Effects of the synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 on type 2 diabetes mellitus rats.

Many synbiotics are effective for the prevention and treatment of type 2 diabetes mellitus (T2DM). In the treatment of T2DM, synbiotics often regulate the composition of intestinal flora, which autoinducer-2 (AI-2) may play an important role. Whether the changes of intestinal flora are related to AI-2 during synbiotics treatment of T2DM is a topic worth studying. We elucidated the effects of synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 (SML) on T2DM rats. Male Spraque-Dawley rats were injected intraperitoneally with streptozotocin (STZ) and randomly grouped. After that, biochemical parameters, intestinal flora, fecal AI-2, and intestinal colonization of L. reuteri were detected. The results showed that SML had a hypoglycemic effect and mitigated the organ lesions of the liver and pancreas. Also, SML regulated biochemical parameters such as short chain fatty acids (SCFAs), lipopolysaccharides (LPS), intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor-α (TNF-α). On the other hand, the proportion of probiotics, such as Lactobacillus acidophilus, L. reuteri, Bifidobacterium pseudolongum, Lactobacillus murinus, and Lactobacillus johnsonii, were elevated by the treatment of SML. In addition, SML promoted the colonization and proliferation of L. reuteri in the gut. Another thing to consider was that AI-2 was positively correlated with the total number of OTUs sequences and SML boosted AI-2 in the gut. Taken together, these results supported that SML may modulate intestinal flora through AI-2 to treat T2DM. This study provided a novel alternative strategy for the treatment of T2DM in future.

TRIM59 promotes steatosis and ferroptosis in non-alcoholic fatty liver disease via enhancing GPX4 ubiquitination.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease around the world. However, no specific medicine has been approved for NAFLD treatment. Our study was conducted to explore the role and mechanism of TRIM59 in NAFLD, aiming to provide a novel target for NAFLD treatment. Here, the expression of TRIM family members was detected in 10 mild and severe NAFLD tissues as well as 10 normal tissues. TRIM59 expression was verified in 10 normal tissues and 25 mild and severe NAFLD tissues. Palmitic acid and high-fatty diet were used for the construction of NAFLD models. Oil Red O staining was used to detect the level of steatosis. The content of TNF-α, IL-6, and IL-8 was measured to reflect the level of inflammation. Lipid reactive oxygen species was estimated by flow cytometry. We found that TRIM59 was highly expressed in NAFLD tissues compared with normal liver tissues. The inhibition of TRIM59 could inhibit the steatosis and inflammation in NAFLD, whereas its overexpression exhibited reversed effects. The application of ferroptosis inhibitor, deferoxamine, could markedly ameliorate steatosis and inflammation, which was mediated by overexpressed TRIM59. Besides, TRIM59 was demonstrated to interact with GPX4 and promoted its ubiquitination. The overexpression of GPX4 could significantly reverse the pathogenic effects of TRIM59 in NAFLD. Additionally, the inhibition of TRIM59 appeared to be a promising strategy to ameliorate NAFLD in mice model. In summary, our study revealed that TRIM59 could promote steatosis and ferroptosis in NAFLD via enhancing GPX4 ubiquitination. TRIM59 could be a potential target for NAFLD treatment.

Targeted delivery of maytansine to liver cancer cells via galactose-modified supramolecular two-dimensional glycomaterial.

A two-dimensional (2D) glycomaterial for targeted delivery of maytansine to liver cancer cells was developed. Host-guest interaction between a galactosyl dye and human serum albumin (HSA) produces supramolecular galactoside-HSA conjugates, which are then used to coat 2D MoS2. The 2D glycomaterial was shown to be capable of the targeted delivery of maytansine to a liver cancer cell line that highly expresses a galactose receptor, resulting in greater cytotoxicity than maytansine alone.

ROS/NF-κB Signaling Pathway-Mediated Transcriptional Activation of TRIM37 Promotes HBV-Associated Hepatic Fibrosis.

