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Metabolic dysfunction-associated Steatohepatitis (MASH), is a prominent cause for liver cirrhosis. MASH-cirrhosis is responsible for liver complications and there is no specific treatment. To develop new therapeutic approaches, animal models are needed. The aim of this study was to develop a fast animal model of MASH-cirrhosis in rats reflecting the human disease. Carbon tetrachloride (CCl4) injections in combination with a high-fat Western diet (WD) were used to induce MASH-cirrhosis. To accelerate liver injury, animals received phenobarbital (PB) in their drinking water using two different regimens. Rats developed advanced MASH-cirrhosis characterized by portal hypertension, blood biochemistry, hepatic ballooning, steatosis, inflammation and fibrosis. Importantly, rats receiving low-dose PB for the long term (LT) showed ascites after 6 weeks, whereas rats with high-dose short-term (ST) PB developed ascites after 8 weeks. ST- and LT-treated rats showed increased portal pressure (PP) and decreased mean arterial pressure (MAP). Of note, hepatocyte ballooning was only observed in the LT group. The LT administration of low-dose PB with CCl4 intoxication and WD represents a fast and reproducible rat model mimicking decompensated MASH-cirrhosis in humans. Thus, CCl4 + WD with LT low-dose phenobarbital treatment might be the preferred rat animal model for drug development in MASH-cirrhosis. [ABSTRACT FROM AUTHOR]

Objective(s): Liver fibrosis is a wound healing response characterized by excessive accumulation of extracellular matrix proteins. This study aimed to investigate the effects of resveratrol treatment on the TGF-β/SMAD signaling pathway and related biochemical parameters, apoptosis, and liver regeneration phenobarbital-CCl4 induced hepatic fibrosis rat model. Materials and Methods: This model was created through phenobarbital and CCl4 (0.2–0.35 ml/kg). Resveratrol (1 mg/kg/day) was administered to the fibrosis and control groups. Immunohistochemical staining was performed to evaluate αSMA, TGF-β1, and PCNA in liver tissue. The TUNEL method and Masson’s Trichome staining were used to determine apoptosis and collagen accumulation. AST, ALP, ALT, total protein, and total bilirubin levels were measured to determine biochemical status. SMAD2, SMAD3, SMAD4, and SMAD7 expression levels were measured to determine TGF-β1 related hepatic fibrosis. Results: The SMAD2, SMAD3, and SMAD4 mRNA expression levels were increased and the SMAD7 mRNA expression level was decreased in the fibrosis control group. The SMAD7 mRNA expression level was higher in the phenobarbital-CCl4 induced resveratrol treated group. Increased biochemical parameters indicating hepatic damage, increased number of apoptotic cells, and collagen accumulation surrounding the central vein were observed in the fibrosis group compared with the other groups. It was concluded that administration of resveratrol ameliorates the adverse effects of hepatic fibrosis by regulating biochemical parameters, controlling TGF-β1/SMAD signaling, enhancing tissue regeneration, and reducing apoptosis in liver cells. Conclusion: Resveratrol can be a beneficial option for the prevention of liver damage in a phenobarbital-CCl4 induced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Objective(s): Liver fibrosis is a wound healing response characterized by excessive accumulation of extracellular matrix proteins. This study aimed to investigate the effects of resveratrol treatment on the TGF-β/SMAD signaling pathway and related biochemical parameters, apoptosis, and liver regeneration phenobarbital-CCl4 induced hepatic fibrosis rat model. Materials and Methods: This model was created through phenobarbital and CCl4 (0.2–0.35 ml/kg). Resveratrol (1 mg/kg/day) was administered to the fibrosis and control groups. Immunohistochemical staining was performed to evaluate αSMA, TGF-β1, and PCNA in liver tissue. The TUNEL method and Masson’s Trichome staining were used to determine apoptosis and collagen accumulation. AST, ALP, ALT, total protein, and total bilirubin levels were measured to determine biochemical status. SMAD2, SMAD3, SMAD4, and SMAD7 expression levels were measured to determine TGF-β1 related hepatic fibrosis. Results: The SMAD2, SMAD3, and SMAD4 mRNA expression levels were increased and the SMAD7 mRNA expression level was decreased in the fibrosis control group. The SMAD7 mRNA expression level was higher in the phenobarbital-CCl4 induced resveratrol treated group. Increased biochemical parameters indicating hepatic damage, increased number of apoptotic cells, and collagen accumulation surrounding the central vein were observed in the fibrosis group compared with the other groups. It was concluded that administration of resveratrol ameliorates the adverse effects of hepatic fibrosis by regulating biochemical parameters, controlling TGF-β1/SMAD signaling, enhancing tissue regeneration, and reducing apoptosis in liver cells. Conclusion: Resveratrol can be a beneficial option for the prevention of liver damage in a phenobarbital-CCl4 induced hepatic fibrosis.

Metabolic dysfunction-associated Steatohepatitis (MASH), is a prominent cause for liver cirrhosis. MASH-cirrhosis is responsible for liver complications and there is no specific treatment. To develop new therapeutic approaches, animal models are needed. The aim of this study was to develop a fast animal model of MASH-cirrhosis in rats reflecting the human disease. Carbon tetrachloride (CCl4) injections in combination with a high-fat Western diet (WD) were used to induce MASH-cirrhosis. To accelerate liver injury, animals received phenobarbital (PB) in their drinking water using two different regimens. Rats developed advanced MASH-cirrhosis characterized by portal hypertension, blood biochemistry, hepatic ballooning, steatosis, inflammation and fibrosis. Importantly, rats receiving low-dose PB for the long term (LT) showed ascites after 6 weeks, whereas rats with high-dose short-term (ST) PB developed ascites after 8 weeks. ST- and LT-treated rats showed increased portal pressure (PP) and decreased mean arterial pressure (MAP). Of note, hepatocyte ballooning was only observed in the LT group. The LT administration of low-dose PB with CCl4 intoxication and WD represents a fast and reproducible rat model mimicking decompensated MASH-cirrhosis in humans. Thus, CCl4 + WD with LT low-dose phenobarbital treatment might be the preferred rat animal model for drug development in MASH-cirrhosis.

