thioacetamide and Non-alcoholic-Fatty-Liver-Disease

The antioxidant effect of caffeine, associated with its ability to upregulate the nuclear factor-E2-related factor-2 (Nrf2)-signaling pathway, was explored as a possible mechanism for the attenuation of liver damage. Nonalcoholic steatohepatitis (NASH) was induced in rats by the administration of a high-fat, high-sucrose, high-cholesterol diet (HFSCD) for 15 weeks. Liver damage was induced in rats by intraperitoneal administration of thioacetamide (TAA) for six weeks. Caffeine was administered orally at a daily dose of 50 mg/kg body weight during the period of NASH induction to evaluate its ability to prevent disease development. Meanwhile, rats received TAA for three weeks, after which 50 mg/kg caffeine was administered daily for three weeks with TAA to evaluate its capacity to interfere with the progression of hepatic injury. HFSCD administration induced hepatic steatosis, decreased Nrf2 levels, increased oxidative stress, induced the activation of nuclear factor-κB (NF-κB), and elevated proinflammatory cytokine levels, leading to hepatic damage. TAA administration produced similar effects, excluding steatosis. Caffeine increased Nrf2 levels; attenuated oxidative stress markers, including malondialdehyde and 4-hydroxynonenal; restored normal, reduced glutathione levels; and reduced NF-κB activation, inflammatory cytokine levels, and damage. Our findings suggest that caffeine may be useful in the treatment of human liver diseases.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Caffeine; Cytokines; Humans; Liver; Male; NF-E2-Related Factor 2; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats; Thioacetamide

Ochratoxin A (OTA) is an abundant mycotoxin, yet the toxicological impact of its disposition is not well studied. OTA is an organic anion transporter (OAT) substrate primarily excreted in urine despite a long half-life and extensive protein binding. Altered renal transporter expression during disease, including nonalcoholic steatohepatitis (NASH), may influence response to OTA exposure, but the impact of NASH on OTA toxicokinetics, tissue distribution, and associated nephrotoxicity is unknown. By inducing NASH in fast food-dieted/thioacetamide-exposed mice, we evaluated the effect of NASH on a bolus OTA exposure (12.5 mg/kg by mouth) after 3 days. NASH mice presented with less gross toxicity (44% less body weight loss), and kidney and liver weights of NASH mice were 11% and 24% higher, respectively, than healthy mice. Organ and body weight changes coincided with reduced renal proximal tubule cells vacuolation, degeneration, and necrosis, though no OTA-induced hepatic lesions were found. OTA systemic exposure in NASH mice increased modestly from 5.65 ± 1.10 to 7.95 ± 0.61 mg*h/ml per kg BW, and renal excretion increased robustly from 5.55% ± 0.37% to 13.11% ± 3.10%, relative to healthy mice. Total urinary excretion of OTA increased from 24.41 ± 1.74 to 40.07 ± 9.19

Topics: Animals; Disease Models, Animal; Humans; Kidney; Mice; Mycotoxins; Non-alcoholic Fatty Liver Disease; Ochratoxins; Organic Anion Transporters; Protein Isoforms; Thioacetamide

Small- and intermediate-conductance Ca

Topics: Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Collagen; Diet, High-Fat; Fatty Liver; Hepatic Stellate Cells; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Modafinil; Non-alcoholic Fatty Liver Disease; Small-Conductance Calcium-Activated Potassium Channels; Stereoisomerism; Thioacetamide

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy.

Topics: Adult; Aged; Aged, 80 and over; Alarmins; Animals; Apoptosis; Disease Models, Animal; Disease Progression; Female; Hepatic Stellate Cells; Hepatocytes; Humans; Liver; Liver Cirrhosis; Macrophages; Male; Mice; Middle Aged; Mitochondria; Non-alcoholic Fatty Liver Disease; Phagocytosis; Thioacetamide; Young Adult

There is an inadequacy of relevant animal models to study non-alcoholic steatohepatitis (NASH) and fibrosis. Here, we co-administered thioacetamide (TH) along with fast food diet (FFD) to C57BL/6 J mice for eight weeks. The treatments were: a) standard chow, SC b) FFD c) FFD + TH [75 mg/kg], FTH d) SC + TH [150 mg/kg], STH for 8 weeks. In in-vitro model, Hep3B cells were exposed to palmitic acid (PA) and TH viz. PA (0.25 mM) + TH (25 mM), PA (0.5 mM) alone and TH (50 mM) alone for 12 h, later supernatant media was transferred to LX-2 cells, for another 12 h. Molecular and cellular events related to inflammation, fibrosis, collagen deposition were studied. The FTH mice featured hepatic inflammation, severe diffuse fibrosis, and collagen deposition, which were less severe in FF & STH groups. In FTH group the protein expressions of α-SMA, TGF-ß, Col1 A1, CYP2E1, were up-regulated as compared to the FF group. The in-vivo findings were complemented in the LX-2 and Hep3B cells. The protein expressions of inflammatory and cellular injury markers were significantly higher in PA + TH exposed LX-2 cells. This novel model manifested hepatic inflammation and fibrosis in just eight weeks, which may be exploited for rapid screening of novel anti-NAFLD and liver anti-fibrotic agents.

