Acute Carbon Tetrachloride Research Articles

Potential hepatoprotective properties of synthetic derivatives of thiourea — 2-aminobenzothiazole and IEM-2320

BACKGROUND: Toxic hepatitis is characterized by a significant severity of the course and by high mortality. So, search for effective means of correcting this condition seems to be relevant. It has previously been shown that some thiazolo[5,4-b]indole derivatives are capable to prevent experimental toxic liver damage in laboratory animals. In continuation of this direction, the study of the hepatoprotective properties of synthetic derivatives of thiourea 2-aminobenzothiazole and IEM-2320 was undertaken. AIM: To study the potential hepatoprotective properties of 2-aminobenzothiazole and IEM-2320 in acute carbon tetrachloride poisoning. MATERIALS AND METHODS: Experiments were carried out on 30 male white outbred rats (150–270 g). On a model of carbon tetrachloride poisoning (50% solution of CCl4 in vaseline oil, 0.2 ml/100 g of body weight), the potential hepatoprotective properties of 2-aminobenzothiazole (32 mg/kg) and IEM-2320 (20 mg/kg) were investigated. Ademethionine (Heptral, AbbVie, S.r.L, Italy) at a dose of 20 mg/kg was used as a comparison drug. The studied drugs were administered intraperitoneally 4 times: one hour before the introduction of CCl4, and then — for three subsequent days after the poisoning with CCl4. The results were compared with those of 2 control groups. Animals of the 1st control group were not exposed to CCl4, instead of the studied drugs, they were injected with an equivalent volume of saline solution (0.2 ml/100 g of body weight). Animals of the 2nd control group did not receive any treatment after the CCl4 poisoning. Blood was taken on the seventh day of the experiment. The total contents of protein, glucose, and total cholesterol in blood serum were determined, and the activities of alanine aminotransferase and aspartate aminotransferase were evaluated. RESULTS: Under the CCl4 poisoning, the administration of 2-aminobenzothiazole led to a significant decrease in the concentrations of glucose, total protein, total cholesterol and alanine aminotransferase activity. When IEM-2320 was administered under the condition of poisoning, a decrease in the concentrations of total protein, glucose, urea, total cholesterol, and the alanine aminotransferase activity was observed. CONCLUSIONS: A significant decrease in the biochemical parameters of blood serum after administration of 2-aminobenzothiazole and IEM-2320 under the condition of CCl4 poisoning demonstrates thir potential hepatoprotective properties under acute hepatotropic poisonings.

Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11.

Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl4) -induced liver injury or fibrosis. Ferroptosis can be induced by hepatic injury, and contributes to liver fibrosis development. The exact functional mechanism underlying luteolin inhibition of hepatic injury and whether ferroptosis is involved are unclear. Mice model and cell model of liver injury were constructed or induced to explore the effect and molecular mechanisms of Luteolin in the treatment of hepatic injury using CCl4. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to evaluate HepG2 cell viability and apoptosis. The differential expressed genes involved in liver injury were scanned using RNA-seq and confirmed using functional study. Western blot was used to detect the indicators related to ferroptosis. Luteolin attenuated hepatic injury by alleviating cell morphology and decreasing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in vivo mice models, and increasing cell viability, downregulating arachidonate 12-lipoxygenase (ALOX12), cyclooxygenase-2 (COX-2) and P21 protein expression, suppressing apoptosis in vitro cell models. Luteolin also inhibited ferroptosis by stimulating glutathione peroxidase 4 (GPX4) and mitochondrial ferritin (FTMT) protein expression, increasing glutathione (GSH) content, and minimizing Fe2+ and malondialdehyde (MDA) levels. Solute carrier family 7a member 11 (SLC7A11) was identified to be a key regulatory gene that participated in luteolin attenuation of CCl4-induced hepatic injuries in HepG2 cells using Microarray assay. Functional study showed that SLC7A11 can alleviate hepatic injury and ferroptosis. Luteolin attenuated CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. SLC7A11 may serve as a novel alternative therapeutic target for hepatic injury.

