Orally administered berberine ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting activation of PPAR-γ and subsequent expression of HGF in colons.

Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showed that either oral or rectal administration of berberine exhibited marked alleviation of bleomycin-induced PF in mice. In contrast, anti-PF activity of berberine disappeared when given by an intravenous injection, implying that it functioned in a gut-dependent manner. Moreover, berberine promoted both mRNA and protein levels of HGF and PTEN in colons, but only their protein levels in lungs of PF mice. In addition, SU11274 but not BPV abolished the anti-PF effect of berberine. In vitro, berberine preferentially induced expression of HGF in fibroblast cells than epithelial, preadipocyte and endothelial cells. Similarly, rosiglitazone and 15dPGJ2 also enhanced expression of HGF in fibroblasts cells, and GW9662 and siPPAR-γ diminished induction of berberine on HGF expression. Berberine could enter into the cytoplasm, activate PPAR-γ directly and synergistically with 15dPGJ2, as shown by an up-regulation of CD36 and aP2 mRNA expression, nuclear translocation and DNA-binding activity of PPAR-γ both in vitro and in vivo. Additionally, GW9662 almost abolished anti-PF effect of berberine and induction of HGF expression in colons. In conclusion, oral administration of berberine displays anti-PF action probably in a colon-dependent manner, and mechanisms involve activation of PPAR-γ and resultant promotion of HGF expression in colonic fibroblasts. The up-regulated HGF arrives in lung tissues via blood circulation to palliate PF.

Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

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 anti-arthritic 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.