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Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its antiarthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg kg-1, i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. [ABSTRACT FROM AUTHOR]

Tripterygium wilfordii (TW) preparations have been utilized in China for treating rheumatoid arthritis and autoimmune diseases. However, their clinical use is limited due to reproductive toxicity, notably premature ovarian failure (POF). Our study aimed to investigate the effect and mechanism of bergenin in attenuating POF induced by triptolide in mice. POF was induced in female ICR mice via oral triptolide administration (50 μg/kg) for 60 days. Mice received bergenin (25, 50, 100 mg/kg, i.g.) or estradiol valerate (EV) (0.1 mg/kg, i.g.) daily, 1 h before triptolide treatment. In vitro , ovarian granulosa cells (OGCs) were exposed to triptolide (100 nM) and bergenin (1, 3, 10 μM). Antioxidant enzyme activity, protein expression, apoptosis rate, and reactive oxygen species (ROS) levels were assessed. The results showed that triptolide-treated mice exhibited evident atrophy, along with an increase in atretic follicles. Bergenin (50, 100 mg/kg) and EV (0.1 mg/kg), orally administered, exerted significant anti-POF effect. Bergenin and EV also decreased apoptosis in mouse ovaries. In vitro , bergenin (1, 3, 10 μM) attenuated triptolide-induced OGCs apoptosis by reducing levels of apoptosis-related proteins. Additionally, bergenin reduced oxidative stress through downregulation of antioxidant enzymes activity and overall ROS levels. Moreover, the combined use with Sh-Nrf2 resulted in a reduced protection of bergenin against triptolide-induced apoptosis of OGCs. Together, bergenin counteracts triptolide-caused POF in mice by inhibiting Nrf2-mediated oxidative stress and preventing OGC apoptosis. Combining bergenin with TW preparations may effectively reduce the risk of POF. [Display omitted] Bergenin can attenuate triptolide-induced premature ovarian failure in mice. Bergenin functions by inhibiting the apoptosis of ovarian granulosa cells (OGCs). Bergenin inhibits the apoptosis of OGCs through down-regulating oxidative stress. Bergenin down-regulates oxidative stress via activation of Nrf2. [ABSTRACT FROM AUTHOR]

Abstract: The present study determined the anti-inflammatory activity of scopoletin in gout air pouch model and revealed the underlying mechanisms by in vitro assays. Monosodium urate (MSU) crystal-induced inflammation in mouse air pouch model, an experimental model for acute gout, was used to assess the efficacy of scopoletin. The neutrophil and mononuclear phagocyte numbers and MPO levels were increased significantly six hours after MSU crystal injection into the air pouch, whereas these changes were inhibited substantially upon scopoletin (100 and 200mg/kg, i.p.) treatment. To get insight into the underlying mechanisms, the in vitro studies were performed to investigate the effects of scopoletin on activation of macrophages and resultant production of inflammatory mediators. The secretions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and nitric oxide (NO) were elevated in MSU crystal-stimulated RAW 264.7 cells, and scopoletin (30–300μM) suppressed the production of all mediators. Moreover, RT-PCR assay and western blot analysis indicated that scopoletin regulated the transcriptional level of these mediators via suppression of NF-κB activation and blockade of MAPK signal pathway. Thus, the results clearly indicated that scopoletin inhibited the monosodium urate crystal-induced inflammation both in vivo and in vitro. In combination with our previous findings that scopoletin shows hypouricemic, anti-angiogenesis and pro-apoptotic activities, this compound may be a potential agent for gout therapy and could serve as a structural base for developing new drugs. [Copyright &y& Elsevier]

The crude powder of the fruit of Arctium lappa L. (ALF) has previously been reported to attenuate experimental colitis in mice. But, its main effective ingredient and underlying mechanisms remain to be identified. In this study, ALF was extracted with ethanol, and then successively fractionated into petroleum ether, ethyl acetate, n -butanol and water fraction. Experimental colitis was induced by dextran sulfate sodium (DSS) in mice. Among the four fractions of ALF, the ethyl acetate fraction showed the most significant inhibition of DSS-induced colitis in mice. The comparative studies of arctigenin and arctiin (the two main ingredients of ethyl acetate fraction) indicated that arctigenin rather than arctiin could reduce the loss of body weight, disease activity index and histological damage in the colon. Arctigenin markedly recovered the loss of intestinal epithelial cells (E-cadherin-positive cells) and decreased the infiltration of neutrophils (MPO-positive cells) and macrophages (CD68-positive cells). Arctigenin could down-regulate the expressions of TNF-α, IL-6, MIP-2, MCP-1, MAdCAM-1, ICAM-1 and VCAM-1 at both protein and mRNA levels in colonic tissues. Also, it markedly decreased the MDA level, but increased SOD activity and the GSH level. Of note, the efficacy of arctigenin was comparable or even superior to that of the positive control mesalazine. Moreover, it significantly suppressed the phosphorylation of MAPKs and the activation of NF-κB, including phosphorylation of IκBα and p65, p65 translocation and DNA binding activity. In conclusion, arctigenin but not arctiin is the main active ingredient of ALF for attenuating colitis via down-regulating the activation of MAPK and NF-κB pathways. [ABSTRACT FROM AUTHOR]

Abstract: Madecassoside is the highest amount of triterpene constituent in Centella asiatica herbs, a frequently prescribed crude drug in southeastern Asian and China for wound healing and scar management. The present study aimed to investigate the therapeutic potential and underlying mechanisms of madecassoside on collagen II (CII)-induced arthritis (CIA) in mice. Madecassoside (10, 20 and 40mg/kg), orally administered from the day of the antigen challenge for twenty consecutive days, dose-dependently alleviated the severity of the disease based on the reduced clinical scores, and elevated the body weights of mice. Histopathological examination indicated that madecassoside alleviated infiltration of inflammatory cells and synovial hyperplasia as well as protected joint destruction. Moreover, madecassoside reduced the serum level of anti-CII IgG, suppressed the delayed type hypersensitivity against CII in ears, and moderately suppress CII-stimulated proliferation of lymphocytes from popliteal lymph nodes in CIA mice. In vitro, madecassoside was ineffective in the activation of macrophages caused by lipopolysaccharide. It was concluded that madecassoside substantially prevented mouse CIA, and might be the major active constituent of C. asiatica herbs responsible for clinical uses for rheumatoid arthritis. The underlying mechanisms of action may be mainly through regulating the abnormal humoral and cellular immunity as well as protecting joint destruction. [Copyright &y& Elsevier]