Flightless-I is a potential biomarker for the early detection of alcoholic liver disease.

Alcoholic liver disease (ALD) is closely linked to oxidative stress induction. Antioxidant enzymes balance oxidative stress and function as intermediary signaling regulators. Nucleoredoxin (NXN), an antioxidant enzyme, regulates physiological processes through redox-sensitive interactions.

A Novel Approach towards Early Detection of Obliteration in Lumbar Lordosis.

The millennial age group (18 to 30 years) spend at least 6 hours sitting, either in college or at their workspace. High screen time as a routine, is the major cause for numerous spinal problems. Despite the wide research carried out on postural abnormalities, there exists numerous unrequited queries with regards to lumbar lordosis estimations, due to indeterminate parameters such as age, gender, lifestyle and diet.

Radiofrequency denervation for chronic back pain: a systematic review and meta-analysis.

Objectives: To assess the effectiveness of radiofrequency denervation (RD) of lumbosacral anatomical targets for the management of chronic back pain.

Design: Systematic review and meta-analysis of randomised controlled trials (RCTs).

Methods: A database search (Medline, Medline in Process, Embase, CINHAL and the Cochrane library) was conducted from January 2014 to April 2019 for placebo or no-treatment controlled trials of RD for the management of chronic back pain.

Nucleoredoxin interaction with flightless-I/actin complex is differentially altered in alcoholic liver disease.

Alcoholic liver disease (ALD) may be attributed to multiple hits driving several alterations. The aim of this work was to determine whether nucleoredoxin (NXN) interacts with flightless-I (FLII)/actin complex and how this ternary complex is altered during ALD progression induced by different ALD models. ALD was recapitulated in C57BL/6J female mice by the well-known ALD Lieber-DeCarli model, and by an in vitro human co-culture system overexpressing NXN.

Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice.

Hepatocellular carcinoma (HCC) arises after a long period of exposition to etiological factors that might be either independent or collectively contributing. Several rodent models resemble human HCC; however, the major limitation of these models is the lack of chronic injury that reproducibly mimics the molecular alterations as it occurs in humans. Thus, we hypothesized that chronic administration of different DEN treatments identifies the best-fit dose to induce the HCC and/or to determine whether small DEN doses act synergistically with other known hepatotoxins to induce HCC in mice.

Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays.

Aims: Stevioside is a diterpenoid obtained from the leaves of Stevia rebaudiana (Bertoni) that exhibits antioxidant, antifibrotic, antiglycemic and anticancer properties. Therefore, we aimed to study whether stevioside has beneficial effects in liver injury induced by long-term thioacetamide (TAA) administration and investigated the possible underlying molecular mechanism using in vivo, in vitro and in silico approaches.

Main Methods: Liver injury was induced in male Wistar rats by TAA administration (200 mg/kg), intraperitoneally, three times per week.

Rebaudioside A administration prevents experimental liver fibrosis: an in vivo and in vitro study of the mechanisms of action involved.

Rebaudioside A (Reb A) is a diterpenoid isolated from the leaves of Stevia rebaudiana (Bertoni) that has been shown to possess pharmacological activity, including anti-inflammatory and antioxidant properties. However, the ability of Reb A to prevent liver injury has not been evaluated. Therefore, we aimed to study the potential of Reb A (20 mg/kg; two times daily intraperitoneally) to prevent liver injury induced by thioacetamide (TAA) administration (200 mg/kg; three times per week intraperitoneally).

Stevioside inhibits experimental fibrosis by down-regulating profibrotic Smad pathways and blocking hepatic stellate cell activation.

Liver cirrhosis is associated with increased morbidity and mortality with important health and social consequences; however, an effective treatment has not been found yet. Previous reports have shown some beneficial effects of stevioside (SVT) in different diseases, but the ability of SVT to inhibit liver cirrhosis has not been reported. Therefore, we studied the potential of this diterpenoid to inhibit liver cirrhosis induced by thioacetamide, a model that shares many similarities with the human disease, and investigated the possible underlying molecular mechanism using in vivo and in vitro approaches.

Ethanol targets nucleoredoxin/dishevelled interactions and stimulates phosphatidylinositol 4-phosphate production in vivo and in vitro.

Nucleoredoxin (NXN) is a redox-regulating protein potentially targeted by reactive oxygen species (ROS). It regulates molecular pathways that participate in several key cellular processes. However, the role of NXN in the alcohol liver disease (ALD) redox regulation has not been fully understood.

Thymosin 4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice.

Thymosin beta 4 (T4), an actin-sequestering protein, is involved in tissue development and regeneration. It prevents inflammation and fibrosis in several tissues. We investigated the role of T4 in chronic ethanol- and acute lipopolysaccharide- (LPS-) induced mouse liver injury.

Low-3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways.

Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-3 fatty acid (Low-3FA) that primarily regulates PGC1 and soy protein (SP) that seems to have its major regulatory effect on PGC1 were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low 3FA fish oil and soy protein. Low-3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver.

