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Background: Chronic alcoholic liver disease (CALD) is a global health problem which includes multiple pathological processes such as immune inflammation and oxidative stress. 4-hydroxy-2(3H)-benzoxazolone (HBOA), an alkaloid isolated from Acanthus ilicifolius L, has been shown to exert hepatoprotective and immunomodulatory effects. However, its effects on CALD remain unclear. This study aimed to investigate the effects and underlying mechanisms of HBOA on CALD. Methods: Rats were administered alcohol by gavage continuously for 12 weeks to establish the CALD model, and then treated with HBOA by gavage for 4 weeks. Transcriptomics and metabolomics were used to predict the potential mechanisms of the effects of HBOA on CALD. Liver histology and function, oxidative stress, inflammatory cytokines, and the TLR4/NF-κB pathway components were evaluated. Results: HBOA significantly improved alcohol-induced liver injury and steatosis. It decreased the expression levels of pro-inflammatory cytokines (tumour necrosis factor-a [TNF-a], interleukin (IL)-1ß, and IL-6), and increased the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione [GSH], and glutathione peroxidase [GSH-Px]). Western blotting confirmed that HBOA treatment largely diminished NF-Bp65 nuclear translocation. Comprehensive transcriptomics and metabolomics analyses indicated that HBOA regulated the glycerophospholipid metabolism pathway to achieve therapeutic effects in rats with CALD. Conclusion: HBOA has a therapeutic effect on rats with CALD. Its mechanism of action mainly affects the glycerophospholipid metabolic pathway to promote lipid metabolism homeostasis by regulating the expression of Etnppl, Gpcpd1, and Pla2g4c. In addition, it may also inhibit the TLR4/NF-B signaling pathway, thereby reducing the immune-inflammatory response. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is an important and potentially life threatening complication in alcoholic patients with decompensated liver function that develop even as they continue drinking. Delirium tremens, on the other hand, is an acute condition resulting from alcohol abstinence in a person dependent on alcohol, making it a life threatening diagnosis that requires intensive care and successful management of the withdrawal. Often in medical wards, these two conditions are mistaken and so is the management plan confused with each other. Making the right diagnosis early on during the hospital course is extremely important in these critical conditions so as to make an appropriate schedule for treatment and a better outcome for the same. A case series of patients who presented with a diagnostic dilemma is reported. Clinical examinations, diagnostic tools to measure the levels of ammonia and liver function tests and hemogram, West Haven criteria and Child–Pugh grading, and clinical scales of these patients are reported. Increased levels of ammonia were present in all the cases. The subtle similarities in the presentation of the two conditions often make it confusing for the clinician to distinguish between them. Using a simple test of measuring ammonia levels in the blood helps in such situations. The detection of raised levels of ammonia in cases of chronic liver disease helps in not just the diagnosis but also is an important prognostic indicator for development of HE.

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Hepatic encephalopathy (HE) is an important and potentially life threatening complication in alcoholic patients with decompensated liver function that develop even as they continue drinking. Delirium tremens, on the other hand, is an acute condition resulting from alcohol abstinence in a person dependent on alcohol, making it a life threatening diagnosis that requires intensive care and successful management of the withdrawal. Often in medical wards, these two conditions are mistaken and so is the management plan confused with each other. Making the right diagnosis early on during the hospital course is extremely important in these critical conditions so as to make an appropriate schedule for treatment and a better outcome for the same. A case series of patients who presented with a diagnostic dilemma is reported. Clinical examinations, diagnostic tools to measure the levels of ammonia and liver function tests and hemogram, West Haven criteria and Child–Pugh grading, and clinical scales of these patients are reported. Increased levels of ammonia were present in all the cases. The subtle similarities in the presentation of the two conditions often make it confusing for the clinician to distinguish between them. Using a simple test of measuring ammonia levels in the blood helps in such situations. The detection of raised levels of ammonia in cases of chronic liver disease helps in not just the diagnosis but also is an important prognostic indicator for development of HE. [ABSTRACT FROM AUTHOR]

Objectives: The study aims to estimate the changes in the serum levels of lipid peroxidation product malondialdehyde (MDA), non-enzymatic antioxidants: vitamin A, E and C and erythrocyte enzymatic antioxidants: superoxide dismutase (SOD) and catalase(CAT) in chronic alcoholic liver disease. Background: Alcohol consumption accounts for about 50% of patients death from end stage liver disease in India. The increased free radical and their metabolites decrease the plasma antioxidants status in chronic alcoholic liver disease (CALD). Method: The study comprised of 100 healthy persons as controls and 100 diagnosed patients of chronic alcoholic liver disease as cases. The estimation of serum MDA, vitamin A, E, C and erythrocyte enzymatic antioxidants SOD and CAT, were carried out along with liver function parameters like serum aspartate amino transferase (AST), serum alanine aminotransferase (ALT), serum alkaline phosphatase (AP), serum gamma glutamyl transferase (GGT), serum total protein, serum albumin, prothrombin time (PT) and serum bilirubin. Statistical analysis was done using unpaired “t” test. Result: The levels of serum MDA were significantly increased in patients with CALD (P

