Rat Model Of Acute Liver Injury Research Articles

Functional Assessment of MGO Nanoparticle Supplementation in an Acute Liver Injury Rat Model

Magnesium supplements have been effective for modulating process of bile resistance, decrease oxidative stress and systemic inflammation. Current study was designed to functionally evaluate the MgO nanoparticle supplementation in an acute liver injury rat model. The animals were randomly divided into five groups. All groups were administrated with CCl4 to induce hepatic injury except of negative control group which received only vehicle. CCl4 administration is followed by MgO nanoparticles in the concentration of 150 and 300 mg/kg in low dose and high dose treated group respectively except of standard control group. After 21 days of treatment, the animals were sacrificed to collect blood and liver samples. Serum levels of bilirubin, AST, ALT and ALP were determined. Liver sample was also subjected to RNA isolation by Trizol method followed by the cDNA synthesis and Real Time PCR. In addition, lipid profile was also assessed. The data obtained was analyzed by one way analysis of variance (ANOVA). The results showed that levels of bilirubin, AST, ALT and ALP were significantly elevated in positive control group while MgO treated groups, somehow, had normal ranges of these enzymes. Furthermore, the qPCR results showed that the expression of Farnesoid X receptor (FXR), transcriptional regulator of the bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP), is reduced in positive control group, while nanoparticles treated groups had normal expression of these genes. In conclusion, our data showed that MgO nanoparticles possess hepatoprotective activity against hepatic injury.

Exploring the Effective Components and Mechanism of Action of Japanese Ardisia in the Treatment of Autoimmune Hepatitis Based on Network Pharmacology and Experimental Verification.

Japanese Ardisia is widely used as a hepatoprotective and anti-inflammatory agent in China. However, the active ingredients in Japanese Ardisia and their potential mechanisms of action in the treatment of autoimmune hepatitis (AIH) are unknown. The pharmacodynamic substance and mechanism of action of Japanese Ardisia in the treatment of AIH were investigated using network pharmacology and molecular docking technology in this study. Following that, the effects of Japanese Ardisia were evaluated using the concanavalin A (Con A)-induced acute liver injury rat model. The active ingredients and targets of Japanese Ardisia were searched using the Traditional Chinese Medicine Systems Pharmacology database, and hepatitis-related therapeutic targets were identified through GeneCards and Online Mendelian Inheritance in Man databases. A compound-target network was then constructed using Cytoscape software, and enrichment analysis was performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Molecular docking technology was used to simulate the docking of key targets, and the AIH rat model was used to validate the expression of key targets. Nineteen active chemical components and 143 key target genes were identified. GO enrichment analysis revealed that the treatment of AIH with Japanese Ardisia mainly involved DNA-binding transcription factor binding, RNA polymerase II-specific DNA transcription factor binding, cytokine receptor binding, receptor-ligand activity, ubiquitin-like protein ligase binding, and cytokine activity. In the KEGG enrichment analysis, 165 pathways were identified, including the lipid and atherosclerotic pathway, IL-17 signaling pathway, TNF signaling pathway, hepatitis B pathway, and the AGE-RAGE signaling pathway in diabetic complications. These pathways may be the key to effective AIH treatment with Japanese Ardisia. Molecular docking showed that quercetin and kaempferol have good binding to AKT1, IL6, VEGFA, and CASP3. Animal experiments demonstrated that Japanese Ardisia could increase the expression of AKT1 and decrease the expression of CASP3 protein, as well as IL-6, in rat liver tissues. This study identified multiple molecular targets and pathways for Japanese Ardisia in the treatment of AIH. At the same time, the effectiveness of Japanese Ardisia in treating AIH was verified by animal experiments.

Vinegar-baked Radix Bupleuri enhances the liver-targeting effect of rhein on liver injury rats by regulating transporters.

This study aimed to explore whether the liver-targeting enhancing effect of vinegar-baked Radix Bupleuri (VBRB) on rhein was achieved by affecting transporters, metabolism enzymes as well as hepatocyte nuclear factor 1α/4α (HNF1α/HNF4α) in liver injury. The effect of VBRB on the efficacy of rhein was performed with the LPS-induced acute liver injury rat model. Aspartate aminotransferase (AST), alanine transaminase (ALT) and superoxide dismutase (SOD) levels were determined and histopathological examination was taken. Drug concentrations in tissues were determined by high performance liquid chromatography (HPLC). The protein expressions of drug transporters, metabolic enzymes and hepatic nuclear factors were determined by Western blotting and ELISA assays. VBRB improved the liver protecting effect of rhein, which was consistent with its promoting effect on targeted enrichment of rhein in the liver. VBRB or in combination with rhein inhibited P-glycoprotein (Pgp) and multi-resistance related protein 2 (MRP2), while increased organic anion transporting polypeptide 2 (OATP2), which might be the reason why VBRB promoted liver-targeting effect of rhein. VBRB enhances the liver-protecting effect of rhein by down-regulating Pgp, MRP2, and up-regulating OATP2.

