Simiao Fan

Bile acids has gradually become a new focus in various diseases, and ASBT as a transporter responsible for the reabsorption of ileal bile acids, is a key hinge associated to the bile acids-cholesterol balance and bile acids of enterohepatic circulation. The cumulative studies have also shown that ASBT is a promising target for treatment of liver, gallbladder, intestinal and metabolic diseases. This article briefly reviewed the process of bile acids enterohepatic circulation, as well as the regulations of ASBT expression, covering transcription factors, nuclear receptors and gut microbiota. In addition, the relationship between ASBT and various diseases were discussed in this paper. According to the structural classification of ASBT inhibitors, the research status of ASBT inhibitors and potential ASBT inhibitors of traditional Chinese medicine (such resveratrol, jatrorrhizine in Coptis chinensis) were summarized. This review provides a basis for the development of ASBT inhibitors and the treatment strategy of related diseases.

Heart failure is a common systemic disease with high morbidity and mortality worldwide. Doxorubicin (DOX) is a commonly used anthracycline broad-spectrum antitumor antibiotic with strong antitumor effect and definite curative effect. However, cardiotoxicity is the adverse reaction of drug dose cumulative toxicity, but the mechanism is still unclear. In this study, proteomics and metabonomics techniques were used to analyze the tissue and plasma of DOX-induced heart failure (HF) in rats and to clarify the molecular mechanism of the harmful effects of DOX on cardiac metabolism and function in rats from a new point of view. The results showed that a total of 278 proteins with significant changes were identified by quantitative proteomic analysis, of which 118 proteins were significantly upregulated and 160 proteins were significantly downregulated in myocardial tissue. In the metabonomic analysis, 21 biomarkers such as L-octanoylcarnitine, alpha-ketoglutarate, glutamine, creatine, and sphingosine were detected. Correlation analysis showed that DOX-induced HF mainly affected phenylalanine, tyrosine, and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, phenylalanine metabolism, biosynthesis of unsaturated fatty acids, and other metabolic pathways, suggesting abnormal amino acid metabolism, fatty acid metabolism, and glycerol phospholipid metabolism. It is worth noting that we have found the key upstream target of DOX-induced HF, PTP1B, which inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc, and AK4 proteins lead to oxidative stress. Therefore, we think that PTP1B may play an important role in the development of heart failure induced by doxorubicin and can be used as a potential target for the treatment of heart failure.

Silibinin, as the major active constituent of silymarin, has its various biological effects. Here, we investigated the inhibitory effects of silibinin on HeLa cell growth in relation to autophagy and apoptosis induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. Silibinin dose and time-dependently decreased cell growth cultured in medium containing 10% fetal bovine serum or in serum free media (SFM) with an IC(50) of approximately 80-100 and 40-60 μM at 24 h, respectively. Silibinin induced autophagy at 12 h, confirmed by monodansylcadervarine (MDC) staining and up-regulation of beclin-1, and induced apoptosis at 24 h, detected by observation of apoptotic bodies and activation of caspase-3. 3-methyladenine (3-MA) inhibited silibinin-induced autophagy and attenuated the silibinin's inhibitory effect on cell viability, suggesting that autophagy enhanced silibinin-induced cell death. Silibinin increased ROS levels at 12 h, and ROS scavenger, N-acetylcysteine (NAC), significantly reversed the cytotoxicity of silibinin through inhibiting both autophagy and apoptosis. Specific antioxidants were applied and results indicated that hydroxyl radical (·OH) was the major ROS induced by silibinin, and OH scavenger glutathione (GSH) inhibited apoptosis and autophagy. Silibinin also generated RNS production in the cells at 12 h. High concentration of N omega-nitro-l-arginine methyl ester (L-NAME) as nitric oxide synthase (NOS) inhibitor attenuated the cytotoxicity of silibinin by decreasing ROS levels, leading to down-regulation of apoptosis. Silibinin also could interrupt the respiring functions of mitochondria, leading to ROS production and oxidative damage.

Silibinin is an active constituent extracted from blessed milk thistle (Silybum marianum). Our previous study demonstrated that silibinin induced autophagy and apoptosis via reactive oxygen species (ROS) generation in HeLa cells. In this study, we investigated whether the autophagy- and apoptosis-associated molecules also involved in ROS generation. Silibinin promoted the expression phosphorylated-p53 (p-p53) in a dose-dependent manner. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced ROS production and reversed silibinin's growth-inhibitory effect. The ROS scavenger N-acetyl cysteine (NAC) attenuated silibinin-induced up-regulation of p-p53 expression, suggesting that p53 might be regulated by ROS and forms a positive feedback loop with ROS. On the other hand, silibinin dose-dependently promoted the expression of phosphorylated-c-Jun N-terminal kinase (p-JNK). Inhibition of JNK by SP600125 decreased ROS generation. NAC down-regulated the expression of p-JNK, indicating that JNK could be activated by ROS. Activation of p53 was suppressed by SP600125 and expression of p-JNK was inhibited by PFT-α, therefore silibinin might activate a ROS-JNK-p53 cycle to induce cell death. Silibinin up-regulated the PUMA and Bax expressions and down-regulated the mitochondrial membrane potential (MMP) level. PFT-α reduced the expression of PUMA and Bax. These results showed that p53 could interfere with mitochondrial functions such as MMP via PUMA pathways, thus resulting in ROS generation. In order to elucidate the functions of p53 in silibinin induced ROS generation, we have chosen the A431 cells (human epithelial carcinoma) because they lack p53 activity (p53His273 mutation). Interestingly, silibinin did not up-regulate the ROS level in A431 cells but lower the ROS level. PFT-α had no influence on ROS level in A431 cells. p53 activation plays a crucial role in silibinin induced ROS generation.