Abnormal Liver Histology Research Articles

Studying the Effect of nano-extract of Nerium Oleander Leaves on the Histological Structure of the Liver in Male Laboratory Mice

Objectives: The purpose of the research was to see how a nano-extract (zinc oxide) of oleander leaves affected the histological structure of the liver in male laboratory mice aged (7-8) weeks and weighing (28-35 g). Methods: They were split up into three groups, with ten mice in each. The control group made the first group. The second group was treated with an oleander leaf nano-extract at a concentration of (20 mg/kg). The group that was administered a 30 mg/kg dosage of oleander leaf nano-extract is the third group. For 30 to 45 days on a daily basis, a (30 mg/kg) concentration of the oleander leaf nano-extract was used. Half of the rodents were sacrificed at the end of the initial thirty days, and histological sections of the liver were obtained. Results: Histological sections of the liver were obtained from the residual half, which was sacrificed after 45 days when the experiment ended. Animals injected with a Nano-extract of oleander leaves at a dose of (20 mg/kg) for 40 days had aberrant liver structure, cells, and histological abnormalities. Animals that received a 45-day injection of a (30 mg/kg) dosage of oleander leaf nano-extract also had pathological alterations and aberrant liver and central vein cell morphology. Conclusions: The results showed the toxic effects of the Nano-extract of the oleander plant and the xistence of histological alterations in the histological structure of the liver in groups treated with varying amounts of oleander leaf nano-extract.

Cynara Cardunculus Flavonoids-rich Fraction Alleviates Liver Injury in Mice Overconsumed Fructose Model.

Non-alcoholic Fatty liver disease (NAFLD) is becoming a major global health burden in the world. Cynara cardunculus is an edible plant growing wild in the North of Algeria. Its potential as a source of health-promoting compounds is still underexplored. This study aimed to explore the preventive effect of Cynara cardunculus (C.cardunculus) on the NAFLD model. Total flavonoid contents (TFC) and in vitro antioxidant effects of butanolic (n- BuTOH) and ethyl acetate (EtOAc) fractions on scavenging the ABTS+ radical, inhibition of lipid peroxidation and reducing power proprieties were assessed. The n-ButOH fraction showed the highest TFC and antioxidant capacity in all realized assays. This fraction is used for anti- NAFLD experiments. Adult male Albinos mice were divided into four groups. Group 1 was normal control. Group 2 was watered with 30% of fructose for three weeks to induce the NAFLD model. Group 3 and Group 4 were co-treated with C. cardunculus n-ButOH fractions and Atorvastatin, respectively for three weeks. Blood and livers were collected for biochemical and histological analysis. The C. cardunculus n-ButOH fractions significantly restored levels of transaminases, triglycerides, cholesterol, LDL, glucose and uric acid. The n-ButOH fraction exerted an improving effect on the body and liver weight and liver index. It also significantly corrected the imbalance in liver MDA and GSH levels. The n-ButOH fractions further ameliorated abnormalities in liver histology through suppression of lipid droplet accumulation. This research proves that the flavonoid-rich fraction of C. cardunculus has protective activity against high fructose intake in mice via reversing hyperlipidemia and boosting liver antioxidant capacity.

Combined effects of hypoxia and ammonia-N exposure ontheimmune response, oxidative stress, tissue injury and apoptosis of hybrid grouper (Epinephelus fuscoguttatus♀×E. lanceolatus♂).

In order to investigate the simultaneous exposure to hypoxia and ammonia-N on oxidative stress, immune response, and apoptosis of the hybrid grouper, 120 healthy groupers were selected for hypoxia and/or ammonia-N exposure experiment. The fish were divided into four experimental groups: hypoxia and ammonia-N group, hypoxia group, ammonia-N group, and control group. The results demonstrated that ammonia-N and hypoxia exposures induced the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities increased first and then decreased, and malondialdehyde (MDA) accumulated. Additionally, antioxidant genes (SOD, CAT, GSH-Px, HSP70, and HSP90), apoptosis genes (p53, bax, caspase 3, caspase 8, and caspase 9), and inflammatory genes (TNF-α, IL-1β, IL-6, and IL-8) were upregulated by hypoxia and ammonia-N exposure. Severe inflammatory features were noticed in fish under hypoxia and ammonia-N co-exposure and speculating that the p53-bax pathway may induce apoptosis in hybrid groupers. Furthermore, hybrid grouper exposed to hypoxia or ammonia-N revealed some abnormalities in liver histology, with combined exposure resulting in the most severe liver tissue lesions. In summary, the hypoxia and ammonia-N co-exposure induced oxidative stress, accelerating the cell damage and activated inflammation and apoptosis.