Hepatocyte survival and proliferation by fibroblast growth factor 7 attenuates liver inflammation, and fibrogenesis during acute liver injury via paracrine mechanisms

Hepatocyte damage during liver injury instigates activation of macrophages and hepatic stellate cells (HSCs) resulting in liver inflammation and fibrosis respectively. Improving hepatocyte survival and proliferation thereby ameliorating inflammation and fibrosis represents a promising approach for the treatment of liver injury. In the liver, fibroblast growth factors (FGFs) play a crucial role in promoting hepatocyte proliferation and tissue regeneration. Among 22 FGFs, FGF7 induces hepatocyte survival and liver regeneration as shown previously in mouse models of cholestatic liver injury and partial hepatectomy. We hypothesized that FGF7 promotes hepatocyte survival and proliferation by interacting with FGFR2b, expressed on hepatocytes, and ameliorates liver injury (inflammation and early fibrogenesis) via paracrine mechanisms. To prove this hypothesis and to study the effect of FGF7 on hepatocytes and liver injury, we administered FGF7 exogenously to mice with acute carbon tetrachloride (CCl4)-induced liver injury. We thereafter studied the underlying mechanisms and the effect of exogenous FGF7 on hepatocyte survival and proliferation, and the consequent paracrine effects on macrophage-induced inflammation, and HSCs activation in vitro and in vivo. We observed that the expression of FGF7 as well as FGFR2 is upregulated during acute liver injury. Co-immunostaining of FGF7 and collagen-I confirmed that FGF7 is expressed by HSCs and is possibly captured by the secreted ECM. Immunohistochemical analysis of liver sections showed increased hepatocyte proliferation upon exogenous FGF7 treatment as determined by Ki67 expression. Mechanistically, exogenous FGF7 improved hepatocyte survival (and increased drug detoxification) via AKT and ERK pathways while maintaining hepatocyte quiescence restricting hepatocarcinogenesis via P27 pathways. Flow cytometry analysis revealed that improved hepatocyte survival and proliferation leads to a decrease in infiltrated monocytes-derived macrophages, as a result of reduced CCL2 (and CXCL8) expression by hepatocytes. Moreover, conditioned medium studies showed reduced collagen-I secretion by HSCs (indicative of HSCs activation) upon treatment with FGF7-treated hepatocytes conditioned medium. Altogether, we show that exogenous administration of FGF7 induces hepatocyte survival and proliferation and leads to amelioration of inflammatory response and fibrosis in acute liver injury via paracrine mechanisms. Our study further demonstrates that FGF7, FGF7 derivatives, or nano-engineered FGF7 may benefit patients with hepatic dysfunction.

Reparative and Antioxidant Effects of New Analogues of Immunomodulator Thymogen in Experimental Model of Liver Damage.

We studied the reparative and antioxidant effects of Thymogen and its new structural analogues obtained by binding amino acid D-Ala to the N- or C-end of the peptide molecule in acute toxic hepatopathy. Intragastric administration of carbon tetrachloride for 5 days caused the development of fat degeneration of hepatocytes, a decrease in catalase activity, and an increase in malondialdehyde concentration. Administration of peptides suppressed oxidative peroxidation and stimulated reparative regeneration of hepatocytes; Thymogen analogues produced more pronounced hepatotropic and antioxidant effects than Thymogen. Inclusion of D-Ala enhanced the effect of Thymogen on the processes of regeneration in hepatocytes and the antioxidant effect under conditions of acute carbon tetrachloride hepatopathy. The highest efficiency was achieved when the amino acid was added to the C-end of the molecule.

Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration

Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration. Hepatocyte proliferation was studied invitro in hepatoma cell lines and exvivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by invivo administration of interferon receptor antibody in MAGLMye-/- mice. Precision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice. Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming. By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.

