Ginkgolide C attenuated Western diet-induced non-alcoholic fatty liver disease via increasing AMPK activation.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a metabolic dysregulation-related disorder that is generally characterized by lipid metabolism dysfunction and an excessive inflammatory response. Currently, there are no authorized pharmacological interventions specifically designed to manage NASH. It has been reported that Ginkgolide C exhibits anti-inflammatory effects and modulates lipid metabolism. However, the impact and function of Ginkgolide C in diet-induced NASH are unclear. METHODS: In this study, mice were induced by a Western Diet (WD) with different doses of Ginkgolide C with or without Compound C (adenosine 5 '-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor). The effects of Ginkgolide C were evaluated by assessing liver damage, steatosis, fibrosis, and AMPK expression. RESULTS: The results showed that Ginkgolide C significantly alleviated liver damage, steatosis, and fibrosis in the WD-induced mice. In addition, Ginkgolide C markedly improved insulin resistance and attenuated hepatic inflammation. Importantly, Ginkgolide C exerted protective effects by activating the AMPK signaling pathway, which was reversed by AMPK inhibition. CONCLUSION: Ginkgolide C alleviated NASH induced by WD in mice, potentially via activating the AMPK signaling pathway.

Chrysin and its nanoliposome ameliorated non-alcoholic steatohepatitis via inhibiting TLR4 signalling pathway.

OBJECTIVES: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease histologically characterized by liver steatosis, hepatocellular injury, inflammation and fibrosis, resulting in cirrhosis and hepatocellular carcinoma, but effective measures and obvious pathogenesis for NASH remain elusive. Chrysin (CH) has been reported to have anti-inflammatory effects but shows lower bioavailability. METHODS: In this study, a chrysin nanoliposome (CH-NL) was first prepared and characterized. Then, we used the methionine-choline-deficient (MCD) diet to induce a mouse model of NASH. Finally, the effects of CH and CH-NL on NASH were evaluated in the liver of NASH mice. KEY FINDINGS: The results showed that CH or CH-NL significantly reduced the accumulation of lipids in hepatocytes, alleviated liver injury, decreased the generation of radical oxygen species, and attenuated the accumulation of collagen fibre in the liver of NASH mice. In addition, CH and its nano-liposomes markedly inhibited the production of inflammatory cytokines and inflammatory cell infiltration in the liver of NASH mice. Further studies found that CH-NL and CH-NL downregulated the MCD diet-induced activation of Toll-like receptor 4 (TLR4) signalling pathway in the liver of mice. CONCLUSIONS: CH and its nanoliposome alleviated MCD diet-induced NASH in mice, which might be through inhibiting TLR4 signalling pathway.

Simultaneous and Sensitive Detection of Three Pesticides Using a Functional Poly(Sulfobetaine Methacrylate)-Coated Paper-Based Colorimetric Sensor.

Chlorpyrifos (CHL), profenofos (PRO) and cypermethrin (CYP) are widely used in combination to increase crop yields. However, these three pesticides can cause serious harm to human health and do not easily degrade. In this study, a novel visible paper sensor has been prepared successfully and different colorimetric reactions were utilized to detect the three pesticides simultaneously. The sensor was constructed by grafting a zwitterionic polymer onto a cellulose filter (CF) and placing it on a glass surface modified with PDMS. The branch shape was designed to form multiple detection areas, which were modified with specific pesticides and corresponding chromogenic reagents. The as-prepared colorimetric platform exhibited high sensitivity, a short detection time, a good linear response and a low detection limit (LOD) for the three pesticides (chlorpyrifos: y = 46.801 - 1.939x, R2 = 0.983, LOD = 0.235 mg/L; profenofos: y = 40.068 + 42.5x, R2 = 0.988, LOD = 4.891 mg/L; cypermethrin: y = 51.993 + 1.474x, R2 = 0.993, LOD = 4.053 mg/L). The comparison of the results obtained by the proposed paper sensor and those obtained by spectrophotometry further revealed the stability and reliability of the paper sensor. In particular, the color intensity of the interaction between the pesticides and coloring agents could be directly observed by the human eye. The consistency of the colorimetric/optical assay was proven in real target pesticide samples. Thus, this sensing strategy provides a portable, cost-effective, accurate and visualized paper platform, which could be suitable for application in the fruit and vegetable industry for monitoring CHL, PRO and CYP in parallel.

A Nomogram for Predicting Portal Hypertensive Gastropathy in Patients With Liver Cirrhosis: A Retrospective Analysis.