Mango (Mangifera indica L.) seed kernel extract suppresses hyperglycemia by modulating pancreatic β cell apoptosis and dysfunction and hepatic glucose metabolism in diabetic rats.

This study investigated the anti-hyperglycemic action of mango seed kernel extract (MKE) and various mechanisms involved in its actions to improve pancreatic β cells and hepatic carbohydrate metabolism in diabetic rats. An intraperitoneal injection of 60mg/kg of streptozotocin (STZ) followed by 30 consecutive days of treatment with MKE (250, 500, and 1000mg/kg body weight) was used to establish a study group of diabetic rats. Using liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS) for identification, 26 chemical compounds were found in MKE and the high-performance liquid chromatography (HPLC) analysis of the MKE also revealed the existence of mangiferin, gallic acid, and quercetin. The results confirmed that in each diabetes-affected rat, MKE mitigated the heightened levels of fasting blood glucose, diabetic symptoms, glucose intolerance, total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C). As demonstrated by a remarkable increment in serum and pancreatic insulin, the diabetic pancreatic β cell function was potentiated by treating with MKE. The effect of MKE on diabetic pancreatic apoptosis clearly reduced the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, which was related to diminished levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and Bax and an increase in Bcl-xL protein expression. Furthermore, diabetes-induced liver damage was clearly ameliorated along with a notable reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver histology. By enhancing anti-oxidant superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, MKE alleviated diabetes-induced pancreatic and liver oxidative damage, as demonstrated by diminished levels of malondialdehyde. In minimizing the expression levels of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase-1 proteins in the diabetic liver, MKE also enhanced glycogen content and hexokinase activity. Collectively, these findings indicate that by suppressing oxidative and inflammatory processes, MKE exerts a potent anti-hyperglycemic activity in diabetic rats which serve to protect pancreatic β cell apoptosis, enhance their function, and improve hepatic glucose metabolism.

Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation.

Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, the low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor-deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria by cell transplantation. Hepatocytes from a wild-type donor animal were edited in vitro to create Cypor deficiency and then transplanted into phenylketonuric animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from < 1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism. We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for phenylketonuria with long-term efficacy and a favorable safety profile.

Clinical and histological features of patients with chronic hepatitis B virus infection in the grey zone.

Chronic HBV infection patients who do not conform to any of the usual immune states are regarded as 'grey zone' patients. We aimed to investigate the proportion of chronic HBV infection patients in the grey zone, and evaluate the clinical characteristics and liver pathological changes in grey zone patients. Clinical data of 1391 treatment-naive chronic HBV infection patients with liver biopsy were collected. Natural history of HBV infection was determined based on European Association for the Study of the Liver (EASL) 2017, American Association for the Study of Liver Diseases (AASLD) 2018 and Chinese 2019 guidelines for the prevention and treatment of chronic HBV infection. Significant liver histological changes and associated risk factors of normal ALT grey zone patients were analysed. According to EASL, AASLD and Chinese criteria, there were 50.0%, 28% and 37.4% chronic HBV infection patients in the grey zone. Among the 353 grey zone patients with normal ALT, 72.4% had significant liver histological changes. ALT (optimal cut-off value 25 IU/L) and HBV DNA (optimal cut-off value 18,000 IU/mL) were independent risk factors of significant liver histological abnormalities. In conclusion, a substantial proportion of grey zone patients with normal ALT have significant liver histological changes that can be predicted by levels of serum ALT and HBV DNA. These results provide guidance of antiviral treatment in grey zone patients.

Indole-3-carbinol ameliorated the thioacetamide-induced hepatic encephalopathy in rats

Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)− 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.

