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Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene) was first identified from white hellebore (Veratrum grandiflorum) root and began to attract interest when its presence in red wine and cardiovascular activities were reported, leading to speculation of its contribution to the 'French paradox'. Besides the cardiovascular protection, potential health benefits of resveratrol include calorie restriction-like effects, cancer prevention and adjunctive therapy, and neuroprotection. In order to achieve translational applications of these potential benefits, pharmacokinetic research was performed for plasma pharmacokinetics and related disposition of orally dosed resveratrol. This paper summarizes the known human pharmacokinetic characteristics of resveratrol after oral administration and various attempts to improve its systemic exposure level from the perspectives of systemic exposure and in vivo process. However, available pharmacokinetic data of resveratrol has raised conundrums that limit translating potential benefits to clinics: (1) differences between the unchanged resveratrol used in bioactivity studies and its major circulating forms (i.e., metabolites) after dosing; (2) resveratrol's test concentrations used to exert in vitro bioactivities related to the benefits significantly higher than the compound's clinically achievable concentrations; (3) resveratrol's concentrations achievable (estimated from the pharmacokinetics) from doses used to produce in vivo efficacy significantly lower than the effective concentrations found in studies of related action mechanism (suggesting unreliability of test mechanism). In the last part of this review, we provide recommendations for future pharmacokinetic investigations of resveratrol, including a more systematic investigation of systemic exposure to resveratrol metabolites, their access to in vivo loci responsible for the benefits, and their disposition in target cells; an investigation of colon-luminal exposure to resveratrol and its metabolites for accessing colonic microbiota; and a multi-compound pharmacokinetic investigation of red wine.
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Objective@#To quantitatively detect CD44 expression in patients with nonalcoholic fatty liver disease (NAFLD) for comparative analysis.@*Methods@#Patients with chronic liver diseases accompanied with or without NAFLD, including chronic hepatitis B, cirrhosis and hepatocellular carcinoma after chronic hepatitis B, and healthy blood donors as normal controls who admitted to the Affiliated Hospital of Nantong University from May to October 2018 were selected. The proportion of CD44 positive cells was analyzed by flow cytometry. CD44 level was quantified by an enzyme-linked immunosorbent assay, and the biochemical indicators such as serum aspartate aminotransferase, alanine aminotransferase activity, total cholesterol and triglyceride were routinely analyzed. The cancerous and adjacent cancerous tissues of patients accompanied with or without NAFLD were collected by self-matching method and analyzed by immunoblotting and histochemistry and compared by CD44 integrated optical density. Image-Pro Plus version 6.0, Image J, GraphPad Prism 5.0, Photoshop, Microsoft Excel and IBM SPSS statistics 23 were used to analyze and draw pictures. An independent sample t-test was used to compare the differences between groups.@*Results@#Patients accompanied with NAFLD had hepatocyte injury and dyslipidemia. NAFLD and chronic liver disease patients had significantly elevated serum CD44 levels than normal control group (P < 0.01). CD44 positive lymphocyte ratio was 78.19 % ± 16.33 % in NAFLD patients and 68.47% ± 20.91% in chronic hepatitis B group, which was higher than the control group (46.51% ± 20.52%). Chronic hepatitis B group with steatosis had significantly higher CD44 concentration (181.42 ± 49.36) ng/ml than chronic hepatitis B group (142.52 ± 53.87) ng/ml and normal control group (99.47 ± 15.23) ng/ml. CD44/GAPDH ratio in the liver cancer group (1.306 ± 0.614) was significantly higher than paracancerous group (0.477 ± 0.291) and the difference between the two groups was statistically significant (t = 3.451, P = 0.004). The integrated optical density of CD44 in the NAFLD-related liver cancer and paracancerous group were 25.721 ± 5.881 and 14.155 ± 4.001 and the difference between the groups was statistically significant (t = 14.544, P < 0.001). The pathological features of high expression of CD44 in patients with hepatocellular carcinoma were significantly correlated with HBV infection, tumor size, single/multi-center, and lymph node metastasis, degree of differentiation, TNM grade, Child-Pugh score, portal vein tumor thrombus and extrahepatic metastasis. HCC patients with NAFLD had significantly higher serum CD44 (234.62 ± 69.40) ng/ml than patients without NAFLD (186.49 ± 58.89) ng/ml (t = -3.191, P = 0.002), but there was no statistically significant difference in the clinicopathological characteristics between the high/low CD44 groups of HCC patients with NAFLD.@*Conclusion@#The results suggest that CD44 is abnormally activated and its mechanism may play an important role in the progression of NAFLD.
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Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.
