Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Toxicol Appl Pharmacol. 2018 Mar 15;343:1-15. doi: 10.1016/j.taap.2018.02.001. Epub 2018 Feb 3.
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.
小檗碱经口给药时尽管其生物利用度极低，但已被证明可减轻肾间质、肝和心肌纤维化。在这里，我们根据肠内分泌系统检查了小檗碱对肺纤维化 (PF) 的影响，并探讨了其潜在机制。结果表明，无论是口服还是直肠给予小檗碱，均可显著缓解博莱霉素诱导的小鼠 PF。相比之下，小檗碱静脉注射给药时抗 PF 活性消失，表明其以肠道依赖的方式发挥作用。此外，小檗碱促进了 PF 小鼠结肠中 HGF 和 PTEN 的 mRNA 和蛋白水平，但仅促进了肺中的蛋白水平。此外，SU11274 但不是 BPV 消除了小檗碱的抗 PF 作用。体外，小檗碱优先诱导成纤维细胞中 HGF 的表达，而不是上皮细胞、前脂肪细胞和内皮细胞。同样，罗格列酮和 15dPGJ2 也增强了成纤维细胞中 HGF 的表达，GW9662 和 siPPAR-γ 减弱了小檗碱对 HGF 表达的诱导。小檗碱可以进入细胞质，直接激活 PPAR-γ，并与 15dPGJ2 协同作用，如体外和体内 CD36 和 aP2 mRNA 表达、PPAR-γ 的核转位和 DNA 结合活性的上调所示。此外，GW9662 几乎消除了小檗碱的抗 PF 作用和结肠中 HGF 表达的诱导。总之，口服小檗碱可能以结肠依赖的方式发挥抗 PF 作用，机制涉及激活 PPAR-γ 和随后促进结肠成纤维细胞中 HGF 的表达。上调的 HGF 通过血液循环到达肺组织以缓解 PF。