Chronic liver injury caused by carbon tetrachloride (CCl4) induces liver fibrosis, which can escalate to cirrhosis and hepatocellular carcinoma. This study investigated emodin's impact on CCl4-induced liver fibrosis and inflammation in mice, along with its underlying mechanisms. While previous studies have acknowledged CCl4's role in liver fibrosis, the potential therapeutic value of emodin remains inadequately explored. The study sought to bridge this gap by assessing morphological changes and molecular mechanisms contributing to CCl4-induced liver fibrosis and investigating emodin's potential therapeutic effects. Thirty male albino rats were split into three groups (n = 10 each), undergoing an 8-week CCl4 regimen, supplemented by emodin during the final 2 weeks. Morphological, biochemical, and molecular analyses were performed on liver tissues. Hematoxylin and eosin staining, as well as enzyme-level assessments, exposed significant liver damage and elevated liver enzyme levels due to CCl4 exposure. In contrast, emodin administration resulted in reduced enzyme levels, indicating potential therapeutic benefits for liver function. Molecular analysis revealed increased mRNA expression of markers like SMAD4, α-SMA, TGF, MDA, Nrf2, and pro-inflammatory factors IL-6 and TNF-α due to CCl4. However, combined emodin and CCl4 treatment downregulated these genes and upregulated anti-inflammatory markers IL-1β and IL-10, alongside hepatic and cancer-specific markers like HNF-α, albumin, p53, and AFP. These findings suggest emodin as a therapeutic agent for mitigating CCl4-induced liver damage and inflammation. Emodin's regulation of the TGFβ/Smad4 pathway plays a pivotal role in attenuating liver fibrosis and inflammation caused by CCl4. Consequently, this study bridges the gap between animal studies and potential clinical applications, providing crucial insights for future therapeutic strategies addressing liver fibrosis and inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation. Methods: Mice lacking SOCS1 in HSCs (Socs1DHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated. Results: Socs1DHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1DHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1DHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1DHSC mice than in Socs1fl/fl mice. Discussion: Our findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and aim: Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl4)-induced fibrotic changes in mice. Methods: Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl4 2 mL/kg BW, intraperitoneal twice weekly) and three CCl4-intoxicated groups receiving either SOF or DAC or their combination. All CCl4 groups received CCl4 for 12 weeks followed by DAAs for another 12 weeks. Results: CCl4-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl4-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl4-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl4-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl4-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone. Conclusions: SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl4-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.

IntroductionHepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation.MethodsMice lacking SOCS1 in HSCs (Socs1ΔHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated.ResultsSocs1ΔHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1ΔHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1ΔHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1ΔHSC mice than in Socs1fl/fl mice. DiscussionOur findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis.

Cichorium intybus and Silybum marianum have therapeutic role in hepatocellular damage in oxidative stress. They play important role to protect hepatic cell in liver injury and normal the serum level of liver enzymes. Aims and Objectives: In this the function of liver and evaluate the liver serum enzyme levels in induced liver injury of rabbits and see the effect of Cichorium intybus and Silybum marianum plants extracts Methodology: Ethanol extracts are prepared of Cichorium intybus and Silybum marianum separately. Liver of rabbits are damaged with CCl4. The elevated values of liver enzymes (ALT, AST, ALP, Total protein, Albumin and Bilirubin). . Results: Cichorium intybus and Silybum marianum decreased the elevated levels of damaged liver enzymes. Silybum marianum has more potential than Cichorium intybus. The combine effect of both plants is more than individual plants. [ABSTRACT FROM AUTHOR]

Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeutic strategy for liver cirrhosis. In this study, we examined the therapeutic effects of NK cells in the carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model. NK cells were isolated from the mouse spleen and expanded in the cytokine-stimulated culture medium. Natural killer group 2, member D (NKG2D)-positive NK cells were significantly increased after a week of expansion in culture. The intravenous injection of NK cells significantly alleviated liver cirrhosis by reducing collagen deposition, HSC marker activation, and macrophage infiltration. For in vivo imaging, NK cells were isolated from codon-optimized luciferase-expressing transgenic mice. Luciferase-expressing NK cells were expanded, activated and administrated to the mouse model to track them. Bioluminescence images showed increased accumulation of the intravenously inoculated NK cells in the cirrhotic liver of the recipient mouse. In addition, we conducted QuantSeq 3′ mRNA sequencing-based transcriptomic analysis. From the transcriptomic analysis, 33 downregulated genes in the extracellular matrix (ECM) and 41 downregulated genes involved in the inflammatory response were observed in the NK cell-treated cirrhotic liver tissues from the 1532 differentially expressed genes (DEGs). This result indicated that the repetitive administration of NK cells alleviated the pathology of liver fibrosis in the CCl4-induced liver cirrhosis mouse model via anti-fibrotic and anti-inflammatory mechanisms. Taken together, our research demonstrated that NK cells could have therapeutic effects in a CCl4-induced liver cirrhosis mouse model. In particular, it was elucidated that extracellular matrix genes and inflammatory response genes, which were mainly affected after NK cell treatment, could be potential targets. [ABSTRACT FROM AUTHOR]

Objective To explore the role and underlying mechanism of C1q/TNF-related protein 6 (CTRP6) in the development process of liver disease. Methods The histopathological examination and biochemical indexes of injured livers from wild-type (CTRP6+/+) and knockout (CTRP6-/-) mice induced by intragastric administration of CCl4 were analyzed. RT-qPCR was used to detect the expression of the fibrosis marker genes (Acta2, Col1al, Mmp2 and TGF-β) and cell proliferation marker genes (Cyclin D, Cyclin E and CDK6). Results Compared with CTRP6+/+ mice, the hepatocytes in CTRP6-/- mice showed mild necrosis, looseness and swelling. The high SOD activity and low MDA level were also observed in CTRP6-/- mice liver. Meanwhile, the expression of fibrosis and cell proliferation markers in CTRP6-/- mice were significantly lower than those in CTRP6+/+ mice. Conclusions CTRP6 gene is closely related to liver disease development, and the liver fibrosis progression induced by CCl4 is alleviated by its deletion. The mechanism may be explained as that CTRP6 knockout affects the proliferative capacity of hepatocytes.

Carbon tetrachloride (CCL4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17β-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1β, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL4 group. In the CCL4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.

Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeutic strategy for liver cirrhosis. In this study, we examined the therapeutic effects of NK cells in the carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model. NK cells were isolated from the mouse spleen and expanded in the cytokine-stimulated culture medium. Natural killer group 2, member D (NKG2D)-positive NK cells were significantly increased after a week of expansion in culture. The intravenous injection of NK cells significantly alleviated liver cirrhosis by reducing collagen deposition, HSC marker activation, and macrophage infiltration. For in vivo imaging, NK cells were isolated from codon-optimized luciferase-expressing transgenic mice. Luciferase-expressing NK cells were expanded, activated and administrated to the mouse model to track them. Bioluminescence images showed increased accumulation of the intravenously inoculated NK cells in the cirrhotic liver of the recipient mouse. In addition, we conducted QuantSeq 3′ mRNA sequencing-based transcriptomic analysis. From the transcriptomic analysis, 33 downregulated genes in the extracellular matrix (ECM) and 41 downregulated genes involved in the inflammatory response were observed in the NK cell-treated cirrhotic liver tissues from the 1532 differentially expressed genes (DEGs). This result indicated that the repetitive administration of NK cells alleviated the pathology of liver fibrosis in the CCl4-induced liver cirrhosis mouse model via anti-fibrotic and anti-inflammatory mechanisms. Taken together, our research demonstrated that NK cells could have therapeutic effects in a CCl4-induced liver cirrhosis mouse model. In particular, it was elucidated that extracellular matrix genes and inflammatory response genes, which were mainly affected after NK cell treatment, could be potential targets.