Background & Aims: Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells. Methods: Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-stimulated PBMCs from 52 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients. Results: Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1588 downregulated genes. In LPS-stimulated “healthy” cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and “healthy” cells were involved in cytokine production/activity and induction of “immune paralysis”. Comparison of functions associated with the 1356 genes, specifically regulated by LPS in cirrhotic cells, to functions of the 1049 genes, specifically regulated in “healthy” cells, allowed to define a cirrhosis-specific phenotype. Unlike in “healthy” cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex vivo LPS-induction of the inflammatory genes IL6 and CXCL5 was a significant predictor of mortality. Conclusions: Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response. [Copyright &y& Elsevier]

Background: Gene expression changes in the liver after acute binge drinking may differ from the changes seen in chronic ethanol feeding in the rat. The changes in gene expression after chronic ethanol feeding may sensitize the liver to alcohol-induced liver damage, which is not seen after acute binge drinking. Methods: To test this hypothesis, gene microarray analysis was performed on the livers of rats ( n = 3) fed an acute binge dose of ethanol (6 g/kg body wt) and killed at 3 and 12 hours after ethanol by gavage. The gene microarrays were compared with those made on the liver of rats from a previous study, in which the rats were fed ethanol by intragastric tube for 1 month (36% of calories derived from ethanol). Results: Microarray analysis data varied between the acute and chronic models in several important respects. Growth factors increased mainly in the chronic alcohol fed rat. Changes in enzymes involved in oxidative stress were noted only with chronic ethanol feeding. Gene expression of fat metabolism was increased only with chronic ethanol feeding. Most importantly, epigenetic related enzymes and acetylation and methylation of histones changed only after chronic ethanol feeding. Conclusions: The results support the concept that chronic ethanol ingestion induces altered gene expression as a result of changes in epigenetic mechanisms, where acetylation and methylation of histones were altered. [ABSTRACT FROM AUTHOR]

• FOXO4 significantly ameliorates liver histopathological damage; • FOXO4 reduces the levels of endotoxin, ALT, AST, ALP, TG, ROS and MDA; • FOXO4 restores the activity of GSH and SOD and levels of IL-10; • FOXO4 inhibits the NF-κB level and elevates the expression of ZO-1 and Occludin; • FOXO4 modulates the gut microbiota composition and certain bacteria. Intestinal mucosa barrier function and gut-liver axis are impaired by ethanol in chronic alcoholic liver disease (ALD). However, the possible mechanism is not clear. This study aimed to investigate the effects of Forkhead Box O4 (FOXO4) on alcohol-induced chronic liver injury and its molecular mechanism(s). Male C57BL/6J mice were injected with or without FOXO4-WT, FOXO4-TB or NF-κB vectors, and fed with Lieber-DeCarli liquid diets containing 36% ethanol for eight weeks to induce chronic ALD. Thereafter, blood, liver, colon and fecal samples were collected. Biochemical parameters, endotoxin and inflammatory cytokines in the blood and antioxidant enzymes in the liver were tested by commercial kits. Histopathological changes in the liver were evaluated by HE staining. In addition, the mRNA and protein expression of FOXO4, NF-κB, ZO-1 and Occluding in the colon were measured by quantitative real-time PCR and Western blot, respectively. Furthermore, gut microbiota composition in the fecal samples was investigated with 16S rDNA sequencing. FOXO4 significantly ameliorated liver histopathological damage. Moreover, FOXO4 reduced the serum endotoxin, biochemical parameters (ALT, AST, ALP and TG), antioxidant enzymes (ROS and MDA), inflammatory cytokines (IL-6, IL-1β, and TNF-α), but restored the levels of GSH, SOD and IL-10. Furthermore, FOXO4 significantly inhibited the expression of NF-κB, p-NF-κB p65, p-IKKα and p-IKKβ, and up-regulated the expression of ZO-1 and Occludin. Additionally, FOXO4 modulated the gut microbiota composition and certain bacteria including Odoribacter, Parasutterella and Psychrobacter. These findings suggest that FOXO4 protects against alcohol-induced chronic liver injury via inhibiting NF-κB and modulating gut microbiota in C57BL/6J mice. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease is a spectrum of conditions that include alcoholic fatty liver disease, alcoholic hepatitis, and chronic alcoholic liver disease. The diagnosis of alcoholic liver disease remains founded in an accurate patient history and detailed physical examination. Concurrent with the physical examination, objective data from laboratory, imaging, and histologic studies are helpful to confirm a diagnosis of alcoholic liver disease. Novel biomarkers, scoring systems, and imaging modalities are improving the ability to diagnose and manage alcoholic liver disease, but for most practicing clinicians, these have not been adopted widely because of their cost, but also because of limitations and uncertainty in their performance characteristics., (Copyright © 2016 Elsevier Inc. All rights reserved.)