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Objective To investigate the effects of capparis spinosa total alkaloid on type collagen (ColⅣ - ),Ⅳmatrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in bleomycin-induced systemic sclerosis (SSc) mice; To explore the effective mechanism of capparis spinosa total alkaloid on fibrosis of SSc. Methods Totally 90 BALB/c mice were randomly divided into control group, model group, penicillamine group and capparis spinosa total alkaloid low-, medium- and high-dose group. Mice models with SSc were established by repeated local injections of bleomycin in mice back, except for the control group. Mice in medication groups received external application with capparis spinosa total alkaloid cream;mice in penicillamine group were given penicillamine for gavage; mice in the control and model group received external application without substance, one time a day, for 60 days. The contents of MMP-9, TIMP-1 and PAI-1 in serum and Col- in skin tissue were dⅣ etected respectively by ELISA after the last medication. Results Compared with the model group, the levels of MMP-9 and ratio of MMP-9/TIMP-1 markedly increased and the levels of Col-Ⅳand TIMP-1 markedly decreased in medium and high- dose of capparis spinosa total alkaloid group (P0.05). Conclusion Capparis spinosa total alkaloid is effective in treating fibrosis of SSc by adjusting imbalance of MMP-9/TIMP-1 and decreasing expression of Col-Ⅳ.
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Objective To investigate the effects of capparis spinosa total alkaloid on the pathological changes and the type Ⅲ collagen(COL?Ⅲ)expression in systemic sclerosis(SSc)mice. Methods Mice models with SSc were established by repeated local injection of bleomycin in BALB/c mice back. After administration of capparis spinosa total alkaloid ,the pathological changes of skin and lung tissue were observed ,and the COL?Ⅲ expression was detected by ELISA. Results Compared with the model group,the inflammation and fibrosis of skin and lung tissue were improved,and the level of COL?Ⅲ was markedly reduced by treatment of high dose capparis spinosa total alkaloid(P<0.05). Conclusion Cap?paris spinosa total alkaloid is effective in treating fibrosis of SSc.
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Objective To investigate the gene expressions of IL-1 and TNF-? in bronchoalveolar lavage fluid(BALF) and lung tissues in mice with pulmonary fibrosis(PF) at various periods and to study the effects of cytokines on pulmonary fibrosis.Methods Forty male mice were randomly divided into two groups:experimental group(n=30) and control group(n=10),and poured respectively by bleomycin solutions and saline and killed on the 3rd,7th,14th,28th and 56th day.RT-PCR method was used to analyse the mRNA expressions of IL-1 and TNF-?.Results ① The expressions of IL-1 mRNA and TNF-? mRNA in BALF in experimental group were higher than those in control group(P
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Objective:To investigate the distribution and expression of the cyclooxygenase-2(COX-2)in lung tissues and the effect of its inhibition in bleomycin(BLM)-induced pulmonary fibrosis in rats.Methods:72 male SD rats were randomly divided into three groups:the control group,model group and celecoxib group.Immunohistochemical method was used to detect the distribution of COX-2 in the stage of acute pulmonary alveolitis.HE and Masson staining methods were used to evaculate the degree of alveolitis and pulmonary fibrosis.Results:(1)In early stage of pulmonary fibrosis except in the control group,COX-2 expression was found in small bronchial epithelial cells in the other two groups,especially the model group.(2)Compared with the control group,the other two groups had alveolitis(P
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Objective:To assess human leucocyte antigen(HLA)-DRB1 allele polymorphism and analyze the association between DRB1 allele polymorphism and clinical classification of ulcerative colitis.Methods:60 patients were investigated for DRB1 gene by DNA microarray.The results were compared with those from healthy subjects.Results:The frequency of DR2 and DRB1*15 in UC patients were 45% and 41.7% respectively,which were significantly higher than those(23.3% and 21.7%)in controls,the odds ratio being 2.688 and 2.582 respectively(P
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Objective To study isolation and identification and culture of rat type A spermatogonial cells in vitro.Methods Percoll discontinue density gradient centrifugation combined with different speeds of different cells adhering to dish was used to purify the type A spermatogonial cells.The c-kit and TERT special antibodies were used to identify the type A spermatogonial cells.The purified cells were cultured in vitro. Results 0.614?10~6 cells per testis finally were obtained and the percentage of viable cells was 92.1% by trypan blue dye exclusion test.The percentage of type A spermatogonial cells expressing c-kit and TERT were 91.7?1.2% and 90.8?1.0% respectively.Type A spermatogonial cells could proliferate and self-renew in the DMEM containing 10% NBS.Conclusion Percoll discontinue density gradient centrifugation combined with different speeds of different cells adhering to dish is an efficiency method for isolation of rat type A spermatogonial cells.The purified cells are type A spermatogonial cells by identification of the immunohistochemistry of c-kit and TERT antibodies.Type A spermatogonial cells can proliferate and self-renew in vitro.