Yes‐associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self‐renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic‐plus‐single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl4). To understand the role of this transcriptional coactivator in alcohol‐related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno‐associated virus (AAV8)‐mediated deletion utilizing Cre recombinase. Yap1 hepatocyte‐specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol/CCl4‐induced liver damage. Analysis of whole‐genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of Yap1 KO. Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol/CCl4‐induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol‐associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification. [ABSTRACT FROM AUTHOR]

In recent years, focus on plant research has increased to show the potential of some medicinal plants in discovery of novel compounds which could be used in treatment of some diseases. Petroselinum crispum is widely used traditionally as a food additive and herbal remedy for many ailments. This study is aimed to assess the effects of Petroselinum crispum on some liver enzymes and some haematological parameters in Carbon tetrachloride (CCL4) - induced hepatotoxicity in male wistar rats. A total of 25 wistar rats were used, which were divided into 5 groups of 5 rats each. Group 1: (control); Group 2: received IP injection of 120mg/kg mixture of CCL4 and olive oil (1:1), Groups 3, 4 and 5 were orally administered 250, 500 and 1000mg/kg extract + IP injection of 120mg/kg mixture of CCL4 and olive oil for 21 days respectively. On the 22nd day, the animals were sacrifice using chloroform anesthesia and the effects of the aqueous extract were assessed by quantifying liver enzymes such as serum aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP) and total serum protein (TP). The haematological parameters were assessed by analysis of parked cell volume (PCV), red blood cell count (RBC), white blood cells (WBC), haemoglobin (Hb) concentrations and platelet count (PLT) and followed by histopathological studies of the liver tissues. The three doses of the plant extract used in this study, showed some level of protective effect on CCL4-induced hepatotoxicity as evident by the significant reduction (P < 0.05) in serum levels of AST, ALT, and ALP along with the improved histopathological liver sections compared to CCL4 -treated animals. However the extract is more effective in the 500mg/kg compared to the 250mg/kg and 1000mg/kg. Also the results obtained for all the haematological parameters used in the study showed no significant difference among all the groups (P > 0.05). [ABSTRACT FROM AUTHOR]

Abstract Background Avocado (Persea americana) is one of the plants widely used in ethnomedicine in Nigeria. The present study was aimed at investigating effects of aqueous Avocado (Persea americana) leaf extract on total cholesterol, triacylglycerols, protein and haematological parameters in carbon tetrachloride (CCl4)-intoxicated rats. Methods We evaluated the possible effects of pre-treatment with aqueous extract of Persea americana (AEPA) on protein, total cholesterol (T-CHOL), triacylglycerols (TAGs) and haematological parameters in Wistar male albino rats intoxicated with CCl4. Group 1 was the healthy control; group 2 rats were pre-treated with Reducdyn® (100 mg/kg/day) as a standard drug, groups 4 and 5 rats were pre-treated with AEPA at a dose of 100 mg/kg and 200 mg/kg per day respectively, the treatments were administered orally for 7 days. On the seventh day, rats in the treatment groups were injected with a fresh mixture of CCl4 and olive oil (3 ml/kg, 1:1; sc). Results Pre-treatment of rats with AEPA resulted in marked increase (p

This research's primary focus was to evaluate the hepatoprotective potentials of Andrographis paniculata in carbon tetrachloride-induced hepatotoxicity in Wistar rats. A total of thirty-six (36) Wistar rats were used for this study. The animals were shared equally into six (6) groups. Three of the six groups (1, 3, and 5) served as control and were given distilled water (1 ml/kg), Silymarin (50 mg/kg), and Andrographis paniculata (500 mg/kg) group. The administration duration was 28 days, after which they were given olive oil and normal saline (1 ml/kg). The other groups (2, 4, and 6) were treated similarly as 1, 3, and 5 for 28 days; after that, they were administered a single dose of carbon tetrachloride in olive oil on the 28th day. All animals were sacrificed on the 29th day after an overnight fast. Animal weights were assessed once a week during the research. Biochemical parameters were measured using the spectrophotometry method. Significant changes (p < 0.05) in the activities of hepatic markers (Alanine transaminase, Aspartate transaminase, Alkaline phosphatase), and concentrations of triglyceride and high-density lipoprotein in the carbon tetrachloride-induced group treated with Andrographis paniculata in comparison with group 2 (negative control) were observed. The outcomes demonstrated that the ethanolic extract of Andrographis paniculata has hepatoprotective properties against carbon tetrachloride-induced liver injury. [ABSTRACT FROM AUTHOR]

Acute liver injury (ALI) is a rapid pathological process that may cause severe liver disease and may even be life‐threatening. During ALI, the function of males absent on the first (MOF) has not yet been elucidated. In this study, we unveiled the expression pattern of MOF during carbon tetrachloride (CCl4)‐induced ALI and role of MOF in the regulation of liver regeneration. In the process of ALI, MOF is significantly overexpressed in the liver injury area. Knockdown of Mof attenuated CCl4‐induced ALI, and promoted liver cell proliferation, hepatic stellate cell activation and aggregation to the injured area, and liver fibrosis. Simultaneously, overexpression of Mof aggravated liver dysfunction caused by ALI. By directly binding to the promoter, MOF suppressed the transcriptional activation of Igf1. Knockdown of Mof promotes the expression of Igf1 and activates the Insulin‐like growth factor 1 signaling pathway in the liver. Through this pathway, Knockdown of Mof reduces CCl4‐induced ALI and promotes liver regeneration. Our results provide the first demonstration for MOF contributing to ALI. Further understanding of the role of MOF in ALI may lead to new therapeutic strategies for ALI. [ABSTRACT FROM AUTHOR]

Oxidative stress is implicated in the pathophysiology of a plethora of diseases. In this research, pilot studies were carried out in the methanol extracts of the ten fruit peels to screen for antioxidant activity. Two fruit peels with the highest antioxidant activity were selected. The methanol peel extracts of the selected two; Citrus sinensis (orange) and Ananas comosus (pineapple) were evaluated for their in vivo antioxidant and hepatoprotective properties. Twenty-eight adult Wistar rats of both sexes were used in this experiment and grouped into seven of four rats each. Group 1 and 2 served as normal and positive controls. Groups 3 to 7 were pre-treated with Silymarin (100 mg/kg), A. comosus methanol peel extract (ACMPE) 250 mg/kg and 500 mg/kg C. sinensis methanol peel extract (CSMPE) 250 mg/kg and 500 mg/kg respectively for seven days before intraperitoneally inducing oxidative stress with carbon tetrachloride (CCl4) on day eight. Serum analysis of biochemical parameters and histological examination of the liver was carried out using standard methods. The DPPH assay showed that the fruit peel of C. sinensis had the highest antioxidant concentration followed by that of A. comosus. Acute toxicity test (LD50) showed that ACMPE and CSMPE were tolerable at 5000 mg/kg. Phytochemical analysis of the two fruit peels extracts revealed the presence of flavonoids, alkaloids, glycosides, tannins, and acidic compounds. Administration of the extracts significantly elevated serum enzymatic levels of SOD and CAT in a dose-dependent manner. Additionally, the extracts substantially normalized altered MDA, ALT, AST, total protein, and total bilirubin levels. The lipid profile of the animals was greatly improved and histopathological studies confirmed the biochemical observations. The results of this study demonstrate that ACMPE and CSMPE possess antioxidant and hepatoprotective activity against CCl4-induced oxidative stress in experimental animals.