BACKGROUND: There is an urgent need for non-invasive methods for predicting portal hypertensive gastropathy (PHG). This study aims to develop and validate a non-invasive method based on clinical parameters for predicting PHG in patients with liver cirrhosis (LC). METHODS: The overall survival (OS) and hepatocellular carcinoma (HCC)-free survival were evaluated in LC patients, both with and without PHG. A prediction model for PHG was then constructed based on a training dataset that contained data on 492 LC patients. The discrimination, calibration, and clinical utility of the predicting nomogram were assessed using the C-index, calibration plot, and decision curve analysis. Internal validation was conducted using a bootstrapping method, and further external validation using data on the 208 other patients. RESULTS: LC patients with PHG had a worse prognosis compared with those without PHG. A nomogram was constructed using clinical parameters, such as age, hemoglobin content, platelet count and Child-Pugh class. The C-index was 0.773 (95% CI: 0.730-0.816) in the training cohort, 0.761 after bootstrapping and 0.745 (95% CI: 0.673-0.817) in the validation cohort. The AUC values were 0.767, 0.724, and 0.756 in the training, validation and total cohorts, respectively. Well-fitted calibration curves were observed in the training and validation cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful at a threshold of 15%. CONCLUSION: The nomogram constructed to predict the risk of developing PHG was found to be clinically viable. Furthermore, PHG is an independent risk factor for OS of LC, but not for the occurrence of HCC.

A Rh(II)-catalyzed highly stereoselective [3 + 2] annulation of vinyl diazoacetates with indole-2-carbaldehyde for the synthesis of indolyl dihydrofurans.

A highly stereoselective Rh2(Oct)4-catalyzed [3 + 2] cycloaddition of vinyl diazoacetates with indolyl aldehyde has been developed. This protocol provides an efficient access to both cis and trans indolyl dihydrofurans with high yields and diastereoselectivities under mild conditions without or with Lewis acid as additive, respectively. Moreover, these generated functionalized dihydrofurans exhibit potent antiproliferation activity in three different cancer cell lines.

SHARPIN stabilizes ß-catenin through a linear ubiquitination-independent manner to support gastric tumorigenesis.

BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/ß-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. METHODS: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/ß-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of ß-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. RESULTS: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with ß-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase ß-Trcp1 for ß-catenin binding, thereby decreasing ß-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner ß-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with ß-catenin expression levels. CONCLUSIONS: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/ß-catenin signaling via SHARPIN-mediated stabilization of ß-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive ß-catenin signaling in a subset of human gastric cancers.

Autophagy and Gastrointestinal Diseases.

Normal gastrointestinal physiology is fundamental for all the living beings. Gastrointestinal diseases mainly include gastrointestinal motility disorders, infectious inflammation (such as Helicobacter pylori infection, cholera, and intestinal parasites), non-infectious inflammation (such as chronic gastritis and Crohn's disease), and gastrointestinal cancers. In addition, intestinal microbial disorder is also an important cause of intestinal diseases, so intestinal microecological treatment (fecal microbiota transplantation) is an important mean of treating gastrointestinal diseases. In recent years, the role of autophagy in gastrointestinal diseases has been studied extensively. Autophagy is observed under various pathological processes of the gastrointestinal tract. For example, it has been demonstrated that autophagy plays an important role in maintaining the homeostasis and integrity of intestinal epithelium. Additionally, autophagy regulates host response to H. pylori infection and development of gastrointestinal cancers. Therefore, we will discuss pivotal roles of autophagy in various gastrointestinal diseases and analyze the underlying molecular mechanisms, which may provide new therapeutic targets applicable for the treatment of gastrointestinal diseases.

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells.

Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.

Angiogenic Factor with G Patch and FHA Domains 1 (AGGF1) Acts as Diagnostic Biomarker and Adverse Prognostic Factor of Hepatocellular Carcinoma (HCC): Evidence from Bioinformatic Analysis.

