Hepatic Histological Lesions Research Articles

Ethyl acetate fraction of Mucuna pruriens leaves mitigates diclofenac-induced hepatotoxicity via modulation of biochemical and histological parameters changes in Wistar Rats

Mucuna pruriens contains saponins and flavonoids, which help to decrease cholesterol, treat hypertension, provide protein and vitamins and prevent premature ageing. This research followed the NIH guidelines (NIH publication 85–23, revised in 1996). Rats weighing 200–250 g were assigned into six groups (n = 6), normal saline only (control), normal saline (NS), Ethyl acetate fraction of Mucuna pruriens leaves (EAFMP) (100, 200 and 400 mg/kg) and Silymarin (100 mg/kg) treated orally for five days, diclofenac (DFN) was administered on days 3 and 4 via intraperitoneal route, biochemical and histology parameters were determined in serum and liver. This research revealed that treatment with EAFMP reversed the elevation of liver enzymes, total bilirubin, LDL and total cholesterol and lipid peroxidation; liver SOD, GSH, and CAT were elevated in EAFMP and Silymarin groups. The hepatic histological lesions in EAFMP were reduced in a dose-dependent manner. This research shows that EAFMP attenuates the deleterious effect of diclofenac-induced liver toxicity in rats.

Ginseng polysaccharides ameliorate abnormal lipid metabolism caused by acute alcoholic liver injury by promoting autophagy

AbstractThe study aimed to examine the effect of ginseng polysaccharide (GP) on acute alcoholic liver injury (AALI) and determine its underlying molecular mechanism. GP's in vitro and in vivo hepatoprotective effects were evaluated using LO2 cells and alcohol‐induced C57BL/6 male mice. Cell Counting Kit‐8, immunofluorescence, hematoxylin‐eosin, immunohistochemistry, and Western blot (WB) were used to detect alcohol‐induced lipid metabolism and autophagy levels in LO2 cells and liver. It was mainly composed of glucose, galactose, and arabinose in a molar ratio of 12.9:1.6:1.0. Experiments in vitro demonstrated that administration of GP to LO2 cells significantly increased the alcohol‐induced increase in cell viability. In addition, it can inhibit lipogenesis, enhance lipolysis, and stimulate autophagy. In alcohol‐induced mice, GP also inhibited hepatic histological lesions, prevented alanine aminotransferase and aspartate aminotransferase elevation, improved abnormal lipid metabolism, and boosted hepatocyte autophagy. In vivo and in vivo analysis of the underlying mechanisms revealed that GP promotes the expression of proteins in autophagy in AALI thereby alleviating it.

EXPERIMENTAL THERAPEUTIC EVALUATION OF THE AFRICAN VEGETABLES (CLERODENDRUM VOLUBILE LEAF AND IRVINGIA GABONENSIS SEED EXTRACTS) IN TRASTUZUMAB-MEDIATED HEPATO-RENAL DYSFUNCTION IN WISTAR RATS

Objective: The use of trastuzumab (TZM) in the clinical management of human epidermal growth factor receptor 2 positive metastatic breast and gastric cancers, gastro-esophageal adenocarcinoma, and colorectal carcinoma has been limited by its off-target cardiac, hepatic, and renal toxicities which till date have no effective therapies in either their prevention or amelioration. Thus, the present study is designed at investigating the protective and therapeutic potentials of 400 mg/kg/day Clerodendrum volubile ethanol leaf extract (CVE) and Irvingia gabonensis ethanol seed extract (IGE) pretreatments in TZM-intoxicated Wistar rats based on their reported folkloric use in the local management of kidney and liver diseases and the previously reported therapeutic potential of these African vegetables in TZM cardiotoxicity.
 Methods: Forty-nine male Wistar rats were randomly allotted into seven groups of seven rats per group. Group I rats were treated with 10 ml/kg/day of 5% dimethyl sulfoxide (DMSO) sterile water p.o. and 1 ml/kg/day 5% DMSO sterile water i.p.; Groups II and III rats were orally pretreated with 400 mg/kg/day CVE and IGE, respectively, 3 h before 1 ml/kg/day/i.p. 5% DMSO sterile water; Group IV rats were orally pretreated with 10 ml/kg/day 5% DMSO sterile water 3 h before 2.25 mg/kg/day/i.p. TZM; and Groups V-VII rats were pretreated with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE, and 400 mg/kg/day IGE all dissolved in 5% DMSO sterile water, respectively, 3 h before i.p. injections of 2.25 mg/kg/day TZM, all for 7 days. Liver function parameters, renal function parameters, oxidative stress markers, and histopathological investigations were the study measuring endpoints.
 Results: Oral pretreatment with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE and IGE significantly ameliorated TZM-mediated hepatic and renal toxicities by effectively lowering the serum alanine transaminase, aspartate transaminase, alkaline phosphatase, creatinine, and urea levels. CVE and IGE pretreatments also significantly reversed TZM-induced decreases in the hepatic and renal tissue catalase, superoxide dismutase, and glutathione- S-transferase activities and reduced malondialdehyde levels. CVE and IGE pretreatments also improved TZM-induced hepatic and renal histological lesions.
 Conclusions: Overall, the chemotherapeutic/chemopreventive potentials of CVE and IGE in TZM-induced hepatorenal dysfunction were either wholly or partly mediated through free-radical scavenging and antioxidant activities.

