补骨脂对肝脏的双重作用:肝保护还是肝毒性?

中药补骨脂(Psoraleae Fructus)为豆科植物补骨脂Psoralea corylifolia L.的干燥成熟果实,主要包含黄酮、香豆素、单萜酚和苯并呋喃类化合物,具有免疫调节、抗氧化、雌激素样等多种药理作用,临床广泛应用于治疗骨质疏松、白癜风、银屑病等。目前,越来越多的药理研究表明,补骨脂及其活性成分在肝脏疾病以及动物模型中具有保护肝细胞、改善肝功能的作用;但随着补骨脂及其相关制剂的临床广泛应用,以及药物不良反应监测体系的完善,补骨脂及其相关制剂引发肝脏损伤的不良反应案例报道越来越多,提示补骨脂及其相关制剂对肝脏可能具有双重作用,即既具有肝脏保护作用又具有肝毒性作用。本文总结了近年来有关补骨脂中单体成分、提取物及其相关制剂的肝保护以及肝毒性作用的研究,归纳了其直接肝毒性及其在不同病理条件下对肝脏的毒/效作用及机制,以期为补骨脂及其相关制剂临床适应症的开发以及安全应用提供理论依据。

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.However,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive relationship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

17β-Estradiol,through activating the G protein-coupled estrogen receptor,exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

A new perspective of triptolide-associated hepatotoxicity:the relevance of NF-κB and NF-κB-mediated cellular FLICE-inhibitory protein

Previously,we proposed a new perspective of triptolide(TP)-associated hepatotoxicity:liver hypersensitivity upon lipopolysaccharide(LPS)stimulation.However,the mechanisms for TP/LPSinduced hepatotoxicity remained elusive.The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation.TSF-αinhibitor,etanercept,was injected intraperitoneally into mice to investigate whether induction of TNF-αby LPS participated in the liver injury induced by TP/LPS co-treatment.Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-αto assess the function of TNF-αin TP/LPS co-treatment.Additionally,time-dependent MF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro.Finally,overexpression of cellular FLICEinhibitory protein(FLIP),the most potent NF-κB-mediated pro-survival protein,was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity.Etanercept counteracted the toxic reactions induced by TP/LPS.TP-treatment sensitized mice and hepatocytes to TNF-α,revealing the role of TNF-αin TP/LPS-induced hepatotoxicity.Mechanistic studies revealed that TP inhibited NF-κB dependent pro-survival signals,especially FLIP,induced by LPS/TNF-α.Moreover,overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-α-induced apoptosis in vitro.Mice and hepatocytes treated with TP were sensitive to TNF-α,which was released from LPS-stimulated immune cells.These and other results show that the TP-induced inhibition of NF-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.