Natural sporopollenin microcapsules: biological evaluation and application in regulating hepatic toxicity of diclofenac sodium in vivo.

Diclofenac sodium (DIC) is a pain reliever and anti-nociceptive medication. Significant limitations of DIC treatment stem from its adverse effects. This study investigates the feasibility of using natural Lycopodium clavatum sporopollenin (LCS) microcapsules loaded with DIC to mitigate the hepatotoxicity associated with DIC treatment. In addition, LCS microcapsules were tracked in the blood, stomach, small intestine, and feces of rats to demonstrate their morphological integrity and uptake behavior. Four groups (6 per group) of adult male albino rats were administered normal saline (control), empty LCS (30 mg kg-1), plain DIC (10 mg kg-1), and DIC-loaded LCS (40 mg kg-1) orally for seven consecutive days. The first comprehensive histological examination of the rat stomach demonstrated the robustness and bioadhesion ability of LCS under severe conditions. The findings suggested that these versatile microcapsules are unlikely to be digested in the gastrointestinal tract (GIT). The administration of DIC-loaded LCS was found to play a potential protective role in regulating DIC-induced substantially increased serum levels of transaminases, alkaline phosphatase, total bilirubin, and pro-inflammatory cytokines. In addition, DIC-loaded LCS restored the antioxidant enzymes, DNA damage, and liver histological architecture abnormalities caused by DIC. Microencapsulation of DIC into pollen-derived biomaterials could be employed as an efficient platform with enough safety coverage on rat liver, pending further clinical studies.

QHBsAg for the Identification of Liver Histological Abnormalities in HBeAg-Negative Chronic Hepatitis B Patients with Normal and Mildly Elevated ALT Levels.

Backgrounds Noninvasive detection of histological abnormalities remains challenging in patients with HBeAg-negative chronic HBV infection with normal or mildly elevated levels of alanine aminotransferase (ALT). This study aimed to assess the utility of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying significant histological lesions in this population. Methods This is a single-center study with retrospective analysis of 392 treatment-naive patients of HBeAg-negative chronic HBV infection with normal or mildly elevated levels of ALT. Results In this cohort, significant necroinflammation and fibrosis were found in 69.4% and 61.5% of patients, respectively. Patients with qHBsAg >1000 IU/mL (N = 236) had more hepatic inflammation of ≥G2 (75.4% vs. 60.9%, P < 0.01) or fibrosis ≥ S2 (66.1% vs. 54.5%, P < 0.05) compared to those without (N = 156). Serum HBsAg (cutoff point = 1000 IU/mL), aspartate aminotransferase (AST) level (cutoff point = 25 IU/L), age (cutoff point = 40 years), and HBV family history were identified as independent predictors of significant histological abnormalities in multivariate logistic analysis. Conclusions A significantly higher proportion of patients with histological abnormalities were found in patients with qHBsAg >1000 IU/mL than those without. The qHBsAg level together with age, AST, and family history of HBV infection could be used as an algorithm to help noninvasive patient selection for antiviral therapy.

A Novel Murine Model for Studying Alcohol‐associated Biliary Dysfunction

Alcoholic hepatitis (AH) is a severe, potentially life‐threatening form of alcohol‐associated liver disease (ALD) with limited therapeutic options. Existing evidence indicates that cholestasis and biliary dysfunction are common in AH patients and can worsen the prognosis. However, most ALD murine models used today can only recapitulate hepatic steatosis with limited features of AH, which significantly curbs research related to ALD pathogenesis. To develop a murine model that is feasible and less time‐consuming, we included a subtoxic dose of α‐naphthylisothiocyanate (ANIT), a well‐studied intrahepatic cholestasis inducer, in an alcohol feeding model, as a second hit. Mice were fed with an ethanol diet (EtOH) for 10 days or 4 weeks, followed by ANIT administration 48 hours before sample collection. Our results showed that ANIT did not cause overt liver injury in pair‐fed mice, but an observable increase in serum levels of AST in mice fed EtOH for 10 days. Remarkably, in the 4‐week ALD model, serum levels of ALT, AST, total bile acids (TBA), and hepatic levels of TBA were all significantly increased in mice given EtOH and ANIT, indicating a synergistic effect of EtOH and ANIT on liver injury that is dependent on EtOH feeding. In the liver, 4‐week EtOH‐fed mice displayed cholangitis, lytic cell death, and neutrophil infiltration around the periportal area following ANIT treatment as shown by H&amp;E and LY6G staining. In contrast, pair‐fed mice did not show abnormal liver histology following ANIT treatment. Expression of several inflammation‐related genes that are increased in livers from AH patients were analyzed. Consistent with histological observations, hepatic expression of genes like Cxcl1, Ccl2, Ccl20, and Lcn2 were significantly increased in 4‐week EtOH‐fed mice following ANIT treatment, suggesting that ANIT synergistically enhanced EtOH‐induced immune response in the liver. Taken together, our results suggest that EtOH‐dependent changes in the liver can cause higher susceptibility to biliary injury and that a subtoxic dose of ANIT pushes alcohol‐associated liver damage towards a more severe phenotype in mice. Overall, our results support a treatment scheme for alcohol‐associated cholestasis that is feasible, less time‐consuming, cost‐effective, and with modulable severity of phenotypes.