The purpose of this study was to determine the phytochemical constituents of Pandanus amaryllifolius as well as to evaluate its ability to protect against acute hepatic damage caused by carbon tetrachloride (CCl4) in rats. In animals pre-treated with P.amaryllifolius and intoxicated with CCl4, biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutathione (GSH), catalase (CAT) and malondialdehyde (MDA) were used to assess hepatic damages. Histopathological assessment was also done to evaluate the CCl4 mediated hepatic injury in rats. P.amaryllifolius antioxidant activity was measured using free radical scavenging DPPH (1,1-diphenyl-2-picrylhydrazyl) method. The stable DPPH level was lowered by P. amaryllifolius extract. The value of the half-maximum inhibitory level (IC50) was 46.8 μg/ml. Phytochemical screening of P. amaryllifolius extract showed the presence of tannins, alkaloids, saponins, terpenoids and flavonoids except pholabatannins and cardiac glycosides. The total phenolic content (TPC) was 35.99 ± 0.04 mg GAE/g and total flavonoid content (TFC) was 59.96 ± 0.013 mg CAE/g of extract. P.amaryllifolius pre-treated groups displayed significantly increased catalase antioxidant enzyme activity relative to the CCl4 treated group (57–82%, P

Objective: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.

Carbon tetrachloride (CCl4) causes hepatotoxicity in mammals, with its hepatocytic metabolism producing radicals that attack the intracellular membrane system and destabilize intracellular vesicle transport. Inhibition of intracellular transport causes lipid droplet retention and abnormal protein distribution. The intracellular transport of synthesized lipids and proteins from the endoplasmic reticulum (ER) to the Golgi apparatus is performed by coat complex II (COPII) vesicle transport, but how CCl4 inhibits COPII vesicle transport has not been elucidated. COPII vesicle formation on the ER membrane is initiated by the recruitment of Sar1 protein from the cytoplasm to the ER membrane, followed by that of the COPII coat constituent proteins (Sec23, Sec24, Sec13, and Sec31). In this study, we evaluated the effect of CCl4 on COPII vesicle formation using the RLC‐16 rat hepatocyte cell line. Our results showed that CCl4 suppressed ER‐Golgi transport in RLC‐16 cells. Using a reconstituted system of rat liver tissue‐derived cytoplasm and RLC‐16 cell‐derived ER membranes, CCl4 treatment inhibited the recruitment of Sar1 and Sec13 from the cytosolic fraction to ER membranes. CCl4‐induced changes in the ER membrane accordingly inhibited the accumulation of COPII vesicle‐coated constituent proteins on the ER membrane, as well as the formation of COPII vesicles, which suppressed lipid and protein transport between the ER and Golgi apparatus. Our data suggest that CCl4 inhibits ER‐Golgi intracellular transport by inhibiting COPII vesicle formation on the ER membrane in hepatocytes. [ABSTRACT FROM AUTHOR]

Introduction: Indigenous herbs such as Momordica charantia L., Nardostachys jatamansi (D. Don) DC., Justicia adhatoda L. and Tephrosia purpurea (L.) Pers. are known to improve several disease characteristics including hepatoprotective activities. Objective: We aimed to demonstrate the hepatoprotective potential of indigenous herbs Momordica charantia L., Tephrosia purpurea(L.) Pers., Justicia adhatoda L. & Nardostachys jatamansi (D. Don) DC. in tetrachloromethane (CCl4) encouraged liver toxicity in Albino (Wister strain) rodent model. Methods: In Albino rats (Wister strain, n=114), hepatotoxicity was induced using CCl4 & the liver enzyme & histopathological profiles with an extent of the regenerative changes were evaluated. A total of 19 groups of rats were created containing six rats in each group & received the following - group 1: control group, group 2: CCl40.7 ml/kg, group 3: Liv-52 1 ml/kg. Light petroleum, trichloromethane, alcohol & watery extricates of Justicia adhatoda L.(200mg/kg), Tephrosia purpurea (L.) Pers. (200mg/kg), Momordica charantia L.(200mg/kg), & Nardostachys jatamansi (D. Don) DC.(500mg/kg)were administered in one group each (total 16 groups). Results-The trichloromethane extricate of Justicia adhatoda L, Light petroleum extricate of Nardostachys jatamansi (D. Don) DC. & Momordica charantia L., alcoholic extricates of Nardostachys jatamansi (D. Don) DC. displayed a noticeable reduction in the concentration of serum glutamic pyruvic transaminase SGPT), serum alkaline phosphatase (SALP), serum glutamic oxaloacetic transaminase (SGOT), bilirubin & other serum markers, indicating prominent hepatocytes with more regenerative activity, which signifies better hepatoprotective action as evaluated with other groups. Light petroleum & watery extricates of Justicia adhatoda L., Momordica charantia L. alcoholic extricates, Light petroleum, alcoholalcohol & trichloromethane extricates of Tephrosia purpurea (L.) Pers. showed moderate reductions in the liver enzyme levels & moderate degree of fatty changes. However, the alcoholic extricates of Justicia adhatoda L., & trichloromethane, watery extricate of Momordica charantia L., watery & trichloromethane extricate of Nardostachys jatamansi (D. Don) DC. & watery extricate of Tephrosia purpurea (L.) Pers. showed no reduction in the enzyme levels, indicating no activity. The total & direct bilirubin was also assessed in the blood serum, & there was no considerable difference among the groups. Conclusion: The hepatoprotective activity screening indicates that trichloromethane extricate of Justicia adhatoda L., Light petroleum extricate of Nardostachys jatamansi (D. Don) DC. & Momordica charantia L., showed more prominent hepatoprotective activity. Light petroleum & watery extricates of Justicia adhatoda L., alcoholic extricates of Nardostachys jatamansi (D. Don) DC. & Momordica charantia L., illustrated moderate antihepatotoxicity action, while alcoholic extricates of Justicia adhatoda L., trichloromethane & watery Gaurav Kumar Sharma et al/Assessment & comparison of hepatoprotective potential of indigenous therapeutic flora by using tetrachloromethane encouraged liver toxicity in Albino (Wister strain) rodent model 2603| International Journal of Pharmaceutical Research | Jan - Mar 2021 | Vol 13 | Issue 1 extricates of Momordica charantia L., watery & trichloromethane extricates of Nardostachys jatamansi (D. Don) DC., & none of the four extricates of Tephrosia purpurea (L.) Pers. showed hepatoprotective activities. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosomal-dependent degradation pathway in eukaryotic cells. Recent studies have reported that autophagy can facilitate the activation of hepatic stellate cells (HSCs) and fibrogenesis of the liver during long-term carbon tetrachloride (CCl4) exposure. However, little is known about the role of autophagy in CCl4-induced acute hepatic failure (AHF). This study aimed to identify whether modulation of autophagy can affect CCl4-induced AHF and evaluate the upstream signaling pathways mediated by CCl4- induced autophagy in rats. The accumulation of specific punctate distribution of endogenous LC3-II, increased expression of LC3-II, Atg5, and Atg7 genes/proteins, and decreased expression of p62 gene were observed after acute liver injury was induced by CCl4 in rats, indicating that CCl4 resulted in a high level of autophagy. Moreover, loss of autophagic function by using chloroquine (CQ, an autophagic inhibitor) aggravated liver function, leading to increased expression of p21 (a cyclin-dependent kinase inhibitor) in CCl4- treated rats. Furthermore, the AMPK-mTORC1-ULK1 axis was found to serve a function in CCl4-induced autophagy. These results reveal that AMPK-mTORC1-ULK1 signaling-induced autophagy has a protective role in CCl4-induced hepatotoxicity by inhibiting the p21 pathway. This study suggests a useful strategy aimed at ameliorating CCl4-induced acute hepatotoxicity by autophagy. [ABSTRACT FROM AUTHOR]

