Protective Role of Quercetin in Carbon Tetrachloride Induced Toxicity in Rat Brain: Biochemical, Spectrophotometric Assays and Computational Approach.

Carbon tetrachloride (CCL4) induces oxidative stress by free radical toxicities, inflammation, and neurotoxicity. Quercetin (Q), on the other hand, has a role as anti-inflammatory, antioxidant, antibacterial, and free radical-scavenging. This study explored protection given by quercetin against CCL4 induced neurotoxicity in rats at given concentrations. Male Wistar rats were divided into four groups Group C: control group; Group CCL4: given a single oral dose of 1 mL/kg bw CCL4; Group Q: given a single i.p injection of 100 mg/kg bw quercetin; and Group Q + CCL4: given a single i.p injection of 100 mg/kg bw quercetin before two hours of a single oral dose of 1 mL/kg bw CCL4. The results from brain-to-body weight ratio, morphology, lipid peroxidation, brain urea, ascorbic acid, reduced glutathione, sodium, and enzyme alterations (aspartate aminotransferase (AST), alanine aminotransferase (ALT), catalase, and superoxide dismutase) suggested alterations by CCL4 and a significant reversal of these parameters by quercetin. In silico analysis of quercetin with various proteins was conducted to understand the molecular mechanism of its protection. The results identified by BzScore4 D showed moderate binding between quercetin and the following receptors: glucocorticoids, estrogen beta, and androgens and weak binding between quercetin and the following proteins: estrogen alpha, Peroxisome proliferator-activated receptors (PPARγ), Herg k+ channel, Liver x, mineralocorticoid, progesterone, Thyroid α, and Thyroid ß. Three-dimensional/four-dimensional visualization of binding modes of quercetin with glucocorticoids, estrogen beta, and androgen receptors was performed. Based on the results, a possible mechanism is hypothesized for quercetin protection against CCL4 toxicity in the rat brain.

Taxifolin, Extracted from Waste Larix olgensis Roots, Attenuates CCl4-Induced Liver Fibrosis by Regulating the PI3K/AKT/mTOR and TGF-ß1/Smads Signaling Pathways.

PURPOSE: Taxifolin is a kind of dihydroflavone and is usually used as a food additive and health food for its antioxidant, anti-inflammatory, and anti-tumor activities. The purpose of this research is to probe into the hepatoprotective activity and the molecular mechanism of taxifolin. MATERIALS AND METHODS: The liver fibrosis model was established by intraperitoneal injection of 5 mL/kg body weight of CCl4 (20% CCl4 peanut oil solution), and taxifolin was dissolved with 0.9% physiological saline and administered intragastrically to mice. RESULTS: The results indicated that CCl4-induced significantly increased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice. Histopathological examination showed severe hepatocyte necrosis and hepatic tissue lesion. Immunohistochemical staining and rt-PCR analysis demonstrated that the expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2), IL-1ß, IL-6, and TNF-α were increased. These changes were significantly reversed when treated with taxifolin. In addition, TUNEL staining and Bcl-2/Bax pathway confirmed that taxifolin significantly inhibited hepatocyte apoptosis. Besides, the research confirmed that taxifolin also inhibited the activation of hepatic stellate cells and the production of extracellular matrix (ECM) by regulating PI3K/AKT/mTOR and TGF-ß1/Smads pathways. CONCLUSION: Taxifolin inhibited inflammation, and attenuated CCl4-induced oxidative stress and cell apoptosis by regulating PI3K/AKT/mTOR and TGF-ß1/Smads pathways, which might in part contributed to taxifolin anti-hepatic fibrosis, further demonstrating that taxifolin may be an efficient hepatoprotective agent.

Hepatoprotective effect of apolipoprotein A4 against carbon tetrachloride induced acute liver injury through mediating hepatic antioxidant and inflammation response in mice.

