Astragalus Polysaccharides and Saponins Alleviate Liver Injury and Regulate Gut Microbiota in Alcohol Liver Disease Mice

Astragalus, a medical and edible plant in China, shows several bioactive properties. However, the role of astragalus in attenuating alcoholic liver disease (ALD) is less clear. The objective of this project is to investigate the improving effect of astragalus saponins (AS) and astragalus polysaccharides (AP), which are the two primary constituents in astragalus on hepatic injury induced by alcohol, and the potential mechanisms of action. Different doses of AS (50 and 100 mg/kg bw) and AP (300 and 600 mg/kg bw) were orally given to alcohol-treated mice for four weeks. The results demonstrated that both AP and AS could reverse the increase of the levels of TC, TG, FFA, and LDL-C in serum, and the decrease of serum HDL-C content, as well as the elevation of hepatic TC and TG levels induced by alcohol. The activities of AST, ALT, ALP, and γ-GT in ALD mice were raised after AP and AS supplementation. The antioxidant markers (SOD, CAT, GSH, and GSH-Px) were obviously augmented and the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) and hepatic histological variations were alleviated by AP and AS, which was in line with the levels of oxidative stress-associated genes (Keap1, Nfe2l2, Nqo1, and Hmox1) and inflammation-associated genes (Tlr4, Myd88 and Nfkb1). In addition, AS exerted a more efficient effect than AP and the results presented dose proportionality. Moreover, AS and AP could modulate the intestinal microbiota disturbance induced by alcohol. Overall, AS and AP administration could ameliorate lipid accumulation in the serum and liver, as well as hepatic function, oxidative stress, inflammatory response, and gut flora disorders in mice as a result of alcohol.

Improvement Lipophagy by Restoring Rab7 Cycle: Protective Effects of Quercetin on Ethanol-Induced Liver Steatosis

Background: Chronic alcohol consumption induces lipophagy retard which contributes the pathogenesis of liver steatosis. Lipophagy-related Rab7 responsible for the fusion between autophagosomes and lysosomes has been presumed as a crucial regulator on the progression of alcohol liver disease (ALD) despite elusive mechanisms. More importantly, whether hepatoprotective quercetin targets Rab7-associated lipophagy disorder or not, still remains uncertain. Results: ALD mice were induced by chronic-plus-single-binge ethanol feeding that manifested by hampering autophagosomes formation with lipid droplets (LDs) and fuse with lysosomes compared with the normal control, which was normalized partially by quercetin. GST-RILP pulldown assay of Rab7 indicated an improved GTP-Rab7 as quercetin treatment for ethanol-feeding mice. Lipophagy was blocked when HepG2 cells were transfected with siRNA-Rab7, which was reversed through co-transfection of Rab7Wt plasmid. Rab7-specific inhibitor CID1067700 aggravated ethanol-induced steatosis and autophagic flux disruption visualized by immunofluorescence co-localization analysis and mCherry-GFP-LC3 transfection. HepG2 cells overexpressing Rab7Wt show a stronger alleviation on alcohol-induced lipophagy dysfunction than Rab7Q67L. Furthermore, TBC1D5 responsible for Rab7 inactivation was downregulated after alcohol administration, but regained by quercetin. Rab7 circulation retarded by ethanol and corrected by quercetin was further revealed by fluorescence recovery after photobleaching (FRAP). Conclusions: Chronic alcoholic not only inactivates Rab7 but also retards TBC1D5-mediated Rab7 turnover, synergistically obstructing lipophagy flux and promoting ethanol-induced steatosis. Quercetin attenuates adipohepatic degeneration by normalizing ethanol-imposed Rab7 disorders and subsequent lipophagy disturbance, highlighting a novel mechanism and promising prospect of quercetin-like phytochemicals against the crucial first hit from the alcohol.

Fenretinide Improves Intestinal Barrier Function and Mitigates Alcohol Liver Disease

Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.

Risk factors, treatment patterns and survival of patients with incident hepatocellular carcinoma in France: A retrospective data analysis.

284 Background: Despite the screening of patients at risk, hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage disease, with a very poor prognosis. Aim: To describe risk factors, treatment patterns and survival of patients with newly diagnosed HCC in France over the period 2015-2017 using SNDS, the national administrative healthcare database covering around 99% of the population. Methods: The database was searched for patients with a diagnosis of HCC (ICD-10: C220) from 1 January 2015–31 December 2017. Disease stage (Barcelona Clinic Liver Cancer B, C or D classification) was defined by the identification of treatment: transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best Supportive Care (BSC). Patients were followed up for a maximum of 2 years. Results: 21,071 patients were identified, mean age 69.2 years (SD: 11.1), 82.2% were male. Liver disease or diabetes was identified in 86.4% of patients. The most frequent risk factors were alcohol liver disease (42.7%), viral hepatitis and alcohol liver disease (7.2%), viral hepatitis alone (12.6%), NASH/NAFLD or diabetes (17.7%). At diagnosis, 6,571 (31.2%) received a curative HCC treatment. Within the total population, 8,616 patients (40.9%) were only managed by BSC, 6,571 (31.2%) received a treatment therapy, of which 3,184 (15.1%) had a TACE or TARE and 2 700 (12.8%) sorafenib. The 1-year survival rates by initial treatment were: curative (88.7%), TACE or TARE (70%), systemic therapy (32.2%) and only 17.8% with BSC. Conclusions: These results show the high burden of HCC, with more than two thirds of patients not receiving active treatment.