Lemon balm and dandelion are commonly used medicinal herbs exhibiting numerous pharmacological activities that are beneficial for human health. In this study, we explored the protective effects of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (MLD) on carbon tetrachloride (CCl4)-induced acute liver injury in mice. CCl4 (0.5 mL/kg; i.p.) injection inhibited body weight gain and increased relative liver weight. Pre-administration of MLD (50–200 mg/kg) for 7 days prevented these CCl4-mediated changes. In addition, histopathological analysis revealed that MLD synergistically alleviated CCl4-mediated hepatocyte degeneration and infiltration of inflammatory cells. MLD decreased serum aspartate aminotransferase and alanine transferase activities and reduced the number of liver cells that stained positive for cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting that MLD protects against CCl4-induced hepatic damage via the inhibition of apoptosis. Moreover, MLD attenuated CCl4-mediated lipid peroxidation and protein nitrosylation by restoring impaired hepatic nuclear factor erythroid 2-related factor 2 mRNA levels and its dependent antioxidant activities. Furthermore, MLD synergistically decreased mRNA and protein levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the liver. Together, these results suggest that MLD has potential for preventing acute liver injury by inhibiting apoptosis, oxidative stress, and inflammation. [ABSTRACT FROM AUTHOR]

In the present study, the protective effects of honey and bee venom (BV) either independently or in combination against lipopolysaccharide (LPS) and carbon tetrachloride (CCl4)-induced hepatoxicity, lipid peroxidation, and hematological alterations in male albino rats were investigated. In addition, histopathological alterations of hepatic tissues induced by LPS/CCL4 were recorded. Sixty-four of male albino rats of average weight 120-150 g were included in this study. Rats were divided into eight equal groups of eight. The obtained results demonstrated that treatment with LPS/CCl4 caused an increase in the levels of alpha-fetoprotein, which was accompanied by changes in the hepatic function biomarkers that characterized by the increased levels of transaminases (AST, ALT). The results showed oxidative stress as assigned by the increase in lipid peroxide. Meantime detraction in the antioxidants, including glutathione peroxidase was observed. Interruptions in biochemical parameters accompanied by disturbances in hematological parameters and liver histopathology were resulted due to exposure to LPS/CCl4. This study showed the use of honey and BV provided a protective effect on hepatotoxicity induced by LPS/CCl4. This might have been occurred through the reduction of hepatic transaminases and the "Alpha-fetoprotein" in serum and the equilibration of the antioxidation system, thereby, inhibiting the reactive oxygen species accumulation. Honey and BV administration reestablish disturbed hematological parameters and liver histopathology persuaded by LPS/CCl4. More interesting, we demonstrated that using a combination of the honey and BV showed promising enhancement in their protective effects over the use of just one of the two reagents. [ABSTRACT FROM AUTHOR]

Background: Avocado (Persea americana) is one of the plants widely used in ethnomedicine in Nigeria. The present study was aimed at investigating effects of aqueous Avocado (Persea americana) leaf extract on total cholesterol, triacylglycerols, protein and haematological parameters in carbon tetrachloride (CCl4)-intoxicated rats. Methods: We evaluated the possible effects of pre-treatment with aqueous extract of Persea americana (AEPA) on protein, total cholesterol (T-CHOL), triacylglycerols (TAGs) and haematological parameters in Wistar male albino rats intoxicated with CCl4. Group 1 was the healthy control; group 2 rats were pre-treated with Reducdyn® (100 mg/kg/day) as a standard drug, groups 4 and 5 rats were pre-treated with AEPA at a dose of 100 mg/kg and 200 mg/kg per day respectively, the treatments were administered orally for 7 days. On the seventh day, rats in the treatment groups were injected with a fresh mixture of CCl4 and olive oil (3 ml/kg, 1:1; sc). Results: Pre-treatment of rats with AEPA resulted in marked increase (p < 0.05) in total protein and reduction in T-CHOL (19–34%) compared to CCl4 alone. Also, there was significant decrease (p < 0.05) in serum TAG concentration when rats were pre-treated with 100 mg and 200 mg kg− 1 b. wt. AEPA. Similarly, AEPA provoked (p < 0.05) a lowering of T-CHOL and TAG levels and an increase in liver protein concentration in the rats. Administration of AEPA at both concentrations restored (p < 0.05) WBC count and ameliorated neutropenia and lymphocytosis caused by CCl4 intoxication. Conclusion: These results suggest that AEPA could be protective against the development of fatty liver and might also be exhibiting the potential to prevent alterations in haematological parameters caused by CCl4 intoxication in rats. [ABSTRACT FROM AUTHOR]

The present study used 20 male rabbits that divided randomly to four groups (each group consist 5 rabbits), control group received only normal diet, the group received carbon tetrachloride (CCL4) for forty days, the group treated (orally) with carbon tetrachloride and (100mg/per day) root extract for forty days, the fourth treated with carbon tetrachloride and (200mg/per day) root extract for forty days. the rabbits that treated with carbon tetrachloride showed decreased in the counts, motility, number of living sperms and increased the deformity of sperms with decreased the levels of LH, FSH and testosterone show high significant changes (P