Apolipoprotein A4 (ApoA4) regulates lipid and glucose metabolism and exerts anti-inflammatory effects in atherogenesis and colitis. The present study explored the presumed protective role of ApoA4 in carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in mice. The ALI model in wild type (WT), ApoA4 knock-out (ApoA4-KO) and ApoA4 transgenic (ApoA4-TG) mice was induced by a single intraperitoneal administration of CCl4. Liver and blood were harvested from mice to assess liver functions, immunohistological changes, immune cell populations and cytokine profiles. ApoA4 deficiency aggravated, and ApoA4 overexpression alleviated CCl4-inflicted liver damage by controlling levels of anti-oxidant enzymes. ApoA4 deletion increased the recruitment of monocytes/macrophages into the injured liver and upregulated the plasma levels of IL-6, TNF-α and MCP-1, but lower IL-10 and IFN-γ. ApoA4 over-expression rescued this effect and resulted in lower percentages of monocytes/macrophages and dendritic cells, the ratio of blood pro-inflammatory to anti-inflammatory monocytes and reduced plasma concentrations of IL-6, but enhanced IL-10 and IFN-γ. We propose ApoA4 as a potential new therapeutic target for the management of liver damage.

MiR-340 suppresses CCl4-induced acute liver injury through exerting anti-inflammation targeting Sigirr.

OBJECTIVE: Acute liver injury (ALI) can be caused by ischemia, viral infection, immune disorders and exogenous substances. Finding novel drugs and methods to treat liver injury is still one of the problems to be precipitously solved in clinical liver diseases. Recent studies have verified that microRNA-340 (miR-340) and the Single immunoglobin interleukin-1 (IL-1)-related receptor (Sigirr) display extensive anti-inflammatory effects against inflammatory diseases. However, their protection against inflammation in ALI is unclear. The purpose of this study was to investigate the regulated mechanism of miR-340 targeting Sigirr on ALI. MATERIALS AND METHODS: Firstly, the expressions of miR-340 and Sigirr in different time of inflammatory Kupffer cells (KCs) were detected. Lipopolysaccharide (LPS) was employed in activating the KCs inflammation, and tetrachloromethane (CCl4) was performed to induce liver injury. Then miR-340 mimic and inhibitor were used to up-regulate or down-regulate the function of miR-340 to explore anti-inflammation function to ALI via the target of Sigirr. RESULTS: The study results exhibited that the expressions of miR-340 and Sigirr were markedly decreased in LPS-induced KCs inflammation, and CCl4 induced the development of ALI. Besides, the overexpression of miR-340 could alleviate the inflammation of LPS induction in KCs via promoting Sigirr. Moreover, miR-340 and Sigirr rescue significantly reduced liver function and tissue lesion by employing miR-340 mimic. CONCLUSIONS: MiR-340 decreases KC inflammation via enhancing Sigirr, but accumulating miR-340 prevents inflammation damage and ameliorates ALI. In addition, increased miR-340 and Sigirr may become novel targets for the therapy of ALI in the future.

A potent protective effect of baicalein on liver injury by regulating mitochondria-related apoptosis.

Liver injury is the early stage of liver disease, which is caused by multiple factors. Baicalein has shown extensive bioactivity. But whether baicalein has a protective effect on liver injury has not been reported thus far. In this study, we aim to investigate the protective effects of baicalein on liver injury induced by oxidative stress. H2O2 and CCl4 were employed to establish liver injury models in vivo and in vitro, respectively. The protective effect of baicalein on oxidative stress-induced liver injury was evaluated by detecting the mitochondrial dynamics, the level of autophagy and apoptosis, the histopathology of liver, the indicators of liver function, and the level of oxidative stress in vitro and in vivo. March5 is the key regulator during liver injury induced by oxidative stress. March5 can ubiquitinate Drp1 and promote Drp1 degradation, then maintain the homeostasis of mitochondrial dynamics, keep the balance of autophagy, and reduce apoptosis. Baicalein is able to effectively reduce liver injury; it can contribute to the expression of March5 by regulating KLF4 during liver injury. These results indicate that baicalein plays a key role in salvaging liver from injury induced by oxidative stress via regulating the KLF4-March5-Drp1 signal pathway.

Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice.