An Unusual Case of COVID-19 Presenting as Acute Psychosis

Purpose To report a case of COVID-19 presenting with acute psychosis, without the hallmark respiratory symptoms of fever, cough, and shortness of breath associated with the novel virus. Case Summary A 58 year-old male presented with acute psychosis and no symptoms associated with COVID-19. He denied fever, chills, chest pain, shortness of breath, or gastrointestinal symptoms. The patient had a medical history of coronary artery disease, chronic hepatitis C, polysubstance abuse (including cocaine and alcohol), liver disease, anxiety, and panic disorder. Patient was confused, disruptive, unable to communicate, and admitted to hallucinations. Prior to transfer to a psychiatric facility, the patient developed a cough, triggering COVID-19 testing and a positive result. He was initially treated with hydroxychloroquine before this was discontinued. The patient was treated with haloperidol and lorazepam before returning to baseline. He was discharged home with continued isolation. Conclusion Acute psychosis, with or without other symptoms, appears to be a potential presentation of COVID-19 and should be considered by clinicians as a possible presenting manifestation. Other coronaviruses appear to have also been linked to neurological manifestations, including psychosis. Neurological manifestations of the virus vary widely, but have been reported multiple times. Treatment, as shown in this case report, appears to be supportive and symptom based for the associated psychotic symptoms. Optimal antiviral treatment is still yet to be clearly defined, as research continues on how to best treat the virus itself.

An Overview of the Mechanism of Penthorum chinense Pursh on Alcoholic Fatty Liver

Alcohol liver disease (ALD) caused by excessive alcohol consumption is a progressive disease, and alcohol fatty liver disease is the primary stage. Currently, there is no approved drug for its treatment. Abstinence is the best way to heal, but patients’ compliance is poor. Unlike other chronic diseases, alcohol fatty liver disease is not caused by nutritional deficiencies; it is caused by the molecular action of ingested alcohol and its metabolites. More and more studies have shown the potential of Penthorum chinense Pursh (PCP) in the clinical use of alcohol fatty liver treatment. The purpose of this paper is to reveal from the essence of PCP treatment of alcohol liver mechanism mainly by the ethanol dehydrogenase (ADH) and microsomal ethanol oxidation system-dependent cytochrome P4502E1 (CYP2E1) to exert antilipogenesis, antioxidant, anti-inflammatory, antiapoptotic, and autophagy effects, with special emphasis on its mechanisms related to SIRT1/AMPK, KEAP-1/Nrf2, and TLR4/NF-κB. Overall, data from the literature shows that PCP appears to be a promising hepatoprotective traditional Chinese medicine (TCM).

Histology of Liver of the Deceased Due to Harmful Use of Alcohol

Aim To study types and incidence of histological changes in liver of people deceased due to harmful use of alcohol. Methods A retrospective review of medico-legal autopsy of 236 adults who died in the years 2015–2016 due to harmful use of alcohol was done. Histopathological liver samples taken during autopsies were evaluated. Blood alcohol content was analyzed. Serological tests for hepatitis B surface antigen and anti-hepatitis C virus (HCV) were performed. Results The most common liver pathology (83.1%) was steatosis, mainly mixed type (50%); 66.9% had high-grade steatosis. Liver fibrosis was detected in 39.4% of cases, with fibrosis of higher than or equal to third grade in 14%, hepatitis in 44.5% and steatohepatitis in 19.1%. Toxic hepatocyte injury features (ballooning degeneration, Mallory–Denk bodies) were found in 20.8% cases and degenerative-damage changes in 41.1%. The correlation between the grade of steatosis and fibrosis (P = 0.0005), toxic injury (0.00000101) and degenerative–traumatic changes (P = 0.00000741) was found. The correlation was found between hepatitis and higher than or equal to third grade steatosis (P = 0.037), cholestasis (P = 0.0139), toxic injury features (P = 2.58 × 10−13), degenerative–damage changes (P = 7.9 × 10−12) and presence of anti-HCV (P = 0.00723) and between progression of fibrosis and presence of toxic injury features (2.28 × 10−19), degenerative–damage changes (P = 4.25 × 10−11) and anti-HCV (P = 0.0263). Conclusions Spectrum of histopathological liver changes is broad regardless of sex, and various traits are present in various patterns. Comorbidities have strong influence on the picture of changes in the liver. Exact evaluation how often and what histopathological changes will develop in alcohol liver disease is not possible by reason of variability of external factors.