ANTIOXIDANT ACTIVITY AND ENERGY PROTECTIVE EFFECT OF HEDYSARUM ALPINUM L. EXTRACT IN ACUTE CCL4-INDUCED HEPATITIS

Relevance. The course of physiological processes in the norm is significantly influenced by the pro- and antioxidant, as well as the energy status of the body. In the liver, biochemical disturbances in the functioning of these systems contribute to the development or aggravate the course of patholog-ical conditions such as chronic hepatitis, cholelithiasis, chronic cholecystitis, etc. In this regard, the assessment of the influence of the studied herbal remedies that have a hepatoprotective effect on energy metabolism and the state of the antioxidant system of the body in experimental pathological processes is still relevant. The purpose of the study was to evaluate the effect of Hedysarum alpinum L. dry extract on antioxidant status and energy metabolism in white rats with acute carbon tetrachloride-induced hepatitis. Material and methods. The studies were carried out on white Wistar rats. Acute carbon tetrachloride hepatitis was induced by subcutaneous injec-tion of a 50% oily solution of CCl4 for 4 days at a dose of 1.0 ml/kg. The dry extract H. alpinum was administered per os to animals at doses of 100 and 200 mg/kg. On the 7th and 14th days of the experiment, the energy metabolism and antioxidant status of the liver were assessed. The content of ATP, lactate, pyruvate, GSH the concentration of malondialdehyde (MDA), the activity of catalase, glutathione peroxidase, glutathione reductase, super-oxide dismutase (SOD) in the liver homogenate were determined. The evaluation of the antiradical activity of the studied agent was carried out in vitro: binding of 2,2-diphenyl-1-picrylhydrazyl (DPPH˙), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS˙+). Results. The dry extract H. alpinum was administered to animals at doses of 100 and 200 mg/kg, increases the activity of SOD, catalase, glutathione peroxidase, glutathione reductase and the content of GSH, reduces the content of MDA, increases the content of ATP, reduces the level of lactate; cor-rects the lactate/pyruvate ratio compared to the control. The dry extract of H. alpinum demonstrated the most pronounced antioxidant activity and en-ergy-protective effect at a dose of 200 mg/kg. The extract of H. alpinum characterized by a pronounced radical-binding activity against DPPH˙ and ABTS˙+ (IC50DPPH˙=25.1 µg/ml; IC50ABTS˙+=47.1 µg/ml), which was due to the high content in its composition of phenolic compounds (2-C-β-D-glucopyranosyl-1,3,6,7-tetraoxyxanthone, rutin, catechins, xanthones), flavonols and polysaccharides. Conclusions. The dry extract H. alpinum at doses of 100 and 200 mg/kg reduces the intensity of oxidative stress and corrects the state of energy metabolism in carbon tetrachloride-induced acute liver injury in white rats, showing a pronounced antioxidant, antiradical and energy-protective effects.

IL-2 availability regulates the tissue specific phenotype of murine intra-hepatic Tregs.

CD4+CD25+Foxp3+ Tregs are known to acquire tissue-specific features and exert cytoprotective and regenerative functions. The extent to which this applies to liver-resident Tregs is unknown. In this study, we aimed to explore the phenotypic and functional characteristics of adult murine liver resident Tregs during homeostasis. Additionally, we investigated their role in ameliorating liver inflammation and tissue damage. Quantification of Foxp3+CD4+CD25+ cells comparing different tissues showed that the liver contained significantly fewer resident Tregs. A combination of flow cytometry phenotyping and microarray analysis of intra-hepatic and splenic Tregs under homeostatic conditions revealed that, although intra-hepatic Tregs exhibited the core transcriptional Treg signature, they expressed a distinct transcriptional profile. This was characterized by reduced CD25 expression and increased levels of pro-inflammatory Th1 transcripts Il1b and Ifng. In vivo ablation of Tregs in the Foxp3-DTR mouse model showed that Tregs had a role in reducing the magnitude of systemic and intra-hepatic inflammatory responses following acute carbon tetrachloride (CCl₄) injury, but their absence did not impact the development of hepatocyte necrosis. Conversely, the specific expansion of Tregs by administration of IL-2 complexes increased the number of intra-hepatic Tregs and significantly ameliorated tissue damage following CCl₄ administration in C57BL/6 mice. The cytoprotective effect observed in response to IL-2c was associated with the increased expression of markers known to regulate Treg suppressive function. Our results offer insight into the transcriptome and complex immune network of intra-hepatic Tregs and suggest that strategies capable of selectively increasing the pool of intra-hepatic Tregs could constitute effective therapies in inflammatory liver diseases.

Effect of dried Persimmon fruit (Diospyros kaki) on acute carbon tetrachloride induced hepatotoxicity in laboratory rats

Effect of dried Persimmon fruit (Diospyros kaki) on acute carbon tetrachloride induced hepatotoxicity in laboratory rats

Effectiveness of food concentrate phenolic compounds of apples in experimental membrane pathologies