Topics: Actins; Animals; Cell Line, Tumor; Cholesterol, Dietary; Collagen; Collagen Type I; Collagen Type I, alpha 1 Chain; Cytochrome P-450 CYP2E1; Diet, High-Fat; Hepatic Stellate Cells; Hepatocytes; Humans; Liver; Liver Cirrhosis, Experimental; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thioacetamide; Time Factors; Transforming Growth Factor beta

Lipogenesis is stimulated in the liver by an unfolded protein response (UPR) to endoplasmic reticulum stress under a variety of pathological conditions and results in the accumulation of lipids in hepatocytes. Assuming that UPR is a protective mechanism against stress, we hypothesized that the accumulated lipids might have a beneficial function. We prepared mice with fatty livers by feeding two types of high-calorie diets; a lard-rich high-calorie diet (LHD) or a menhaden oil-containing high-calorie diet (MHD), for two weeks and treated them, as well as control diet (CD)-fed mice, with thioacetamide (TAA), a liver toxicant. When a lethal dose (500mg/kg) of TAA was administered, the LHD-fed mice and the MHD-fed mice survived longer than those fed with CD. The accumulated lipids appeared to be associated with protecting the liver against TAA toxicity (200mg/kg). Consistently, lipid-loaded Hepa 1-6 cells showed a partial resistance to hydrogen peroxide toxicity compared to those cultured in conventional media. In conclusion, while sustained steatosis impairs liver function and leads to hazardous conditions, lipids that transiently accumulate as the result of UPR or other stimuli may exert a beneficial function in the liver at least partly through scavenging reactive oxygen species.

Topics: Animals; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Fish Oils; Hepatocytes; Hydrogen Peroxide; Lipid Droplets; Lipid Peroxidation; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Reactive Oxygen Species; Thioacetamide; Time Factors

To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD).. We have performed a series of. Upregulation of KCa3.1 expression was recorded in TAA-induced and high fat diet-induced liver disease. Treatment with Senicapoc decreased palmitic acid-driven HepG2 cell death. (. These data suggest that Senicapoc interrupts more than one node in progressive fatty liver disease by its anti-steatotic and anti-fibrotic activities, serving as a double-edged therapeutic sword.

Topics: Acetamides; Animals; Apoptosis; Biomarkers, Tumor; Diet, High-Fat; Fibrosis; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Inflammation; Intermediate-Conductance Calcium-Activated Potassium Channels; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Rats; Rats, Wistar; Thioacetamide; Trityl Compounds; Up-Regulation

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic condition of the liver in the western world. There is only little evidence about altered sensitivity of steatotic liver to acute toxic injury. The aim of this project was to test whether hepatic steatosis sensitizes rat liver to acute toxic injury induced by thioacetamide (TAA). Male Sprague-Dawley rats were fed ad libitum a standard pelleted diet (ST-1, 10% energy fat) and high-fat gelled diet (HFGD, 71% energy fat) for 6 weeks and then TAA was applied intraperitoneally in one dose of 100 mg/kg. Animals were sacrificed in 24-, 48- and 72-h interval after TAA administration. We assessed the serum biochemistry, the hepatic reduced glutathione, thiobarbituric acid reactive substances, cytokine concentration, the respiration of isolated liver mitochondria and histopathological samples (H+E, Sudan III, bromodeoxyuridine [BrdU] incorporation). Activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase and concentration of serum bilirubin were significantly higher in HFGD groups after application of TAA, compared to ST-1. There were no differences in activities of respiratory complexes I and II. Serum tumour necrosis factor alpha at 24 and 48 h, liver tissue interleukin-6 at 72 h and transforming growth factor β1 at 24 and 48 h were elevated in TAA-administrated rats fed with HFGD, but not ST-1. TAA-induced centrilobular necrosis and subsequent regenerative response of the liver were higher in HFGD-fed rats in comparison with ST-1. Liver affected by NAFLD, compared to non-steatotic liver, is more sensitive to toxic effect of TAA.

Topics: Animals; Carcinogens; Cell Proliferation; Cholesterol; Cytokines; Dietary Fats; Disease Models, Animal; Electron Transport Complex I; Electron Transport Complex II; Fatty Liver; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Thioacetamide; Thiobarbituric Acid Reactive Substances; Triglycerides