Detection of Aflatoxin adducts as potential markers and the role of curcumin in alleviating AFB1-induced liver damage in chickens

In this study, we identified AFB1 adducts as potential markers and investigated the role of curcumin in alleviating AFB1-induced liver damage by suppressing the production of AFB1 adducts and oxidative stress in AA broilers liver. A total of 64 one-day-old Arbor Acres (AA) broilers were randomly divided into four groups, including control group, AFB1 group (5 mg/kg AFB1), cur + AFB1 group (300 mg/kg curcumin+5 mg/kg AFB1) and curcumin group (300 mg/kg). Serum biochemical parameters, liver antioxidant abilities, AFB1 adducts and oxidative stress mechanism were studied in broilers. AFB1 administration accompany with signs of liver injury, including hepatic histological lesions, increased serum enzymes activities, decreased liver antioxidant enzymes activities and the suppression of ROS and 8-OHdG. Meanwhile, Nrf2/HO-1 pathway was depressed by AFB1 treatment. Immunohistochemistry and ELISA showed that AFB1 significantly increased AFB1-DNA adduct in liver (p < 0.05) and AFB1-lysine adduct in serum (p < 0.05). Importantly, supplementation of curcumin can ameliorate these alterations. Intriguingly, curcumin alleviated AFB1-induced toxicity and oxidative stress by inhibiting the generation of ROS, 8-OHdG and AFB1 adducts, and activated Nrf2 signaling pathway in broilers. Conclusively, our experiments suggest that curcumin could be considered as a potential agent for prevention of AFB1-induced toxicity and oxidative stress, and AFB1 adducts could be suitable therapeutic targets.

Xyloketal B Attenuates Fatty Acid-Induced Lipid Accumulation via the SREBP-1c Pathway in NAFLD Models.

The goal of this study was to examine the effects of xyloketal B on nonalcoholic fatty liver disease (NAFLD) and to explore the molecular mechanisms underlying its effects in both in vivo and in vitro models. We discovered an association between xyloketal B and the sterol regulatory element-binding protein-1c (SREBP-1c) signaling pathway, which is related to lipid metabolism. Mice were dosed with xyloketal B (5, 10 and 20 mg/kg/d) and atorvastatin (15 mg/kg/d) via intraperitoneal injection once daily for 40 days after being fed a high fat diet plus 10% high fructose liquid (HFD+HFL) for 8 weeks. Xyloketal B significantly improved HFD+HFL-induced hepatic histological lesions and attenuated lipid and glucose accumulation in the blood as well as lipid accumulation in the liver. Xyloketal B increased the expression of CPT1A, and decreased the expression of SREBP-1c and its downstream targeting enzymes such as ACC1, ACL, and FAS. Xyloketal B also significantly reduced lipid accumulation in HepG2 cells treated with free fatty acids (FFAs). These data suggested that xyloketal B has lipid-lowering effects via the SREBP-1c pathway that regulate lipid metabolism. Thus, targeting SREBP-1c activation with xyloketal B may be a promising novel approach for NAFLD treatment.