Objectives: Liver fibrosis is a wound healing response characterized by excessive accumulation of extracellular matrix proteins. This study aimed to investigate the effects of resveratrol treatment on the TGF-β/SMAD signaling pathway and related biochemical parameters, apoptosis, and liver regeneration phenobarbital-CCl 4 induced hepatic fibrosis rat model., Materials and Methods: This model was created through phenobarbital and CCl 4 (0.2-0.35 ml/kg). Resveratrol (1 mg/kg/day) was administered to the fibrosis and control groups. Immunohistochemical staining was performed to evaluate αSMA, TGF-β1, and PCNA in liver tissue. The TUNEL method and Masson's Trichome staining were used to determine apoptosis and collagen accumulation. AST, ALP, ALT, total protein, and total bilirubin levels were measured to determine biochemical status. SMAD2, SMAD3, SMAD4, and SMAD7 expression levels were measured to determine TGF-β1 related hepatic fibrosis., Results: The SMAD2, SMAD3, and SMAD4 mRNA expression levels were increased and the SMAD7 mRNA expression level was decreased in the fibrosis control group. The SMAD7 mRNA expression level was higher in the phenobarbital-CCl 4 induced resveratrol treated group. Increased biochemical parameters indicating hepatic damage, increased number of apoptotic cells, and collagen accumulation surrounding the central vein were observed in the fibrosis group compared with the other groups. It was concluded that administration of resveratrol ameliorates the adverse effects of hepatic fibrosis by regulating biochemical parameters, controlling TGF-β1/SMAD signaling, enhancing tissue regeneration, and reducing apoptosis in liver cells., Conclusion: Resveratrol can be a beneficial option for the prevention of liver damage in a phenobarbital-CCl 4 induced hepatic fibrosis., Competing Interests: The authors have no conflicts of interests to declare.

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD). Obesity is a known risk factor of NASH, which, in turn, increases the risk of developing cirrhosis (liver scarring) and hepatocellular carcinoma (HCC). In addition to being a potentially life-threatening condition, public health concerns surrounding NASH are amplified by the lack of FDA-approved treatments. Although various preclinical models reflecting both the histopathology and the pathophysiological progression of human NASH exist, most of these models are diet-based and require 6-13 months for NASH symptom manifestation. Here, we describe a simple and rapid-progression model of NASH and NASH-driven HCC in mice. Mice received a western diet equivalent (WD; i.e., a high-fat, high-fructose, and high-cholesterol diet), high-sugar water (23.1 g/L fructose and 18.9 g/L glucose), and weekly intraperitoneal injections of carbon tetrachloride (CCl 4 ) at a dose of 0.2 μL/g of body weight. The resulting phenotype, consisting in liver fibrosis and HCC, appeared within 24 weeks of diet/treatment initiation and presented similar histological and transcriptomic features as human NASH and NASH-driven HCC, thereby supporting the adequacy of this preclinical model for the development and evaluation of drugs that can prevent or reverse these diseases., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatotoxicity causes a very high mortality all over the world. Several hepatotoxins are responsible for the development of hepatotoxicity. This study was aimed to evaluate the potential effect of Diethyl nitrosamine (DEN)/Carbon tetra chloride (CCL4)-induced hepatotoxicity in obese rats. Forty male albino rats were divided equally into four groups; G1; control group, G2; DEN/ CCL4 group (IP injection of DEN (200 mg/kg Bwt) followed by weekly SC injectionof CCL4 (3 mg/kg Bwt) for six weeks, G3; obese group (fed HFD) for 11 weeks&G4; DEN/ CCL4/ obese group (DEN/ CCL4 +obesity). Serum samples of all rats were analyzed for lipid profile and liver enzymes, ALP, total & direct albumin and alpha fetoprotein.Liver tissues were collected for analysis of oxidative stress markers, gene expression of Caspase-3 expression and histopathological examination. DEN/ CCL4 induced hepatotoxicity in G2 significantly increase serum lipid profile, liver enzymes, ALP, total & direct bilirubin, alpha-fetoprotein and liver MDA, meanwhile significantly decreased serum HDL-C, albumin, liver SOD, CAT, GSH and Caspase-3 expressionwhen compared to control group. DEN /CCl4/ obese treated rats in G4 showed insignificantly changed lipid profile, while serum activities of ALT, ALP, as well as serum levels of total & direct bilirubin, alpha-fetoprotein, and Caspase-3 expression were significantly elevated, while AST, albumin and liver SOD were significantly decreased when comparedwith obese rats. This study highlights the ameliorative effects of obesity in delaying the progress of toxic effects of DEN / CCL4 on liver of obese rats. [ABSTRACT FROM AUTHOR]

The underlined effects of diallyl sulfide (DAS) against CCL4-induced oxidative, inflammatory, and apoptotic acute hepatic damage were assessed. Administration of DAS (50, 100, and 200 mg/kg) along with CCL4 effectively mitigated serum aspartate aminotransferase, alanine aminotransferase activities, MDA, TNF-α, IL-1β, and MCP-1 levels, as well as significantly restored HO-1, GSH levels and SOD activity in liver tissues compared with those in rats treated with CCL4. Moreover, DAS inhibited CCL4-induced increase of liver NF-κB (p65), Bax, p38 MAPK, and JNK protein expression. In addition, DAS accelerated protein expression of Nrf2 and Bcl-2. The hepatoprotective properties of DAS were further confirmed by the reduced severity of hepatic damage as demonstrated by histopathological findings. In conclusion, DAS achieved its protective potential against CCL4-induced hepatotoxicity through antiapoptotic activity, as well as the synchronized modulation of NF-κB and Nrf2 for the favor of antioxidant/anti-inflammatory effects via suppression of the upstream stress-activated MAPKs pathways. [ABSTRACT FROM AUTHOR]

Some plants have high antioxidant properties that can improve the damage to the tissues of the body. Rumex alveollatus L. is proposed to contain flavonoids, a group of antioxidants that exert their protective effects against free radicals. Carbon tetrachloride (CCl4) is a factor that damages the liver. This study was carried out to explore the protective effects of Rumex alveollatus L. on the liver damage induced by CCl4 in mice. In this experimental study, 30 male mice (35 ± 4) were divided into five groups, each with six mice. The negative control group was administered 0.5-ml olive oil; positive control group was administered 2-ml/kg CCl4 plus olive oil at 1:1 ratio for 4 days, and the experimental groups were administered 2 ml/kg CCl4 and Rumex alveollatus L. extract at 150, 300, and 450 mg/kg for 4 days. All administrations were done intraperitoneally. Twenty days later, blood samples were taken from the heart, and liver serum enzymes (ALT, AST, and ALP) were measured. After sacrificing the samples, liver samples were fixed in formalin to prepare the histological sections. Then, factors such as liver volume, hepatocytes, sinusoids, central veins, portal vein, bile duct, and hepatic artery were measured. Rumex alveollatus L. extract (450 mg/kg) reduced the serum level of all three liver enzymes (p < 0.05). At this dose, the volume of sinusoids, hepatocytes, and bile duct decreased significantly (p < 0.05), but the volume of portal vein and central vein increased significantly (p < 0.05). Rumex alveollatus L. extract has protective effects against CCl4-induced damages in the liver. [ABSTRACT FROM AUTHOR]

