Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity.

Propolis is commonly used in traditional Chinese medicine. Studies have demonstrated the therapeutic effects of propolis extracts and its major bioactive compound caffeic acid phenethyl ester (CAPE) on obesity and diabetes. Herein, CAPE was found to have pharmacological activity against nonalcoholic fatty liver disease (NAFLD) in diet-induced obese mice. CAPE, previously reported as an inhibitor of bacterial bile salt hydrolase (BSH), inhibited BSH enzymatic activity in the gut microbiota when administered to mice. Upon BSH inhibition by CAPE, levels of tauro-ß-muricholic acid were increased in the intestine and selectively suppressed intestinal farnesoid X receptor (FXR) signaling. This resulted in lowering of the ceramides in the intestine that resulted from increased diet-induced obesity. Elevated intestinal ceramides are transported to the liver where they promoted fat production. Lowering FXR signaling was also accompanied by increased GLP-1 secretion. In support of this pathway, the therapeutic effects of CAPE on NAFLD were absent in intestinal FXR-deficient mice, and supplementation of mice with C16-ceramide significantly exacerbated hepatic steatosis. Treatment of mice with an antibiotic cocktail to deplete BSH-producing bacteria also abrogated the therapeutic activity of CAPE against NAFLD. These findings demonstrate that CAPE ameliorates obesity-related steatosis at least partly through the gut microbiota-bile acid-FXR pathway via inhibiting bacterial BSH activity and suggests that propolis enriched with CAPE might serve as a promising therapeutic agent for the treatment of NAFLD.

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.

BACKGROUND: Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance. METHODS: Suppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs). RESULTS: Sulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC50 superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2. CONCLUSIONS: Our study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.

Small molecular floribundiquinone B derived from medicinal plants inhibits acetylcholinesterase activity.

Being a neurodegenerative disorder, Alzheimer's disease (AD) is the one of the most terrible diseases. And acetylcholinesterase (AChE) is considered as an important target for treating AD. Acetylcholinesterase inhibitors (AChEI) are considered to be one of the effective drugs for the treatment of AD. The aim of this study is to find a novel potential AChEI as a drug for the treatment of AD. In this study, instead of using the synthetic compounds, we used those extracted from plants to investigate the interaction between floribundiquinone B (FB) and AChE by means of both the experimental approach such as fluorescence spectra, ultraviolet-visible (UV-vis) absorption spectrometry, circular dichroism (CD) and the theoretical approaches such as molecular docking. The findings reported here have provided many useful clues and hints for designing more effective and less toxic drugs against Alzheimer's disease.

Mechanism-based anti-anxiety effects of polysaccharides extracted from shudihuang (radix rehmanniae preparata) by two-dimensional electrophoresis analysis in rat hippocampus proteins.

OBJECTIVE: To investigate mechanism-based anti-anxiety effects of Shudihuang (Radix Rehmanniae Preparata) polysaccharides (RRPPs) through two-dimensional electrophoresis (2-DE) analysis with mass spectrometry (MS) of hippocampus proteins in rats treated with monosodium L-glutamate (MSG). METHODS: MSG (4 g/kg) or normal saline (NS) was injected subcutaneously into infant male rats on days 2, 4, 6, 8, 10 after birth. MSG-treated rats at 8 weeks old were given NS, diazepam, or RRPPs daily for seven consecutive days by intragastric administration, while NS-treated rats given the same volume of NS. Elevated plus maze (EPM) and light/dark transition (LDT) tests were used to observe anti-anxiety effects of RRPPs at 1 h after the last administration. After EPM and LDT tests, hippocampus tissues were excised on ice rapidly from the brains of rats. Thereafter, 2-DE and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) were used for detecting differential proteins in hippocampus of rats so as to explore the potential mechanisms. RESULTS: RRPPs (200, 400 mg/kg) could significantly inhibit MSG-induced decrease of time and entries percentages in open zones in EPM test and numbers of light-dark transition in LDT test. Further analysis of 2-DE and MALDI-TOF/MS indicated that beta-synuclein, protein DJ-1, peroxiredoxin-2, peroxiredoxin-6, dimethylarginine dimethylaminohydrolase 1 (DDAH-1) and iron-sulfur proteins were all found to be down-regulated significantly in MSG-treated rats, while such down-regulation was significantly inhibited after treatment with RRPPs. CONCLUSION: RRPPs showed anti-anxiety effects and potential mechanisms might be related to inhibiting MSG-induced down-regulation of beta-synuclein, DJ-1, peroxiredoxin-2, peroxiredoxin-6, DDAH-1 and iron-sulfur proteins in hippocampus of rats.

Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

[Effect of lactuside B on the expression of bcl-2 and bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury].

This study is to investigate the effect of the major chemical composition in rhizome of Pterocypsela elata, lactuside B, on expression of bcl-2, bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury. First, middle cerebral artery ischemia-reperfusion injury model was established, and each group was treated with the corresponding medicines. Animals were separately sacrificed at 24 h and 72 h. The brain infarct volumes were detected by TTC dye, bcl-2 and bax mRNA expression was checked by RT-PCR, and the proteins of bcl-2 and bax were explored by two-step immunohistochemistry in cerebral cortex of rats. Lactuside B can reduce brain infarct volume of cerebral cortex of rats, increase the expression of bcl-2 mRNA and decrease that of bax mRNA. Moreover, the ratio of bcl-2 to bax mRNA is higher in 12.5 and 25 mg kg(-1) dose group, respectively, which is significantly different from that of model group (P < 0.05 or P < 0.01). Generally, either 12.5 or 25 mg kg(-1) dose group is better than positive control medicine nimodipine (P < 0.05 or P < 0.01). In addition, the expression of bcl-2 and bax protein is consistent with their gene expression. Infarct volume and the ratio of bcl-2 to bax mRNA expression are significantly different (P < 0.05 or P < 0.01) between 72 h and 24 h group. The results demonstrated that lactuside B could play a good role in resisting cerebral ischemia by upregulating the expression of bcl-2 mRNA and protein and downregulating that of bax mRNA and protein.