AIM: To investigate the effect of carvedilol on liver fibrosis and hepatic sinusoidal capillarization in mice with carbon tetrachloride (CCl4)-induced fibrosis. METHODS: A liver fibrosis mouse model was induced by intraperitoneal CCl4 injection for 8 weeks. The mice were divided into five experimental groups: the normal group, the oil group, the CCl4 group, the CCl4+carvedilol (5 mg/kg/d) group, and the CCl4+carvedilol (10 mg/kg/d) group. The extent of liver fibrosis was evaluated by histopathological staining, and the changes in fenestrations of hepatic sinus endothelial cells were observed by scanning electron microscope (SEM). The expression of α-smooth muscle actin (α-SMA) and vascular endothelial markers was detected by immunohistochemistry and Western blot assays. The effect of carvedilol on cell apoptosis was studied via Terminal deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) assay, and the serum levels of matrix metalloproteinase-8 (MMP-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 were detected through a Luminex assay. RESULTS: Liver fibrosis in CCl4-treated mice was attenuated by reduced accumulation of collagen and the reaction of inflammation with carvedilol treatment. Carvedilol reduced the activation of hepatic stellate cells (HSCs) and increased the number of apoptotic cells. The expression of α-SMA, CD31, CD34 and VWF (von Willebrand factor) was significantly decreased after carvedilol treatment. In addition, the number of fenestrae in the hepatic sinusoid showed notable differences between the groups, and the serum levels of MMP-8, VEGF and angiopoietin-2 were increased in the mice with liver fibrosis and reduced by carvedilol treatment. CONCLUSION: The study demonstrated that carvedilol could prevent further development of liver fibrosis and hepatic sinusoidal capillarization in mice with CCl4-induced fibrosis.

Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents.

A novel series of thiazole-based heterocycles was synthesized using 1,3-dipolar cycloaddition reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. The molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis. Various in vitro biological assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of the newly synthesized compounds. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compounds displayed antitumor activities with the chlorine-containing derivatives, 11c and 6g, being the most potent. The majority of the tested thiazole derivatives exhibited satisfactory antibacterial activity towards the used gram positive and gram-negative bacterial species. Moreover, many derivatives showed weak hepatoprotective activity against CCl4-induced hepatotoxicity.

Solid Dispersion of Hesperetin Co-crystals Synergistically Attenuates Hepatic Toxicity of Carbon Tetrachloride Oxidative Stress in Rats.

BACKGROUND: Hesperetin (HSP) is a low water-soluble flavanone aglycone with low bioavailability. OBJECTIVES: This study aimed at enhancing the hepatoprotective effects of HSP by a combinatory technique based on solid dispersions of co-crystals of HSP. METHODS: Co-crystals were prepared using citric acid, tartaric acid, caffeine and isonicotinamide (INM) using two methods of solvent evaporation and co-grinding. The solid dispersion of co-crystals with different ratio of INM, PVP K30 and drug was prepared by the solvent evaporation method. The resulting material was characterized by DSC, XRD, FTIR and SEM, their saturated solubility and dissolution rate were compared to the pure drug. Finally, liver toxicity was induced in rats by carbon tetrachloride (CCl4) and mice were treated with different formulations of HSP. The liver function was tested by measurement of glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (ALP) and bilirubin as well as histopathological tests. RESULTS: Although saturation solubility of HSP was enhanced about 5 times by co-crystals of HSP/INM (1:2), solid dispersions of the co-crystals of HSP obtained from PVP K30 and INM enhanced it up to 200 folds. Functional parameters of liver in rats pretreated with a solid dispersion of co-crystals of HSP were significantly lower than those with pure HSP and co-crystals of INM/HSP with 2:1 ratio. Furthermore, this formulations reduced liver damage effectively compared with the CCL4 group. CONCLUSION: Solid dispersion of HSP co-crystals synergistically attenuates hepatic toxicity of carbon tetrachloride oxidative stress in rats more effectively than its solid dispersions or co-crystals alone.

Fermented camel milk by Lactococcus lactis subsp. cremoris attenuates erythrocytes oxidative stress-induced hematological and immunological damage in CCl4-intoxicated mice.