Hepatic fibrosis is an inflammatory response that leads to liver cirrhosis in the most advanced condition. Liver cirrhosis is a leading cause of deaths associated with liver diseases; hence, understanding the underlying mechanisms of hepatic fibrosis is critical to develop effective therapies. Tripartite motif (TRIM) family proteins have been shown to be involved in liver fibrosis; however, the exact role of several TRIM proteins in this process remained unexplored. In this study, we investigated the role of TRIM37 in hepatitis B virus (HBV)-associated hepatic fibrosis. We analyzed TRIM37 expression in hepatic fibrosis patients and performed functional and mechanistic studies in tissue culture and mouse models to identify the role of TRIM37 in hepatic fibrosis. We found an increased expression of TRIM37 in hepatic fibrosis patients. Mechanistically, we showed that TRIM37 physically interacts with SMAD7 and promotes ubiquitination-mediated degradation of SMAD7, and that SMAD7 is a key mediator of TRM37-induced hepatic fibrosis. Furthermore, we showed nuclear factor κB (NF-κB) activation mediated by reactive oxygen species (ROS) is necessary for the transcriptional induction of TRIM37 during HBV infection. Our study shows TRIM37 as an important promoter of HBV-associated hepatic fibrosis.

Qizhufang (ZSF) Ameliorates Hepatic Iron Overload via Signal Transducer and Activator of Transcription 3 (STAT3) Pathway.

BACKGROUND Iron overload is a prominent characteristic of liver injury, but there is no effective treatment at present. Qizhufang (ZSF) is a Chinese herbal formula showed anti-HBV activities, improved liver function, and anti-fibrosis effect. ZSF showed a series of liver-protection functions, but whether ZSF can relieve hepatic iron overload is still unclear. MATERIAL AND METHODS Ferric ammonium citrate (FAC) was used to construct iron-overloaded LO2 cells. The cell apoptosis and proliferation were measured by flow cytometry and CCK-8 assay, respectively. ROS level was analyzed by fluorescence probe. RNA and protein expressions were assessed by real-time PCR and Western blot. RESULTS FAC upregulated apoptosis rate, ROS level, and expression of hepcidin and p-STAT3, but suppressed proliferation and expression of DMT1, FPN1, and CP in LO2 cells. However, Qizhufang (ZSF) reversed the effect of FAC. We also found that hepcidin overexpression suppressed the expressions of DMT1, FPN1, and CP, which were reversed by ZSF. Additionally, STAT3 inhibitor AG490 suppressed hepcidin expression. Moreover, exogenous IL-6 reversed the effect of ZSF on apoptosis rate, ROS level, and the expression of hepcidin, DMT1, FNP1, CP, and p-STAT3. CONCLUSIONS Qizhufang (ZSF) can ameliorate iron overload-induced injury by suppressing hepcidin via the STAT3 pathway in LO2 cells.

Protective Effect of Astragaloside IV on Hepatic Injury Induced by Iron Overload.

Suitable content of iron is essential for human body, but iron overload is associated with many kinds of diseases including chronic liver damage. Recently, researchers find that iron overload promotes hepatocyte autophagy and apoptosis. However, the mechanism of iron overload in liver damage remains unclear. In this study, Lo2 cells were selected as the research object, iron dextran was a model drug, and astragaloside IV was a therapeutic drug to explore the role of iron overload. MTT assay and Annexin/PI double staining were used to measure cell viability and apoptosis. Ultrastructure was observed by transmission electron microscopy. The expression levels of apoptosis and autophagy-related proteins were determined by real-time PCR and Western Blot. The results showed that iron dextran could significantly inhibit Lo2 cell viability and increase the apoptosis rate, while astragaloside IV could reverse the inhibition of Lo2 cell viability and decrease the apoptosis rate. Transmission electron microscopy showed a significant increase in the number of autophagosomes after administration of iron dextran, and the application of astragaloside IV reduced the production of autophagosomes. LC3II/I was significantly upregulated in the model group but decreased in the astragaloside IV treatment group, and P62 showed the opposite trend. Iron dextran significantly upregulated the expression of Bax and downregulated Bcl2, while astragaloside IV reversed this trend. Finally, the inhibition of hepcidin caused by iron dextran was counteracted by astragaloside IV. In conclusion, the experimental results show that the iron overload model mainly induces excessive autophagy and apoptosis of hepatocytes, thus causing damage to hepatocytes, but astragaloside IV plays a certain therapeutic role in reversing this damage.