The in vitro total antioxidant and anti-inflammatory capacity of the methanol extract of Ixora duffii leaf (Trang to in Vietnamese) was investigated using the phosphomolypdenum method and the bovine serum albumin denaturation test, respectively. The results showed that the methanol extract of I. duffii leaf possessed relatively high antioxidant activity (OD0,5 = 15.551 ± 0.344 µg/mL) compared to that of the standard, trolox (OD0,5=2.315 ± 0.083 µg/mL). The antiinflammatory effect using bovine serum albumin denaturation test showed that the activity of the methanol extract of I. duffii leaf (EC50= 6.03 ± 0.12 µg/mL) was comparable to that of the reference drug, diclofenac sodium (EC50=0.57 ± 0.21 µg/mL). To evaluate the hepatoprotective activity of the methanol extract of I. duffii leaf, the liver damage was induced in mice given with carbon tetrachloride (CCl4) mixed in olive oil (1:4) at a dose of 2.5 mL/kg body weight/day. As a control, the standard hepatoprotective agent, silymarin, was used at the dose of 16 mg/kg body weight for 4 consecutive weeks. I. duffii leaf extract was given at three different doses 100, 200 and 400 mg/kg body weight. The results showed the effective dose-dependent reduction of transaminase enzyme (ALT and AST) levels in sera. In addition, I. duffii leaf extract also improved the oxidative stress status of the liver through effective reduction of MDA level and increase of GSH level in the liver. Histopathological examination of the liver tissue revealed that the mice treated with I. duffii leaf extract showed significant improvement of liver tissue damages similar to silymarin treatment compared to the non-treated control group. The present results demonstrated that I. duffii leaf extract has potent antioxidant and hepatoprotective activity. [ABSTRACT FROM AUTHOR]

Liver disease is still a global health concern and the drugs used to treat the condition are also implicated in exacerbating the problem. Many are sources are constantly screened for bioactivity in order to compensates shortcomings from current treatments. Thus, the current study evaluates the hepatocurative potential of aqueous stem bark extract of Cassia sieberiana in liver-damaged albino rats. Phytochemical analysis, acute toxicity study and effect of aqueous stem bark extract of Cassia sieberiana in rats induced with CCl4 liver damaged were conducted. The rats were randomly divided into five groups of six rats each. With one group being normal control while the others were induced with 150 mg/kg CCl4 to induce liver damage followed by daily administration of graded doses (50, 100 and 150 mg/kg) of aqueous stem bark extract of Cassia sieberiana (ASBEC) for four weeks. Three rats from each group were randomly selected and sacrificed 48hours after CCl4 induction in order to confirm liver damage, while the remaining three rats in all the groups were sacrificed after four weeks. The blood samples were collected to determine serum levels of liver enzymes, total proteins, bilirubin(s) and albumin. Histopathological examination on the liver section was carried out. The phytochemical analysis revealed the presence of tannins, saponins, cardiac glycosides, alkaloid and flavonoids. The acute toxicity of ASBEC shows no sign of toxicity at a maximum dose of 5000mg/kg. The extract produced dose-dependent reduction in the biochemical markers of liver injury (P ≤ 0.05) compared to the negative (CCl4-only treated group) control. There is no statistically significant change (P > 0.05) in the serum biomarkers of liver injury in the extract treated groups compared to the positive (normal saline) control. The results of the biochemical parameters indicate some hepatocurative effects of the extract against CCl4 induced liver toxicity and this was supported by the hispathological examination of rat's liver. Hence, the curative latent of the Cassia sieberiana may be due to the presence of high concentration of tannins and saponins. [ABSTRACT FROM AUTHOR]

Lemon balm and dandelion are commonly used medicinal herbs exhibiting numerous pharmacological activities that are beneficial for human health. In this study, we explored the protective effects of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (MLD) on carbon tetrachloride (CCl4)-induced acute liver injury in mice. CCl4 (0.5 mL/kg; i.p.) injection inhibited body weight gain and increased relative liver weight. Pre-administration of MLD (50–200 mg/kg) for 7 days prevented these CCl4-mediated changes. In addition, histopathological analysis revealed that MLD synergistically alleviated CCl4-mediated hepatocyte degeneration and infiltration of inflammatory cells. MLD decreased serum aspartate aminotransferase and alanine transferase activities and reduced the number of liver cells that stained positive for cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting that MLD protects against CCl4-induced hepatic damage via the inhibition of apoptosis. Moreover, MLD attenuated CCl4-mediated lipid peroxidation and protein nitrosylation by restoring impaired hepatic nuclear factor erythroid 2-related factor 2 mRNA levels and its dependent antioxidant activities. Furthermore, MLD synergistically decreased mRNA and protein levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the liver. Together, these results suggest that MLD has potential for preventing acute liver injury by inhibiting apoptosis, oxidative stress, and inflammation.

Background/Aims: Keratinocyte growth factor (KGF) plays a critical role in prevention of cirrhosis and enhancement of liver regeneration. However, the molecular regulation of KGF in liver is unknown. MicroRNAs (miRNAs) control the pathogenesis of cirrhosis, whereas the exact involved miRNAs and molecular signaling pathways remain ill-defined. Here we addressed these questions. Methods: We examined the correlation of the levels of miR-219-5p and KGF in the liver biopsies from patients with liver diseases. The effects of overexpression or suppression of miR-219-5p on KGF were examined in both human and mouse hepatic stellate cells (HSCs). Bioinformatics analysis was applied to examine the binding of human/mouse miR-219-5p to the 3'-UTR of human/mouse KGF mRNA, respectively. Finally, adeno-associated viruses carrying antisense of miR-219-5p were infused into the liver from the mice that had developed cirrhosis by carbon tetrachloride (CCl4), and the effects on KGF levels and liver damage and function were examined. Results: The levels of miR-219-5p and KGF in the liver biopsies were inversely correlated. MiR-219-5p inhibited KGF expression in both human and mouse HSCs, through directly binding the 3'-UTR of KGF mRNA. Expression of antisense of miR-219-5p significantly attenuated the levels of liver fibrosis, portal hypertension and sodium retention caused by CCl4. Conclusions: Suppression of miR-219-5p may benefit the liver regeneration and prevent cirrhosis through increasing KGF.