Curcumin Prevents Aflatoxin B₁ Hepatoxicity by Inhibition of Cytochrome P450 Isozymes in Chick Liver.

This study was designed to establish if Curcumin (CM) alleviates Aflatoxin B1 (AFB1)-induced hepatotoxic effects and to determine whether alteration of the expression of cytochrome P450 (CYP450) isozymes is involved in the regulation of these effects in chick liver. One-day-old male broilers (n = 120) were divided into four groups and used in a two by two factorial trial in which the main factors included supplementing AFB1 (< 5 vs. 100 μg/kg) and CM (0 vs. 150 mg/kg) in a corn/soybean-based diet. Administration of AFB1 induced liver injury, significantly decreasing albumin and total protein concentrations and increasing alanine aminotransferase and aspartate aminotransferase activities in serum, and induced hepatic histological lesions at week 2. AFB1 also significantly decreased hepatic glutathione peroxidase, catalase, and glutathione levels, while increasing malondialdehyde, 8-hydroxydeoxyguanosine, and exo-AFB1-8,9-epoxide (AFBO)-DNA concentrations. In addition, the mRNA and/or activity of enzymes responsible for the bioactivation of AFB1 into AFBO—including CYP1A1, CYP1A2, CYP2A6, and CYP3A4—were significantly induced in liver microsomes after 2-week exposure to AFB1. These alterations induced by AFB1 were prevented by CM supplementation. Conclusively, dietary CM protected chicks from AFB1-induced liver injury, potentially through the synergistic actions of increased antioxidant capacities and inhibition of the pivotal CYP450 isozyme-mediated activation of AFB1 to toxic AFBO.

Hemostatic assessment of dogs associated with hepatic parasite load of Leishmania infantum chagasi

Abstract Leishmania infantum chagasi liver parasite load was compared to hemostatic abnormalities, as well as to clinical, laboratorial, and histopathological findings in dogs with visceral leishmaniasis. The liver parasite load of 30 dogs L. infantum chagasi naturally-infected was evaluated by quantitative real- time PCR and the results were compared with serum biochemistry and primary and secondary hemostasis findings. Moreover, hepatic histological lesions were described in these dogs. Prolonged bleeding time, prothrombin time (PT), and activated partial thromboplastin time (APTT), were observed in the group with visceral leishmaniasis. Eleven dogs presented inflammatory liver lesions, with predominance of mild multifocal mononuclear periportal hepatitis. No association between the presence of parasites and abnormalities in screening tests was observed by Spearman’s rank correlation coefficient. The clinical progression in leishmaniasis is associated with the occurrence of hemorrhagic diathesis, which depends not only on the presence of the parasite but also the inflammatory process, compromised immunological response, hepatic and renal failure in symptomatic dogs.

Houttuynia cordata alleviates high-fat diet-induced non-alcoholic fatty liver in experimental rats

Context: Houttuynia cordata Thunb. (Saururaceae) is used traditionally in Asian countries to treat various disease symptoms.Objective: To study the effect of H. cordata ethyl acetate (HC-EA) extract on high-fat diet (HFD)-induced hepatic steatosis.Materials and methods: HFD fed rats were orally dosed with HC-EA (100, 200, or 300 mg/kg) once daily for 8 weeks and the lipid profiles and protein expressions in hepatocytes were evaluated.Results: HFD rats showed an increase (p < 0.05) in the plasma lipid levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), free fatty acids (FFAs), and reduced the high-density lipoprotein (HDL) levels. Treatment with HC-EA extract (300 mg/kg) restored the changes in plasma lipid levels of TC, TG, LDL, FFA, and HDL in HFD-fed rats by 34.8, 31.1, 51.4, 32.4, and 56.3%, respectively, compared with control rats (p < 0.01). HC-EA treatment also decreased the hepatic lipid accumulation (p < 0.001 at 300 mg/kg) and improved hepatic histological lesions. HC-EA extract enhanced AMPK phosphorylation and its primary downstream targeting enzyme, acetyl-CoA carboxylase (ACC), up-regulated the gene expression of carnitine palmitoyl transferase-1 (CPT-1), and down-regulated sterol regulatory element binding protein 1, fatty acid synthase, and glutamate pyruvate transaminase protein levels in the livers of HFD-fed rats. Further, the increased expression of hepatic cytochrome P450 (CYP) composition such as CYP2E1 and CYP4A was also suppressed.Discussion and conclusion: Data suggest that HC-EA extract might act by regulating the AMPK-dependent pathway and related mediators and might be used in treating obesity-related liver diseases.