Fermented camel by Lactococcus lactis subsp. cremoris has been recently discovered to protect against the toxic effect of carbon tetrachloride (CCl4), but its beneficial effects in the presence of oxidative stress in the erythrocytes have not been established. In the present study, 28 mice were randomly divided into four groups: control group; CCl4 group: intoxicated by a single intraperitoneal injection (ip) of CCl4; group FCM-LLC + CCl4: pretreated with FCM-LLC daily during 14 days, and received a single dose of CCl4. FCM-LLC group received FCM-LLC alone. The occurrence of oxidative stress in erythrocytes was evidenced by an increase in lipid peroxidation, protein carbonyl, and changes in antioxidant enzyme activities and non-enzymatic antioxidant. The oxidative injury induced by CCl4 in the erythrocytes was confirmed by modifications in hematological parameters and decreases in protein, albumin, and globulin content in the serum of intoxicated mice. Therefore, CCl4 caused a significant decrease in immunotoxic indices, including immunoglobulin G (IgG), immunoglobulin M (Ig M), and immunoglobulin A (IgA) levels, and an increase of inflammatory markers such as C-reactive protein (CRP) level. Meanwhile, FCM-LLC effectively restored the parameters cited above to near-normal values. It can be suggested that fermented camel milk could regulate deviant physiological effects induced by CCl4 which is due to its powerful antioxidant and immunomodulatory and anti-inflammatory capacity.

Lyophilized Extract of the Horse Mushroom, Agaricus arvensis (Agaricomycetes), Delays Erythrocyte Hemolysis and Stabilizes Some Blood Parameters in Carbon Tetrachloride-Intoxicated Rats.

This study evaluates the protective effects of a lyophilized extract of the horse mushroom, Agaricus arvensis, on hematological parameters and its antioxidative role against carbon tetrachloride (CCl4)-induced oxidative stress in rats. The protective effects of the A. arvensis extract were evaluated by comparing hematological parameters, erythrocyte fragility, and components of the antioxidant defense system (e.g., reduced glutathione [GSH] level; glutathione S-transferase, catalase, glutathione peroxidase [GPx], and superoxide dismutase activities; and malondialdehyde content in erythrocytes). The 4 experimental groups included the controls (group I), CCl4-treated rats (group II), rats treated with CCl4 + 100 mg/kg A. arvensis extract (group III), and those treated with CCl4 + 500 mg/kg A. arvensis extract (group IV). Erythrocyte hemolysis in 0.6% NaCl was lower in groups I, III, and IV (at 38%, 22%, and 34%, respectively) than in group II. GSH levels in groups I, III, and IV were higher by 54%, 12%, and 11%, respectively, than that in group II. GPx enzyme activity in group II was significantly lower than the activity in groups I, III, and IV (by 138%, 70%, and 64%, respectively). In addition, administration of the A. arvensis extract resolved the dangerous effects of CCl4 on some hematological parameters such as red blood cells, hemoglobin, hematocrit, white blood cells, platelet count, plateletcrit, and red cell distribution width. We conclude that the A. arvensis extract has therapeutic effects against CCl4-induced oxidative stress, reduces erythrocyte fragility, and improves a number of hematological parameters in rats.

Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-ß/Smad signaling pathways.

Liver fibrosis is a major pathological feature of chronic liver diseases and there is no effective therapy program at present. Schisandrin B (Sch B) is the major bioactive ingredient of Schisandra chinensis, with antioxidative, anti-inflammatory, antitumor, and hepatoprotective properties. This study aimed to investigate the protective effect and related molecular mechanism of Sch B against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The in vivo therapeutic effect of Sch B on liver fibrosis induced by CCl4 was examined in rats. In vitro, rat hepatic stellate cells (HSC-T6) were used to assess the effect of Sch B on the activation of HSCs. Sch B effectively attenuated liver damage and progression of liver fibrosis in rats, as evidenced by improved liver function and decreased collagen deposition. The effects of Sch B were associated with attenuating oxidative stress by activating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling and suppressing HSC activation by inhibiting the transforming growth factor-ß (TGF-ß)/Smad signaling pathway. In an in vitro study, it was shown that Sch B inhibited TGF-ß-induced HSC activation. Finally, Sch B significantly inhibited TGF-ß1-stimulated phosphorylation of Smad and signaling of mitogen-activated protein kinases. This study demonstrates that Sch B prevents the progression of liver fibrosis by the regulation of Nrf2-ARE and TGF-ß/Smad signaling pathways, and indicates that Sch B can be used for the treatment of liver fibrosis.

Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg-1 , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg-1 , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg-1 ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg-1 ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg-1 ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg-1 didn't show significant efficacy above 3 mg kg-1 which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats.

BACKGROUND AND PURPOSE: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were treated with either CCl4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α-SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF-κB, TNF-α, COX-2, IL-1ß), TGF-ß1 and Hh signalling markers (Ptch-1, Smo, Gli-2) were also assessed. KEY RESULTS: Hepatic fibrosis induced by CCl4 was significantly reduced by forskolin, as indicated by decreased α-SMA expression and collagen deposition. Forskolin co-treatment significantly attenuated oxidative stress and inflammation, reduced TGF-ß1 levels and down-regulated mRNA expression of Ptch-1, Smo and Gli-2 through cAMP-dependent PKA activation. CONCLUSION AND IMPLICATIONS: In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti-inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP-dependent activation of PKA.

Antioxidant activities of crude phlorotannins from Sargassum hemiphyllum.

Brown algae are well known as a source of biologically active compounds, especially those having antioxidant activities, such as phlorotannins. In this study we examined the antioxidant activities of crude phlorotannins extracts (CPEs) obtained from Sargassum hemiphyllum (SH) and fractionated according to the molecular weights. When CPEs were administrated at a dose of 30 mg/kg to Kunming mice pre-treated with carbon tetrachloride (CCl4), the levels of oxidative stress indicators in the liver, kidney and brain were significantly reduced in vivo. All the components of various molecular weight fractions of CPEs exhibited greater scavenging capacities in clearing hydroxyl free radical and superoxide anion than the positive controls gallic acid, vitamin C and vitamin E. Particularly, the components greater than 30 kD obtained from ethyl acetate phase showed the highest antioxidant capacities. These results indicated that SH is a potential source for extracting phlorotannins, the algal antioxidant compounds.

Antioxidant and Hepatoprotective Activities of Mycelia Selenium Polysaccharide by Hypsizigus marmoreus SK-02.

This work was designed to investigate the characteristic properties (bond types and monosaccharide compositions), and hepatoprotective effects on carbon tetrachloride (CCl4)-induced liver damage of mycelia selenium polysaccharides (MSPS) separated and purified from Hypsizigus marmoreus SK-02. Characteristic analysis of MSPS showed the selenium content (70.15 µg/g) in mycelia. The antioxidant activities in vitro demonstrated that MSPS had potential effects on scavenging reactive oxygen species and enhancing the reducing power. The treatment of MSPS for CCl4-induced animal experiment demonstrated that the MSPS could reduce the levels of malondiadehyde (MDA), lipid peroxide (LPO), glutamic oxalacetic transaminase (AST), and glutamic-pyruvic transaminase (ALT) activities and improve the levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), total cholesterol (TC), and triglyceride (TG) in serum/liver homogenate against CCl4-induced injures. Findings presented in this study clearly demonstrated that MSPS might be suitable for functional foods and natural drugs in preventing the CCl4-induced acute liver damage.

Tissue-type plasminogen activator suppresses activated stellate cells through low-density lipoprotein receptor-related protein 1.