BACKGROUND Angiogenic factor with G patch and FHA domains 1 (AGGF1) is a novel identified initiator of angiogenesis through promoting the proliferation of endothelial cells. The continuous angiogenesis plays a key role in the growth, invasion, and metastasis of hepatocellular carcinoma (HCC), while the diagnostic and prognostic roles of AGGF1 for HCC need to be further studied. MATERIAL AND METHODS The mRNA sequencing datasets and clinical features of HCC patients were extracted from The Cancer Genome Atlas database. The relationship between clinical features and AGGF1 expression was analyzed by Wilcoxon test. Further validation explorations were carried out using online database Oncomine. The diagnostic receiver operating characteristic curves of AGGF1 and alpha-fetoprotein were compared to examine the diagnostic efficacy of AGGF1. Survival analysis and Gene Set Enrichment Analysis were performed to explore the prediction value and potential mechanism of AGGF1 dysregulation in HCC. RESULTS Comprehensive overexpression of AGGF1 was observed in HCC, correlating with poor overall survival. Upregulated level of AGGF1 was statistically associated with poor differentiated histological grade, advanced cancer stage and T classification. AGGF1 was a more effective diagnostic marker than alpha-fetoprotein in HCC. Several important pathways related to HCC including pathway in cancer and P53 signaling pathway were differentially enriched in the high AGGF1 expression phenotype. CONCLUSIONS AGGF1 was a potential diagnostic and prognostic marker for poor clinical outcomes in HCC patients. Moreover, vital pathways regulated by AGGF1 in HCC may include regulation of autophagy, Wnt signaling pathway, pathway in cancer, cell cycle, and P53 signaling pathway.

Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice.

Emodin has been reported to possess anti-inflammatory and anti-oxidant activities. The aim of this study was to explore the effect and mechanism of emodin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with emodin inhibited the elevation of plasma aminotransferases, alleviated the hepatic histopathological abnormalities and improved the survival rate of LPS/D-GalN-primed mice. Moreover, emodin markedly attenuated the increased serum and hepatic tumor necrosis factor-α (TNF-α) production, and activated hepatic p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signal pathways in LPS/D-GalN-challenged mice. Furthermore, using an in vitro experiment, we found that emodin dose-dependently suppressed TNF-α production, dampened AP-1 and NF-κB activation, and blocked toll-like receptor (TLR) 4/myeloid differentiation factor (MD) 2 complex expression in LPS-elicited RAW264.7 mouse macrophage cells. Taken together, these data suggested that emodin could effectively prevent LPS-induced FHF, which might be mediated by inhibition of TNF-α production, deactivation of MAPKs and NF-κB, and blockade of TLR4/MD2 complex expression.

Synthetic RGDS peptide attenuated lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice.

BACKGROUND AND AIM: Fulminant hepatic failure (FHF) is a serious clinic syndrome with extremely poor prognosis and no effective treatment except for liver transplantation. Synthetic RGDS peptide, an inhibitor of integrins, was proved to suppress integrin signals. In this study, we investigated the protection effects of RGDS peptide on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced FHF and the underlying molecular mechanisms. METHODS: Synthetic RGDS peptide was given intraperitoneally 30 min before LPS/D-GalN injection. Liver function and the extent of liver injury were analyzed biochemically and pathologically respectively. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction and Western blotting were used to detect effectors and signaling molecules. RESULTS: Pretreatment with synthetic RGDS peptide significantly improved LPS/D-GalN-induced mortality, and liver injury as determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as well as pathological analysis. In addition, RGDS peptide significantly reduced tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 production, and decreased myeloperoxidase (MPO) and NF-κB activity. Furthermore, Western blotting indicated that the levels of phospho-integrin ß3, phospho-focal adhesion kinase (FAK) and phospho-p38 mitogen-activated protein kinases (MAPK) decreased with RGDS peptide pretreatment. CONCLUSION: Together, these data suggest that synthetic RGDS peptide protect against LPS/D-GalN-induced FHF by inhibiting inflammatory cells migration and blocking the integrin αVß3-FAK-p38 MAPK and NF-κB signaling.

Hepatoprotective effects of syringin on fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide in mice.

The prognosis for fulminant hepatic failure (FHF) still remains extremely poor with a high mortality and, therefore, better treatments are urgently needed. Syringin, a main active substance isolated from Eleutherococcus senticosus, has been reported to exhibit immunomodulatory and anti-inflammatory properties. In this study, we investigated the effects and underlying mechanisms of syringin on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FHF in mice. Mice were administered syringin (10, 30 and 100 mg kg(-1), respectively) intraperitoneally (i.p) 30 min before LPS/D-GalN then mortality and liver injury were evaluated subsequently. We found that syringin dose-dependently attenuated LPS/D-GalN-induced FHF, as indicated by reduced mortality, inhibited aminotransferase and malondialdehyde (MDA) content, an increased glutathione (GSH) concentration and alleviated pathological liver injury. In addition, syringin inhibited LPS/D-GalN-induced hepatic caspase-3 activation and hepatocellular apoptosis, myeloperoxidase (MPO) activity and intercellular adhesion molecule-1 (ICAM-1) expression, as well as hepatic tissues tumor necrosis factor-alpha (TNF-α) production and NF-κB activation in a dose-dependent manner. These experimental data indicate that syringin might alleviate the FHF induced by LPS/D-GalN through inhibiting NF-κB activation to reduce TNF-α production.