Apple fruits are an available source of phenolic compounds that exhibit a wide range of biological activities (antioxidant, anti-inflammatory, membrane stabilizing, etc.). The antioxidant properties of food concentrate phenolic compounds of apples (Concentrate) were studied in vitro in models of spontaneous and ascorbate induced lipid peroxidation (LPO) in rat liver homogenate, and acute carbon tetrachloromethane hepatitis was chosen as in vivo model in rats. Membrane stabilizing activity was evaluated by the degree of hemolysis in blood samples from the tail vein. The effect of Concentrate on vascular permeability was studied considering the time of animal skin papules staining at the site of injection of phlogogenic substances. Hepatoprotective activity in the model of acute carbon tetrachloride hepatitis was assessed by changes in prooxidant-antioxidant status in liver homogenate and liver enzymes activity in serum. Significant antioxidant effect of Concentrate was fixed in models of spontaneous and ascorbate induced LPO (TBA reactants’ content was 3.12 times and 2.25 times lower than control for spontaneous LPO and ascorbate induced LPO, respectively) and under tetrachloride hepatitis (Concentrate antioxidant activity was 47.8%). The membrane-protective activity of the studied Concentrate was also high and reached 50.1%. Also, Concentrate demonstrated capillary-strengthening properties, reducing the permeability of the vascular wall, which was caused by three different chlorogens, most notably by zymosan (Concentrate significantly delayed the stain utilization from the bloodstream by 2.14 times compared to control). Newly developed concentrate showed complex hepatoprotective activity, improving the indices of antioxidant-prooxidant status and activity of liver cytolysis enzymes in rats with tetrachloromethane hepatitis. The transparent corrective effects of Concentrate are the result of synergism and additivity of its multiple components and indicate the prospects of its further research in order to develop medications for the prophylaxis and treatment of diseases associated with membrane damage.

Comparative Evaluation of Hepatoprotective Activities of <i>Trigonella</i><i> foenum-graecum</i> (seeds), <i>Cymbopogon</i><i> proximus</i> and <i>Acacia nilotica</i> on a model of acute carbon tetrachloride hepatitis in rats

An experimental study of the beneficial effect of herbal preparations on acute toxic liver damage with carbon tetrachloride (CCl4) in animals was conducted The goal is to Compare the hepatoprotective effect of three water extracts of herbal preparations: (I) Trigonella foenum-graecum (seeds), (II) Cymbopogon proximus, (III) Asasia nilotica Material and methods. To simulate acute toxic liver damage, 50% CCl4 was administered once intraperitonally in doses of 0.6 ml, 0.3 ml, and 0.2 ml. Control groups: K1-1 group intact animals without injections; K2: groups 2, 3, 4. introduced saline solution (FR) without Ssl4 in the volume of 2 ml. Experimental groups: 5, 6, 7 and 8 studied the hepatoprotective properties of aqueous solutions of the studied drugs after intraperitoneal administration of Ssl4 or FR. Researched herbs: I, II, III, in different doses were administered 2 ml of an aqueous solution in breeding 1:10, observation period 5 days, the blood, for research stabilized solution of sodium citrate in the ratio of 1:10, studied the properties of blood cells hematological analyzer PCE-90Vet (USA). The content of total protein, albumin, total cholesterol, triglycerides, urea, creatinine and transaminase activity - ALT, AST-were recorded in the blood serum using an automatic analyzer of the company “ HUMASTAR 600 “(Germany)», Results and discussion. Water extracts of preparations I and II prevented the reduction of red blood cells and platelets, and activated the macrophage pool. All the herb extracts studied prevent platelet reduction, however, but do not bring them up to the indicators of intact animals. The use of solution III prevented the growth of the cytolysis enzyme-ALT. All studied extracts in acute carbon tetrachloride intoxication. they warned of an increase in hypertriglyceremia. The introduction of water extracts II, III in the 1:10 ratio prevented the development of necrotic changes in hepatocytes, inflammatory infiltration, manifestations of fatty dystrophy, and preserved the architectonics of the liver lobule.

Morphological changes in parenchymal organs of laboratory animals in acute effect of carbon tetrachloride

Introduction. Among noninfectious diseases, one of the leading places belongs to pathologies caused by the action of industrial toxicants. In this regard, the search for drugs for the prevention and treatment of various intoxications is one of the priority tasks of public health. Treatment of intoxication with drugs with antioxidant and antihypoxic activity is more effective. The aim of this study was to investigate morphological changes in parenchymal organs (liver, kidneys, and pancreas) under acute exposure to high doses of carbon tetrachloride and to evaluate the effectiveness of their correction with a new composition of oxymethyluracil with ascorbic acid. Material and methods. The composition of 5-hydroxy-6-methyluracil with ascorbic acid was first synthesized at the Ufa Institute of Chemistry, Ufa Federal Research Center, RAS. The preventive effect of the new drug was studied in comparison with “Heptor” on the carbon tetrachloride-induced liver injury model. Morphological studies of the liver, pancreas, and kidneys of laboratory animals were carried out. Results. Studies have shown the prophylactic administration of new composition of 5-hydroxy-6-methyluracil with ascorbic acid to have a protective effect on the structure of parenchymal organs in acute carbon tetrachloride intoxication, comparable to the drug “Heptor” (possibly superior). However, reparative properties were observed only in the drug “Heptor”. Conclusion. Comparative estimation of morphological changes in parenchymal organs under acute exposure to high doses of carbon tetrachloride indicates the protective effect of prophylactic administration of the composition of 5-hydroxy-6-methyluracil with ascorbic acid, comparable to the drug “Heptor” (possibly superior).

Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo

Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl4)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.

THE EFFECTS OF L-ORNITINE AND L-ARGININE ON THE PROCESSES OF LIPID PEROXIDATION IN THE FUNCTIONAL LAYERS OF KIDNEYS ON THE BACKGROUND OF ACUTE TOXIC HEPATITIS

The aim is to evaluate the effects of L-arginine and L-ornithine on the processes of lipid peroxidation in homogenates of renal cortex, renal medulla and renal papilla under conditions of acute toxic hepatitis. Materials and methods: The study was performed on 40 outbred white male rats with experimental hepatitis, caused by carbon tetrachloride. The animals were divided into five groups: control group (the rats were simulated carbon tetrachloride poisoning and its correction by administering of olive oil and normal saline in equivalent doses), acute carbon tetrachloride hepatitis (single intraperitoneal injection of 50% carbon tetrachloride oil solution at the dose of 2 mlxkg-1 of body weight and simulation of treatment by administration of normal saline in equivalent doses), acute carbon tetrachloride hepatitis + L-ornithine (1000 mgxkg-1), acute carbon tetrachloride hepatitis + L-arginine (500 mgxkg-1) and acute carbon tetrachloride hepatitis + combination of substances. Results: On the background of acute carbon tetrachloride intoxication it was observed the development of renal failure in experimental animals, manifested by activation of lipid peroxidation processes in homogenates of renal cortex, renal medulla and renal papilla. The administration of L-ornithine and L-arginine demonstrates positive impact on renal function and hepato-renal syndrome by stabilization of cell membranes and regeneration of functional capacity of injured renal cells. Conclusions: The results of our study confirm both the presence of unidirectional effects and absence of toxic influences of L-ornithine and L-arginine on renal cells under the conditions of acute carbon tetrachloride intoxication, which are the most important requirements for modern drugs for the treatment of hepato-renal syndrome.

Hepatic injury and inflammation alter ethanol metabolism and drinking behavior

While liver injury is commonly associated with excessive alcohol consumption, how liver injury affects alcohol metabolism and drinking preference remains unclear. To answer these questions, we measured the expression and activity of alcohol dehydrogenase 1 (ADH1) and acetaldehyde dehydrogenase 2 (ALDH2) enzymes, ethanol and acetaldehyde levels in vivo, and binge-like and preferential drinking behaviors with drinking in the dark and two-bottle choice in animal models with liver injury. Acute and chronic carbon tetrachloride (CCl4), and acute LPS-induced liver injury repressed hepatic ALDH2 activity and expression and consequently, blood and liver acetaldehyde concentrations were increased in these models. In addition, chronic CCl4 and acute LPS treatment inhibited hepatic ADH1 expression and activity, leading to increases in blood and liver ethanol concentrations. Consistent with the increase in acetaldehyde levels, alcohol drinking behaviors were reduced in mice with acute or chronic liver injury. Furthermore, oxidative stress induced by hydrogen peroxide attenuated ADH1 and ALDH2 activity post-transcriptionally, while proinflammatory cytokines led to transcriptional repression of ADH1 and ALDH2 in cultured hepatocytes, which correlated with the repression of transcription factor HNF4α. Collectively, our data suggest that alcohol metabolism is suppressed by inflammation and oxidative stress, which is correlated with decreased drinking behavior.

Dietary chia seeds (Salvia hispanica) improve acute dyslipidemia and steatohepatitis in rats.