Protective Role of Dietary Curcumin in the Prevention of the Oxidative Stress Induced by Chronic Alcohol with respect to Hepatic Injury and Antiatherogenic Markers.

Curcumin, an antioxidant compound found in Asian spices, was evaluated for its protective effects against ethanol-induced hepatosteatosis, liver injury, antiatherogenic markers, and antioxidant status in rats fed with Lieber-deCarli low menhaden (2.7% of total calories from ω-3 polyunsaturated fatty acids (PUFA)) and Lieber-deCarli high menhaden (13.8% of total calories from ω-3 PUFA) alcohol-liquid (5%) diets supplemented with or without curcumin (150 mg/kg/day) for 8 weeks.

Assessing the Quality of VA Animal Care and Use Programs.

A set of 13 quality indicators were developed to assess the quality of VA animal care and use programs, emphasizing the measurement of performance outcomes.

Novel modulators of hepatosteatosis, inflammation and fibrogenesis.

Alcoholic steatosis, instead of being innocuous, plays a critical role in liver inflammation and fibrogenesis. The severity of fatty liver is governed by the concerted balance between lipid transport, synthesis, and degradation. Whereas scavenger receptor class B, type I (SR-B1) is critical for reverse cholesterol uptake by the liver, peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α and -β (PGC1α and PGC1β) are critical for lipid degradation and synthesis, respectively.

Synergy between NAFLD and AFLD and potential biomarkers.

Fatty liver (hepatosteatosis) is the earliest abnormality in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) due either to metabolic risk factors associated with insulin resistance and/or metabolic syndrome in the absence of alcohol consumption or to chronic alcohol abuse. When unchecked, both NAFLD and AFLD lead to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and eventual death. A number of common mechanisms contribute to the above various stages of hepatocyte injury, including lipotoxicity, endotoxin release, oxidative and ER stress leading to increased pro-inflammatory cytokines that stimulate hepatic fibrogenesis and cirrhosis by activating the quiescent hepatic stellate cells (HSC) into myofibroblasts.

Adverse signaling of scavenger receptor class B1 and PGC1s in alcoholic hepatosteatosis and steatohepatitis and protection by betaine in rat.

Because scavenger receptor class B type 1 is the cholesterol uptake liver receptor, whereas peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) and PGC-1α are critical for lipid synthesis and degradation, we investigated the roles of these signaling molecules in the actions of ethanol-polyunsaturated fatty acids and betaine on hepatosteatosis and steatohepatitis. Ethanol-polyunsaturated fatty acid treatment caused the following: i) hepatosteatosis, as evidenced by increased liver cholesterol and triglycerides, lipid score, and decreased serum adiponectin; ii) marked inhibition of scavenger receptor class B type 1 glycosylation, its plasma membrane localization, and its hepatic cholesterol uptake function; and iii) moderate steatohepatitis, as evidenced by histopathological characteristics, increased liver tumor necrosis factor α and IL-6, decreased glutathione, and elevated serum alanine aminotransferase. These actions of ethanol involved up-regulated PGC-1β, sterol regulatory element-binding proteins 1c and 2, acetyl-CoA carboxylase, and HMG-CoA reductase mRNAs/proteins and inactive non-phosphorylated AMP kinase; and down-regulated silence regulator gene 1 and PGC-1α mRNA/proteins and hepatic fatty acid oxidation.

Mechanisms of action of acetaldehyde in the up-regulation of the human α2(I) collagen gene in hepatic stellate cells: key roles of Ski, SMAD3, SMAD4, and SMAD7.

Alcohol-induced liver fibrosis and eventually cirrhosis is a leading cause of death. Acetaldehyde, the first metabolite of ethanol, up-regulates expression of the human α2(I) collagen gene (COL1A2). Early acetaldehyde-mediated effects involve phosphorylation and nuclear translocation of SMAD3/4-containing complexes that bind to COL1A2 promoter to induce fibrogenesis.

TGF-β1 up-regulates the expression of PDGF-β receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6K) -dependent proliferative response in activated hepatic stellate cells.

Background: Transforming growth factor beta 1 (TGF-β1) is a pleiotropic cytokine that activates hepatic stellate cell (HSC) proliferation, but inhibits parenchymal cell proliferation. Therefore, we hypothesize that TGF-β1 regulates HSC proliferation and elucidated its molecular action.

Methods: In order to elucidate the molecular mechanism whereby TGF-β1 up-regulates platelet derived growth factor beta (PDGF-β) receptor mRNA and induces a delayed proliferation of HSC, we used proliferation and apoptosis assays as well as RT-PCR, Western blot analysis, immunostaining, and flow cytometry in mouse and rat HSC.

Fibrogenic actions of acetaldehyde are β-catenin dependent but Wingless independent: a critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells.