Cassia tora (Leguminosae) seed extract alleviates high-fat diet-induced nonalcoholic fatty liver

The aim of this study was to examine the effects of Cassia tora seeds on high-fat diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. After being fed a HFD for two weeks, rats were orally dosed with Cassia seed ethanol extract (CSEE) (100, 200, or 300mg/kg) once daily for 8weeks. CSEE induced dose-dependent reductions in plasma lipid levels, as well as decreased the over hepatic lipid accumulation. Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions. CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats. AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin. Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK-dependent signaling pathway. Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non-alcoholic fatty liver disease.

Increased hepatic apoptosis in high-fat diet-induced NASH in rats may be associated with downregulation of hepatic stimulator substance

The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Hepatocellular apoptosis could be one of the key factors in the pathogenesis of non-alcoholic steatohepatitis (NASH). Hepatic stimulator substance (HSS) protects liver cells from various toxins. We previously reported that HSS is critically important for the survival of hepatocytes due to its mitochondrial association. This study aims to investigate the relationship between HSS and hepatocellular apoptosis in vivo models of high-fat diet-induced NASH and in vitro models of palmitic acid-induced hepatocyte injury. Sprague-Dawley rats were fed a high-fat diet for 8, 12 and 16weeks. Hepatic histological lesions, liver function and apoptosis were examined. HSS expression, in association with caspase-3 and cytochrome c leakage, which are both indicators of cell apoptosis, was measured. Results showed that a high-fat diet altered liver function and histology in a manner resembling NASH. Hepatic protein and mRNA HSS expression was decreased as NASH progressed. Meanwhile, cell apoptosis increased as result of caspase-3 activation and cytochrome c release, indicating that HSS might be involved in NASH pathogenesis. Furthermore, in palmitic acid-induced hepatic cell damage, over-expression of HSS decreased cells apoptosis. In contrast, repression of HSS expression by siRNA increased cell apoptosis. In conclusion, these data imply that cell apoptosis contributes to the pathogenesis of NASH, during which HSS expression is downregulated. Increasing HSS expression in hepatocytes may forestall cell apoptosis as result of fatty acid insult.

Anti-obesity and antihyperlipidaemic effect of Hunteria umbellata seed extract in experimental hyperlipidaemia

Aim of the study In Nigerian folk medicine, water infusion of the dried seeds of Hunteria umbellata (K. Schum.) Hallier f. has a reputation for the local management of obesity and hyperlipidaemia. The present study is aimed at evaluating the anti-obesity and antihyperlipidaemic activities as well as the underlying mechanisms of action of the aqueous seed extract of Hunteria umbellata ( HU) in normal, triton-induced, and olive oil-induced hyperlipidaemic rats. Materials and methods Normal and olive oil-induced hyperlipidaemic, and triton-induced hyperlipidaemic rats were pre-treated with single, daily oral administration of 10 ml/kg of distilled water, 20 mg/kg of simvastatin, 50 mg/kg, 100 mg/kg and 200 mg/kg of HU in 10 ml/kg of distilled water for 28 days and 24 h. The effects of these drugs on % body weight change, feeding pattern, serum lipids, coronary artery risk index (CRI) and atherogenic index (AI) and Lee's index (LI) were investigated. Results Oral pre-treatment with simvastatin and graded oral doses of HU significantly ( p < 0.05) reduced the weight gain pattern and caused dose related ( p < 0.05, p < 0.01 and p < 0.001) reductions in the serum lipids, CRI, AI and LI. Also, HU pre-treatment significantly improved triton-induced hepatic histological lesions. Conclusions Results of this study showed that HU has both anti-obesity and antihyperlipidaemic effects which may partly be mediated via inhibition of intestinal lipid absorption and de novo biosynthesis of cholesterol. Thus, the results justify the ethnopharmacological use of the extract in the management of obesity and hyperlipidaemia.