Chia seeds (Salvia hispanica L.) are rich in omega fatty acids. Dyslipidemia and steatohepatitis are diseases that require effective treatments in obese and non-obese patients. The aim was to evaluate the effect of chia intake on acute tyloxapol (TI)-induced dyslipidemia, on acute carbon tetrachloride (TC)-induced steatohepatitis, and on mixed damage (TC+TI) in non-obese rats. Four experimental groups were fed for 4weeks a diet with established rodent food (DE), and four groups were fed a diet with 15% added chia (DC). Plasma samples were analyzed for total cholesterol, triglycerides, glucose, biochemical liver damage markers, and tumor necrosis factor-α (TNF-α). Liver samples were used to quantify glycogen, catalase, lipid peroxidation, and TNF-α. A histopathological analysis was performed. DC intake partially or totally prevented steatohepatitis, and reduced lipids in the dyslipidemic groups. The hypolipidemic and hepatoprotective effects of chia may be correlated to its high content of α-linolenic acid (omega-3) and phenolics. PRACTICAL APPLICATIONS: Metabolic syndrome is associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are currently the most common causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Dyslipidemia is a significant risk factor for NAFLD and NASH. Non-obese patients may have NAFLD or NASH. Metabolic syndrome and dyslipidemia are more strongly associated with NAFLD in non-obese than in obese patients. This is the first study evaluating the hypolipidemic and hepatoprotective effects of chia seed intake on acute dyslipidemia and/or steatohepatitis caused by the individual or combined administration of the inducers tyloxapol and carbon tetrachloride, respectively, in non-obese rats. The pharmacological effects of dietary chia are correlated to its high content of omega-3 and omega-6 (1:1), protein, dietary fiber, and phenolics. The results suggest that inclusion of chia in diets of non-obese patients with dyslipidemia and/or NAFLD/NASH may improve their health state and preventing cirrhosis or HCC.

Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/β-Catenin Signaling.

In the liver, Wnt/β-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of β-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.

MORPHOLOGIC SPECIFICITIES OF HEPATOPROTECTIVE EFFECTS OF ANTIHYPOXANTS IN EXPERIMENTAL ACUTE LIVER DAMAGE WITH CARBON TETRACHLORIDE

The article presents the results on liver morphologic changes in acute carbon tetrachloride damage and its preventive correction by antihypoxants: complex oxymethyluracil agents (with sodium succinate and ascorbic acid). It has been shown that carbon tetrachloride causes pronounced morphologic changes in the liver and preventive use of the antihypoxants studied decreases intensity and prevalence of dystrophic processes in liver tissues. The analysis of comparative efficiency of the agents studied has been carried out.

Atriplex halimus aqueous extract abrogates carbon tetrachloride-induced hepatotoxicity by modulating biochemical and histological changes in rats

ABSTRACTThe objective of this study was to evaluate the potential protective effect of Atriplex halimus aqueous leaves extract (AHAE) against acute carbon tetrachloride (CCl4)-induced oxidative stress in rats. Rats were randomly divided into four groups: group (C) served as a control treated with 1 ml/(kg bw) of olive oil, and group (CCl4) was treated with 1 ml CCl4/(kg bw) dissolved in olive oil administered by intraperitoneal way. Rats of group (CCl4+AHAE) have received CCl4 and treated with 200 mg AHAE/(kg bw). Animals of group (AHAE) were treated with 200 mg/(kg bw) of AHAE. A significant increase in malondialdehyde levels in liver associated with a decrease in antioxidant enzyme activities and reduced glutathione content was observed in CCl4 group compared to controls. The administration of AHAE to CCl4+AHAE group improved all parameters studied. We conclude that CCl4 induces oxidative stress and modifies biochemical parameters and histological aspects of liver. Administration of AHAE alleviates the toxicity induced by this organic compound.

Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage

ObjectiveLiver injury impacts hepatic inflammation in part via Toll-like receptor (TLR) signalling. Triggering receptor expressed on myeloid cells 2 (TREM-2) modulates TLR4-mediated inflammation in bone marrow (BM)-derived macrophages but its...

Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency

BackgroundCell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl4)-induced liver damage compared to healthy controls (Wt Igf+/+). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1+/−).MethodsThree groups of 25 ± 5-week-old healthy male mice (Wt Igf+/+) were included in the protocol: untreated controls (Wt). Controls that received CCl4 (Wt + CCl4) and Wt + CCl4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl4 + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1+/−) groups were studied: untreated Hz, Hz + CCl4, and Hz + CCl4 + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM.ResultsAn altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl4 + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl4. Moreover, there was a correlation between MDA levels and the histological damage score (Pearson’s r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma.ConclusionsIGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.