Effects of water extract of Paeoniae Radix Alba on a thioacetamide induced acute liver injury rat model

Effects of water extract of Paeoniae Radix Alba on a thioacetamide induced acute liver injury rat model

Protective Effect of Antioxidative Liposomes Co-encapsulating Astaxanthin and Capsaicin on CCl4-Induced Liver Injury.

Our previous study reported that co-encapsulation of potent antioxidants astaxanthin (Asx) and capsaisin (Cap) into liposomes brought about synergistically higher antioxidative activity than the calculated additive activity of each single antioxidant encapsulating liposome. Based on the previous computational chemistry analysis, the synergistic effect was revealed to be resulted from intermolecular interactions between Asx, especially 3R,3'R-form of Asx stereoisomer (Asx-R), and Cap, by which changes of electronic states of the polyene moiety of Asx-R were induced. Although liposomes co-encapsulating Asx-R and Cap (Asx-R/Cap-Lipo) at an optimal ratio clearly showed synergistic antioxidative activity in vitro, it is unclear whether the effective antioxidative activity derived from intermolecular interaction between Asx-R and Cap is also exerted in vivo. Therefore, in this study, we investigated therapeutic potential of Asx-R/Cap-Lipo as an antioxidant formulation in vivo. For this purpose, we employed carbon tetrachloride (CCl4)-induced acute liver injury rat model, since CCl4 is known to cause oxidative damage in liver. CCl4 administration significantly increased the levels of aspartate transaminase (AST) and alanine aminotransferase (ALT). Intravenous combined administration of liposomes encapsulating Asx-R (Asx-R-Lipo) and liposomes encapsulating Cap (Cap-Lipo) significantly decreased CCl4-induced increase of AST and ALT levels. Importantly, the treatment with Asx-R/Cap-Lipo tended to show higher protective effect on acute liver injury than combined treatment with Asx-R-Lipo plus Cap-Lipo. These results suggest that co-encapsulated Asx-R and Cap in liposomal membranes could exert more effective antioxidative activities in vivo, and that Asx-R/Cap-Lipo would be a hopeful antioxidant formulation for treating reactive oxygen species-related diseases.

Exploration of the Hepatoprotective Effect and Mechanism of Swertia mussotii Franch in an Acute Liver Injury Rat Model.

Swertia mussotii Franch, also known as "Zangyinchen", is one of a Tibetan traditional herb used for treatment of liver diseases over thousands of years at Qinghai-Tibet Plateau, has been confirmed to be hepatoprotective. However, the underlying mechanism is largely unknown. In this study, we evaluated the effect of S. mussotii treatment in a carbon tetrachloride-induced acute liver injury rat model by examining the serum alanine aminotransferase, aspartate aminotransferase, total bilirubin levels and performing histological observations of the liver tissues. Meanwhile, the metabolomics analysis was used to explore the molecular mechanism of S. mussotii treatment by high performance liquid chromatography tandem mass spectrometry. The results showed that S. mussotii treatment could effectively improve the serum alanine aminotransferase, aspartate aminotransferase, total bilirubin in acute liver injury rat model. Histological observation showed that S. mussotii treatment could effectively alleviate liver injury. Moreover, the metabolomics analysis showed that S. mussotii treatment could normalize the levels of many fatty acid metabolism related metabolites. And the results of pathway analysis showed that these metabolites significantly enriched in fatty acid biosynthesis pathway (myristic acid, dodecanoic acid and capric acid) and linoleic acid metabolism pathway (13-OxoODE). The results indicated that S. mussotii treatment could significantly improve acute liver injury through affecting the pathways related to lipid metabolism.

Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2

BackgroundAlthough silybin serves as a well-known hepatoprotective agent with prominent anti-inflammatory, anti-oxidant and anti-fibrotic activities, its low bioavailability limits its application in the treatment of chronic liver diseases. However, novel formulation products with increased solubility were not sufficient to achieve pharmacologically meaningful concentrations of silybin in the clinical studies even used at high dosage. Hypothesis/PurposeWe hypothesized that inhibiting efflux transporter(s) and/or glucuronidation by piperine might enhance the bioavailability and efficacy of silybin. MethodsPharmacokinetics of silybin given alone or in-combination with piperine was determined by a validated LC-MS method. A CCl4 induced rat model of liver injury was prepared and verified for comparing the effects of silybin and combination treatment. To investigate the underlying mechanism, the inhibition effects of piperine on transportation of silybin were performed in Caco-2 and transfected MDCKII cell lines as well as sandwich–cultured rat hepatocytes (SCH). Human liver microsomes incubation was used for exploring the modulation effects of piperine on the phase-2 metabolism of silybin. ResultsIn the present study, we demonstrated for the first time that piperine as a bioenhancer increased the bioavailability of silybin (146%– 181%), contributing to a boosted therapeutic effect in CCl4-induced acute liver-injury rat model. The underlying mechanisms involved that piperine enhanced the absorption of silybin by inhibiting the efflux transporters including MRP2 and BCRP but not MDR1 in Caco-2 and transfected MDCKII cell lines. Moreover, piperine could inhibit the biliary excretion of silybin and conjugated metabolites in sandwich–cultured rat hepatocytes. Notably, we found that piperine did not affect the phase-2 metabolism of silybin. ConclusionEfflux transporters play an important role in the pharmacokinetic behavior of flavolignans, and modulating these transporters by bioenhancer such as piperine could enhance the in vivo absorption of silybin, leading to more effective treatments.