Genotype–phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.

Effect of tobacco consumption on hepatic histological lesions in patients with chronic hepatitis C

Effect of tobacco consumption on hepatic histological lesions in patients with chronic hepatitis C

Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions

Background/Aims: Liver iron accumulation has been described in patients with chronic active hepatitis (CAH) C, and could play a role in the course of liver disease and negatively influence the response to interferon. The aim of this study was to determine the prevalence and severity of liver iron accumulation in CAH C, to assess its relationship with the HFE C282Y and H63D mutations, and to study its interactions with hepatic histological lesions. Methods: Two hundred and nine patients (131 men, 78 women, mean age 44.3±12.0 years) with CAH C, including 19 patients with cirrhosis (9.1%) were studied. A semiquantitative grading system from 0 to 3 was used for histological assessment of liver iron accumulation on Perls' staining. The HFE C282Y and H63D mutations were screened for by restriction enzyme analysis performed on PCR-amplified products. Histological scores of activity and fibrosis were determined according to a previously validated METAVIR score system. Results: Liver iron accumulation was found in 88/209 patients (42.1%), and was generally mild. The C282Y and H63D allele frequencies were in 23 (11.0%), and 50 (23.9%), respectively. No association was found between the presence of liver iron accumulation and the detection of the C282Y and H63D mutations. A significant relationship was found between the severity of histological activity and liver iron accumulation of macrophagic or mixed (i.e. both macrophagic and hepatocytic) type ( p=0.04). Although the number of cirrhotic patients was small, cirrhosis was more frequently observed in patients with than without liver iron accumulation (17.2% vs. 3.3%, p=0.004). Conclusions: Overall, these data suggest that the liver iron accumulation in patients with CAH C is significantly associated with histological activity and cirrhosis, whereas the two missense hemochromatosis gene mutations are not major determinants.

Liver iron overload in patients with chronic active hepatitis C. Prevalence, role of the hemochromatosis gene and relation with hepatic histological lesions

Liver iron overload in patients with chronic active hepatitis C. Prevalence, role of the hemochromatosis gene and relation with hepatic histological lesions

Cholestatic effect of cyclosporine in the rat. An inhibition of bile acid secretion.

Cyclosporine administration in patients with organ transplants may cause cholestasis. In the rat, intraperitoneal administration of cyclosporine, 10 mg/kg, for three weeks did not cause liver function test abnormalities or hepatic histological lesions. However a significant reduction of bile flow and bile acid secretion rates was observed. The fact that reduction of bile flow was related to a decrease of the bile acid-independent flow suggests that cyclosporine-induced cholestasis results from an inhibition of bile acid secretion. Whether this inhibition is caused by the parental molecule or by cyclosporine metabolites needs to be clarified.

Hepatic Toxicity in the Rhesus Monkey Treated with Chenodeoxycholic Acid for 6 Months: Biochemical and Ultrastructural Studies

The long term administration of chenodeoxycholic acid in man has to be regarded with caution because chenodeoxycholic acid has caused liver damage in various species of animals, including primates. To study the effect of three doses of chenodeoxycholic acid (10, 40, and 100 mg per kg per day) on hepatic function and morphology, biliary bile acid composition and the reversibility of changes were investigated in 22 rhesus monkeys. After 6 months of treatment with 40 and 100 mg per kg per day, bile duct proliferation, portal tract inflammation and fibrosis, bile canalicular bleb formation, and hypertrophy of the smooth endoplasmic reticulum were associated with elevated serum levels of oxaloacetic transaminase, glutamic pyruvic transaminase, and leucine aminopeptidase. In the bile, the proportion of chenodeoxycholic acid and its bacterial metabolite, lithocholic acid, rose to approximately 85 and 10% of the total bile acids. After chenodeoxycholic acid was withdrawn for 3 months, the hepatic morphological lesions persisted in some animals although biliary bile acid composition returned to normal. No hepatic abnormalities were seen in the animals treated with 10 mg per kg per day. The findings suggest that long term treatment of rhesus monkeys with high doses of chenodeoxycholic acid results in severe hepatic histological lesions that can persist after discontinuation of the bile acid.