*10 group were significantly higher than those in the CYP2D6*wt/*wt group. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT correlated well with the CYP2D6 genotypes. We demonstrated that oral fluid is a promising biofluid for pharmacokinetic evaluation in relation to genetic variations.
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The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. ⋯ Furthermore, we also predicted the docking interactions of HRAR with coumarins 1-7 using AutoDock Vina, and as a result, the simulated enzyme-inhibitor complexes exhibited negative binding energies (Autodock Vina = - 9.6 to - 8.1 kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. Our results clearly indicate the potential HRAR and AGE formation inhibitory activities of dihydroxanthyletin-type coumarins, which could be further explored to develop therapeutic modalities for the treatment of diabetes and related complications.
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Ten caffeic acid derivatives (1-10) were isolated from the roots of Salvia miltiorrhiza by using various chromatographic methods and their chemical structures were spectroscopically elucidated. The absolute configurations of chiral centers were determined by comparison with reported coupling constants, optical rotation values, and CD techniques. Anti-inflammatory activities were evaluated using nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 inhibition assays, and by determining the expression of heme oxygenase (HO)-1. ⋯ Compounds 2 and 3 inhibited NO production with IC50 values of 1.4 and 0.6 μM, respectively. These compounds also strongly inhibited the production of iNOS and COX-2. In addition, compound 3 induced the expression HO-1 in a concentration-dependent manner at 0.1, 0.3, and 1.0 μM.