We investigated whether the fibrogenic actions of acetaldehyde, the immediate oxidation product of ethanol, are mediated via Wingless (WNT) and/or β-catenin pathways in human hepatic stellate cells (HSC). First, we show that both β-catenin small inhibitory RNA and a dominant negative-MYC expression vector markedly down-regulated the expressions of fibrogenic genes in freshly isolated HSC. We further show that acetaldehyde up-regulated platelet-derived growth factor receptor beta mRNA and protein expressions ranging from 4.

CYP2E1, oxidative stress, post-translational modifications and lipid metabolism.

Chronic alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective VLDL assembly and intracellular lipid and lipoprotein transport, which in turn is responsible for alcoholic hepatosteatosis and ALD. The mechanism of ethanol action involves thedepletion of a unique RNA binding protein that specifically interacts with its 3'-UTR region of ST6Gal1 mRNA resulting in its destabilization and consequent appearance of asialoconjugates as alcohol biomarkers. With respect to ETOH effects on Cardio-Vascular Diseases, we conclude that CYP2E1 and ETOH mediated oxidative stress significantly down regulates not only the hepatic PON1 gene expression, but also serum PON1 and HCTLase activities accompanied by depletion of hepatic GSH, the endogenous antioxidant.

Protective effects of thymosin β4 on carbon tetrachloride-induced acute hepatotoxicity in rats.

Thymosin β4 (Tβ4) plays a role in fibrosis, inflammation, and in the reparative process of injured cells and tissues. Here, we discuss our preliminary work on the protective effect of Tβ4 on carbon tetrachloride (CCl(4) )-induced acute hepatotoxicity. Our studies thus far indicate that Tβ4 can prevent necrosis, inflammatory infiltration, and upregulation of α1(and 2) collagen, α-SMA, PDGF-β receptor, and fibronectin mRNA expression; in addition, Tβ4 can prevent downregulation of PPARγ and upregulation of MECP2 mRNA levels in acute liver injury.

Characterization of sialic acid index of plasma apolipoprotein J and phosphatidylethanol during alcohol detoxification--a pilot study.

Background: Apolipoprotein J (ApoJ) is a component of plasma high-density lipoproteins. Previous studies have shown progressive recovery of ApoJ sialic acid content with increased duration of alcohol abstinence. Therefore, the sialic acid index of plasma apolipoprotein J (SIJ) seems to be a promising alcohol biomarker.

Quercetin up-regulates paraoxonase 1 gene expression via sterol regulatory element binding protein 2 that translocates from the endoplasmic reticulum to the nucleus where it specifically interacts with sterol responsive element-like sequence in paraoxonase 1 promoter in HuH7 liver cells.

We previously showed that quercetin expresses its antiatherogenic effects by up-regulating paraoxonase 1 (PON1) gene and high-density lipoprotein's protective capacity against low-density lipoprotein oxidation. In an attempt to elucidate the mechanism of action of quercetin, we have now determined the effects of quercetin on PON1 gene expression, activity, protein level, nuclear mature sterol regulatory element binding protein 2 (SREBP2) level, and its translocation from the endoplasmic reticulum to nucleus and its interaction with PON1 promoter in human HuH7 liver cells using real-time reverse transcriptase polymerase chain reaction, spectrophotometry, immunoblot, confocal microscopy, and electrophoretic mobility shift assay techniques, respectively. Quercetin (20 micromol/L) treatment increased PON1 messenger RNA by 75% (P < .

Quercetin and ethanol attenuate the progression of atherosclerotic plaques with concomitant up regulation of paraoxonase1 (PON1) gene expression and PON1 activity in LDLR-/- mice.

Background: As moderate wine drinking is atheroprotective, it is clinically relevant to elucidate its possible mechanism/s of action/s. Our objective is to demonstrate the potential benefits of the wine components, quercetin and ethanol, on the development of aortic plaques with parallel changes in antiatherogenic factors.

Methods And Results: The effects of quercetin and ethanol on the development of aortic atherosclerotic lesions, liver PON1 gene expression, and serum PON1 activity were measured in LDLR(-/-) mice on an atherogenic diet for 4 and 8 weeks.

Betaine protects chronic alcohol and omega-3 PUFA-mediated down-regulations of PON1 gene, serum PON1 and homocysteine thiolactonase activities with restoration of liver GSH.

Background: Paraoxonase (PON1) is an antioxidant enzyme that prevents LDL oxidation as well as detoxifies homocysteine thiolactone (HCTL), both of which can cause atherosclerosis. Chronic alcohol (ETOH) and high omega-3 polyunsaturated fatty acids (omega-3 PUFA) consumption may affect PON1 status presumably via reactive oxygen species by depleting liver glutathione (GSH), whereas betaine may counter their effects. Therefore, we investigated the influence of ETOH, omega-3 PUFA, and betaine on liver GSH, PON1 expression, lipid score, as well as serum PON1 and HCTLase activities.