Background and Aim: Brittle star possess bioactive compounds which confer the wound healing capacity and regenerative potency of damaged arms and organisms to this creature. The aim of the current study was to assess the protective effect of the star extract on liver damages induced by carbon tetrachloride in adult male Wistar rats. Materials and Methods: In this experimental study, 32 adult male rats were randomly divided into 4 equal groups: control, Sham exposed, experimental 1 (treated with %25 extract) and experimental 2 (treated with %50 extract) of star Ophiocoma Erinaceus. The control group received no treatment. The sham exposed groups received carbon tetrachloride .(50% in olive oil) .0.5 ml/kg for 7 days. The experimental groups firstly received carbon tetrachloride, then received %25, %50 brittle star extract as intragastric for 7 days. Finally, the animals were sacrificed, and their bodies and livers were weighed. Then, the livers sections were prepared and were examined by means of light microscope. Finally, the obtained quantitative data was analyzed using SPSS (V; 20), Mini Tab software, ANOVA, and Tukey. at the significant level of P

Hiệu quả bảo vệ gan của cao lá Mơ Leo - LML (Paederia scandens L.) được khảo sát trên chuột tổn thương gan bằng carbon tetrachloride (CCl4). Chuột được gây tổn thương gan bằng CCl4 pha trong dầu olive với tỷ lệ 1:4 với liều uống là 2,5 ml/kg/ngày và uống mỗi ngày trong thời gian 4 tuần. Hiệu quả bảo vệ gan của cao LML được khảo sát bằng cách cho chuột uống cao LML ở các nồng độ 100, 200 và 400 mg/kg trọng lượng chuột sau 1 giờ uống CCl4. Silymarin được sử dụng như đối chứng dương. Kết quả thí nghiệm cho thấy, sau 4 tuần thí nghiệm, hàm lượng các enzyme AST giảm lần lượt 94,2%, 98%, 99%, enzyme ALT giảm lần lượt 91,6%, 93,5%, 95,2%. Hiệu quả bảo vệ gan của cao LML có thể so sánh tương đương với sylimarin liều 16 mg/kg trọng lượng chuột. Quan sát tiêu bản hiển vi lát cắt ngang gan chuột cho thấy mô gan của nhóm chuột được điều trị bằng cao LML nồng độ 200 và 400 mg/kg cải thiện đáng kể so với nhóm chuột không được điều trị.

Natural killer (NK) cells are known for their ability to kill activated hepatic stellate cells (HSCs), which has been confirmed both in patients and animal models. But the killing function is depressed in period of advanced liver injury. Salvia Miltiorrhiza (SM), a Chinese herbal medicine for invigorating blood circulation and eliminating stasis, is widely used to treat liver fibrosis in clinic. Nevertheless, the immunological mechanism remains unclearly. Here, we put forward the hypothesis that the anti-fibrotic effect of SM is concerned with boosting the activation of hepatic NK cells. Liver fibrosis was induced with carbon tetrachloride (CCl4) and effects of SM on NK cells and HSC (JS-1 cell line, HSC) were investigated in vivo and in vitro. Hepatic NK cells were isolated from C57BL/6 mice, and pre-incubated with SM before they were co-cultured with HSCs. We found that SM increased frequency of NK cells, enhanced activities of NKG2D and Nkp46 on NK cells and inhibited activation of HSCs in vivo and in vitro. SM could promote the activities of NK cells by increasing the expressions of NKG2D and IFN-γ before or after co-cultured with HSCs in vitro. Besides, SM could partially antagonize ASGM-1-induced NK cell depletion and enhance the cell activities to inhibit HSCs activation in vitro. Therefore, our work provided a new insight into the anti-fibrotic mechanism that SM could enhance the activities of NK cell to reduce liver fibrosis in vivo and in vitro.

Background/Aims: New strategies for the prevention and treatment of cirrhosis are urgently needed for improving therapeutic outcome. A role of microRNAs (miRNAs) in the pathogenesis of cirrhosis has been recently acknowledged, whereas the exact involved miRNAs as well as the associated molecular signaling pathways have not been determined. Specifically, the studies on the relationship between miR-22 and bone morphogenic protein 7 (BMP7) in the development of cirrhosis are lacking. Methods: We examined the correlation of the levels of miR-22 and bone morphogenic protein 7 (BMP7) in the liver biopsies from patients with cirrhosis. We examined overexpression or suppression of miR-22 on BMP7 in hepatocytes. We examined the binding of miR-22 to the 3'-UTR of BMP7 mRNA. Finally, in a carbon tetrachloride (CCl4)-induced cirrhosis model in mice, we gave mice adeno-associated viruses carrying antisense of miR-22, and examined its effects on BMP7 levels and the hallmarks of cirrhosis. Results: The levels of miR-22 and BMP7 in the liver biopsies from patients were strongly and inversely correlated. MiR-22 inhibited BMP7 expression in hepatocytes, through directly binding the 3'-UTR of BMP7 mRNA. Expression of antisense miR-22 significantly attenuated the levels of liver fibrosis, portal hypertension and sodium retention caused by CCl4, possibly through upregulation of BMP7. Conclusions: MiR-22 promotes the development of cirrhosis through BMP7 suppression.

Abstract: Oxidative stress and inflammatory response are well known to be involved in the pathogenesis of acute liver injury. This study was performed to examine the hepatoprotective effect of ginsenoside Rg1 (Rg1) against CCl4‐induced acute liver injury, and further to elucidate the involvement of Nrf2 signaling pathway in vivo and in vitro. Mice were orally administered Rg1 (15, 30, and 60 mg/kg) or sulforaphane (SFN) once daily for 1 week prior to 750 μL/kg CCl4 injection. The results showed that Rg1 markedly altered relative liver weights, promoted liver repair, increased the serum level of TP and decreased the serum levels of ALT, AST and ALP. Hepatic oxidative stress was inhibited by Rg1, as evidenced by the decrease in MDA, and increases in GSH, SOD, and CAT in the liver. Further research demonstrated that Rg1 suppressed liver inflammation response through repressing the expression levels of inflammation‐related genes including TNF‐α, IL‐1β, IL‐6, COX‐2, and iNOS. In addition, Rg1 enhanced antioxidative stress and liver detoxification abilities by up‐regulating Nrf2 and its target‐genes such as GCLC, GCLM, HO‐1, NQO1, Besp, Mrp2, Mrp3, Mrp4, and down‐regulating Cyp2e1. However, the changes in Nrf2 target‐genes, as well as ameliorative liver histology induced by Rg1 were abrogated by Nrf2 antagonist all‐transretinoic acid in vivo and Nrf2 siRNA in vitro. Overall, the findings indicated that Rg1 might be an effective approach for the prevention against acute liver injury by activating Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background and aim: While diethylcarbamazine citrate (DEC) displays important anti-inflammatory effects in experimental models of liver injury, the mechanisms of its action remain poorly understood. The aim of the present study was to investigate the fibrolytic potential of DEC.Methods: Mice receive two injections of carbon tetrachloride (CCl4) per week for 8 weeks. DEC 50 mg/kg body weight was administered through drinking water during the last 12 days of liver injury.Results: The expression of hepatic stellate cells (HSCs) activation markers, including smooth muscle α-actin (α-SMA), collagen I, transforming growth factor-β 1 (TGF-β1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) was assessed. The influence of DEC on the intracellular MAPK pathways of the HSCs (JNK and p38 MAPK) was also estimated. DEC inhibited HSCs activation measured as the production of α-SMA and collagen I. In addition, it down regulated the production of TGF-β1 and TIMP-1, and concomitantly increased MMP-2 activity. Furthermore, DEC significantly inhibited the activation of the JNK and p38 MAPK signaling pathways.Conclusions: In conclusion, DEC significantly attenuated the severity of CCl4-induced liver injury and the progression of liver fibrosis, exerting a potential fibrolytic effect in the CCl4-induced fibrosis model. [ABSTRACT FROM AUTHOR]