Endocut Versus Conventional Blended Electrosurgical Current for Endoscopic Biliary Sphincterotomy: A Meta-Analysis of Complications.

BACKGROUND AND AIMS: Endoscopic biliary sphincterotomy (EST) is commonly performed during therapeutic endoscopic retrograde cholangiopancreatography (ERCP), but is an independent risk factor for post-ERCP pancreatitis, bleeding and duodenal perforation. These are partly ascribed to the electrosurgical current mode used for EST, and currently the optimal current model for EST remains controversial. In this study, we aimed to compare the rate of complications undergoing EST using the Endocut versus the blended current. METHODS: A systematic search of databases was performed for relevant published and prospective studies including randomized clinical trials (RCTs) to compare Endocut with blended current modes for EST. Data were collected from inception until 1 July 2018, using post-ERCP pancreatitis, bleeding and perforation as primary outcomes. RESULTS: Three RCTs including a total of 594 patients met the inclusion criteria. Our meta-analysis results showed the rate of post-ERCP pancreatitis, primarily mild to moderate pancreatitis, was no different between Endocut versus blended current modes [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.25-1.52, P = 0.29]. However, the risk of endoscopically bleeding events, primarily mild bleeding, was lower in studies using Endocut versus blended current (RR 0.54, 95% CI 0.31-0.95, P = 0.03). Notably, none of the patients experienced perforation in these three trials. CONCLUSIONS: The rate of post-ERCP pancreatitis was not significantly different when using the Endocut versus blended current during EST. Nevertheless, compared with the blended current, Endocut reduced the incidence of endoscopically evident bleeding; however, the available data were insufficient to assess the perforation risk.

ARHGAP10 Inhibits the Proliferation and Metastasis of CRC Cells via Blocking the Activity of RhoA/AKT Signaling Pathway.

INTRODUCTION: ARHGAP10 belongs to the ARHGAP family, which is downregulated in certain human tumors. However, the detailed function of ARHGAP10 remains unclear in human colon carcinoma (CRC). In the current study, we aimed to explore the role of ARHGAP10 in the growth and metastasis of CRC cells. METHODS: ARHGAP10 was induced silencing and overexpression using RNA interference (RNAi) and lentiviral-vector in CRC cells. Quantitative real-time PCR (qRT-PCR) and Western blot were used to quantify the mRNA and protein contents of ARHGAP10. Cell proliferation was determined by using Cell counting kit-8 (CCK-8). Transwell assay was utilized to examine the role of ARHGAP10 in the migration and invasion of CRC cells. RESULTS: Our results indicated that ARHGAP10 was downregulated in human CRC tissues and low expression of ARHGAP10 was associated with poor prognosis of patients with CRC. Moreover, ARHGAP10 overexpression significantly inhibited the proliferation and metastasis of CRC cells. Moreover, a PI3K/AKT inhibitor LY294002 was utilized to examine the connection between ARHGAP10 and AKT. Our findings demonstrated that the AKT inhibitor LY294002 could rescue the function of ARHGAP10 in CRC cells. DISCUSSION: It was the first time to elucidate that AKT involved in the ARHGAP10 signaling pathway and ARHGAP10 negatively mediated the phosphorylation of AKT (p-AKT) and RhoA activity in CRC cells. Interestingly, the Rho/MRTF/SRF inhibitor CCG-1423 significantly inhibited the phosphorylation of AKT in ARHGAP10 siRNA transfected CRC cells. Much importantly, overexpression of ARHGAP10 deeply suppressed the metastasis of CRC cells in the lung in vivo. Taken together, our findings not only enhanced the understanding of the anti-cancer effect of ARHGAP10 in CRC cells but also indicated its underlying pathway in CRC.