Hepatic stellate cell (HSC) activation and trans-differentiation into myofibroblast (MFB)-like cells is key for fibrogenesis after liver injury and a potential therapeutic target. Recent studies demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1)-dependent signaling by tissue-type plasminogen activator (t-PA) is a pro-fibrotic regulator of the MFB phenotype in kidney. This study investigated whether LRP1 signaling by t-PA is also relevant to HSC activation following injury. Primary and immortalized rat HSCs were treated with t-PA and assayed by western blot, MTT, and TUNEL. In vitro results were then verified using an in vivo, acute carbon tetrachloride (CCl4) injury model that examined the phenotype and recovery kinetics of MFBs from wild-type animals vs mice with a global (t-PA) or HSC-targeted (LRP1) deletion. In vitro, in contrast to kidney MFBs, exogenous, proteolytically inactive t-PA suppressed, rather than induced, activation markers in HSCs following phosphorylation of LRP1. This process was mediated by LRP1 as inhibition of t-PA binding to LRP1 blocked the effects of t-PA. In vivo, following acute injury, phosphorylation of LRP1 on activated HSCs occurred immediately prior to their disappearance. Mice lacking t-PA or LRP1 retained higher densities of activated HSCs for a longer time period compared with control mice after injury cessation. Hence, t-PA, an FDA-approved drug, contributes to the suppression of activated HSCs following injury repair via signaling through LRP1. This renders t-PA a potential target for exploitation in treating patients with fibrosis.

Effects of polysaccharides from selenium-enriched Pyracantha fortuneana on mice liver injury.

We have previously reported that polysaccharides extracted from Pyracantha fortuneana (Maxim.) Li (P. fortuneana) lowered the oxidative stress and inhibited the inflammatory responses in mice. Our present study aims to determine the effects of Selenium enriched P. fortuneana polysaccharides (Se-PFPs) against carbon tetrachloride (CCl4)-induced liver injury in a mouse model. Our results displayed that CCl4 remarkably elevated the levels of alanine transferase (ALT), aspartate transaminase (AST), lactic dehydrogenase (LDH), cholesterol, triglycerides in serum. However, similar to BP treatment, supplementation of mice with Se-PFPs resulted in reversal of ALT, AST, LDH, cholesterol, triglycerides in serum. Contrary to CCl4, supplementation of mice with Se-PFPs elevated the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of glutathione (GSH) in liver. Furthermore, Se-PFPs treatment increased the expression of GPx and catalase (CAT) at mRNA and protein levels in liver which were decreased in CCl4 group. Contrary to CCl4, Se-PFPs supplement decreased the levels of thiobarbituric acid reactive substances (TBAR) and H2O2, which served as lipid peroxidation biomarker. Our study indicates that Se-PFPs administration is effective in attenuating CCl4-induced liver injury. The mechanism underlying this effect may be attributed to the reduction of oxidative stress and inflammation in the liver by Se-PFPs through up-regulation of the antioxidant system. Our study suggests that Se-PFPs might be a potential dietary agent in the prevention of hepatic damage.

Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice.

Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress.

Oral administration of Saccharomyces boulardii ameliorates carbon tetrachloride-induced liver fibrosis in rats via reducing intestinal permeability and modulating gut microbial composition.

To investigate the effects of orally administrated Saccharomyces boulardii (S. boulardii) on the progress of carbon tetrachloride (CCl4)-induced liver fibrosis, 34 male Wistar rats were randomly divided into four experimental groups including the control group (n = 8), the cirrhotic group (n = 10), the preventive group (n = 8), and the treatment group (n = 8). Results showed that the liver expression levels of collagen, type I, alpha 1 (Col1A1), alpha smooth muscle actin (αSMA), transforming growth factor beta (TGF-ß) and the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) increased significantly in cirrhotic rats compared with control and decreased by S. boulardii administration. Treatment of S. boulardii also attenuated the increased endotoxin levels and pro-inflammatory cytokines in CCl4-treated rats. And, these were associated with the changes of intestinal permeability and fecal microbial composition. Our study suggested that oral administration of S. boulardii can promote the liver function of CCl4-treated rats, and the preventive treatment of this probiotic yeast may decelerate the progress of liver fibrosis.

Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4-induced acute hepatotoxicity in mice.

CONTEXT: The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. OBJECTIVE: The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. MATERIALS AND METHODS: Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. RESULTS: Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. DISCUSSION AND CONCLUSION: The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.