Role of tangeretin as a potential bioavailability enhancer for silybin: Pharmacokinetic and pharmacological studies

Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl4-induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use.

Radix Paeoniae Rubra and Radix Paeoniae Alba Attenuate CCl4-Induced Acute Liver Injury: An Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) Based Metabolomic Approach for the Pharmacodynamic Study of Traditional Chinese Medicines (TCMs)

Metabolomics has been frequently used in pharmacodynamic studies, especially those on traditional Chinese medicine (TCM). Radix Paeoniae Alba and Radix Paeoniae Rubra are popularly used in TCM, and both have hepatoprotective effects. In this study, a CCl4-induced acute liver injury rat model was established and confirmed by the observed serum aminotransferase activities. The metabolomics approach was applied to study the influence of Radix Paeoniae Alba and Radix Paeoniae Rubra on the metabolic changes in rats with acute liver injury. The partial least-squares-discriminant analysis (PLS-DA) of rat serum and their ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) fingerprints allowed discrimination of controlled, acute liver injury-model rats after administration of the two types of TCMs. The time-dependent PLS-DA plots showed that the changes in the metabolic patterns of the rats, which were administered with the TCMs, had stabilized within 2 h after they received the intraperitoneal CCl4 injection. The results indicated the protective effect of TCMs against liver injury. Several potential biomarkers were detected and identified, which included creatine, deoxycholic acid, choline, 5-methylenetetrahydrofolate, folic acid, and glycocholic acid. The physiological significance of these metabolic changes was discussed.

Protective effect of physcione on acute liver injury in rats

目的 探讨大黄有效成分大黄素甲醚对急性肝损伤的保护作用.方法 以2 ml/kg体质量四氯化碳(CCl4)灌服雄性Wistar大鼠3 d诱导急性肝损伤动物模型,观察大黄素甲醚对实验性肝损伤大鼠血清酶含量、血清肿瘤坏死因子(TNF)水平及肝组织病理学改变的影响.结果 大黄素甲醚组与模型组相比,血清酶学指标[ALT(U/L):(670.3±42.0)vs(917.1±78.0),AST(U/L):(1 157.2±86.2)vs(2 701.4±108.4)]及TNF水平明显降低[(1.6±0.3)μg/L vs(2.1±0.4)μg/L](均P＜0.05).大黄素甲醚组肝组织病理改变较模型组明显减轻.结论 大黄素甲醚对大鼠急性肝损伤具有保护作用。

Effects of different probiotic strains of Lactobacillus and Bifidobacterium on bacterial translocation and liver injury in an acute liver injury model

Septic complications represent frequent causes of morbidity in liver diseases and following hepatic operations. Most infections are caused by the individual own intestinal microflora. The intestinal microflora composition is important in physiological and pathophysiological processes in the human gastrointestinal tract, but their influence on liver in different situations is unclear. We therefore studied the effect of different Lactobacillus strains and a Bifidobacterium strain on the extent of liver injury, bacterial translocation and intestinal microflora in an acute liver injury model. Sprague–Dawley rats were divided into five groups: acute liver injury control, acute liver injury+ B. animalis NM2, acute liver injury+ L. acidophilus NM1, acute liver injury+ L. rhamnosus ATCC 53103, and acute liver injury+ L. rhamnosus DSM 6594 and L. plantarum DSM 9843. The bacteria were administered rectally daily for 8 days. Liver injury was induced on the 8th day by intraperitoneal injection of d-galactosamine (1.1 g/kg BW). Samples were collected 24 h after the liver injury. Liver enzymes and bilirubin serum levels, bacterial translocation (to arterial and portal blood, liver and mesenteric lymph nodes (MLNs)), and intestinal microflora were evaluated. L. acidophilus NM1; L. rhamnosus ATCC 53103, and L. rhamnosus DSM 6594+ L. plantarum DSM 9843 decreased bacterial translocation compared to the liver injury control group. B. animalis NM2 increased bacterial translocation to the mesenteric lymph nodes. The levels of alanine aminotransferase (ALAT) were significantly lower in the L. acidophilus, L. rhamnosus ATCC 53103, L. rhamnosus DSM 6594+ L. plantarum DSM 9843 groups compared to the liver injury group. The L. rhamnosus and L. rhamnosus+ L. plantarum groups significantly reduced ALAT levels compared to the B. animalis group. All administered bacteria decreased the Enterobacteriaceae count in the cecum and colon. Administration of different lactobacilli and a Bifidobacterium strain in an acute liver injury rat model, has shown different effects on bacterial translocation and hepatocellular damage. L. acidophilus, L. rhamnosus, and L. rhamnosus+ L. plantarum reduced bacterial translocation and hepatocellular damage. B. animalis NM2 increased bacterial translocation to the mesenteric lymph nodes and did not affect hepatocellular damage.