Evaluation of Nano-curcumin effects against Tartrazine-induced abnormalities in liver and kidney histology and other biochemical parameters.

In the current study, 40 albino male rats were investigated to evaluate the impact of Nano‐curcumin (Nano‐CUR) administration against Tartrazine (TZ)‐induced variations in kidney and liver histology and their related functions. The liver function biomarkers are (glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyl transaminase (GGT), alkaline phosphatase (ALP), total bilirubin (T. BiLL)), whereas the kidney biomarkers are (creatinine, uric acid, urea, globulin, total protein (TP)), as well as blood parameters of (serum glucose (sGlu), alpha‐fetoprotein (AFP), protein Kinase‐C (PKC)) and lipid profiles that include (total lipids (TL), triglyceride (TG), total cholesterol (TC), low‐density lipoprotein‐cholesterol (LDL‐C), high‐density L‐C (HDL‐C), and very‐low‐density L‐C (VLDL‐C)). The collected rats were randomly separated into four different groups (G1, G2, G3, and G4) of 10 rats each, where G1 stands for control, G2 for TZ‐ingestion, G3 for Nano‐CUR‐ingestion, and G4 for (TZ + Nano‐CUR mix.) ingestion. TZ‐ingestion significantly (p < .05) increases the liver function enzymes’ activity, total bilirubin and kidney biomarkers (creatinine, urea, uric acid, total protein (TP), globulin (Glu)). Also, TZ‐ingestion significantly increased sGlu, PKC, AFP, as well as lipid profiles, while there were significant (p < .05) decreases in HDL‐C and albumin (Alb) concentrations compared to control. Histopathological changes in liver, such as dilatation of blood sinusoids and central vein with hemorrhage and necrosis, were observed due to TZ‐ingestion. Similarly, TZ‐ingestion influenced kidney tissues in terms of tubular dilatation with tubular degeneration, thickened basement membrane, and dilatation of the glomerular capillaries. Markedly, the administration of Nano‐CUR significantly decreased liver and kidney function enzymes as well as sGlu, AFP, and PKC, whereas it significantly increased serum Alb and HDL‐C levels compared to control and TZ‐ingested rats. All values arranged around normal control values. Also, the liver tissue of Nano‐CUR‐ingested rats showed a normal arrangement of normal blood sinusoids(s), hepatic cords, and hepatocytes as compared to controls. The same results were also found in the section of rat kidney ingested with 2.00 g of Nano‐CUR/(kg B.W.) showing near‐normal architecture as compared to control rats. The liver tissue of rats ingested by a mixture of (7.5 mg of TZ + 2.0 g of Nano‐CUR/kg B.W.) showed little necrosis. Similarly, a section of rat kidney ingested a mixture of (7.5 mg of TZ + 2.00 g of Nano‐CUR/kg B.W.) which revealed mild tubular degeneration and dilatation of the glomerular capillaries. These results support the protective and therapeutic effects of Nano‐CUR on the histology of liver and kidneys and their related function biomarkers. Also, Nano‐CUR corrects the imbalance in serum glucose (sGlu), AFP, PKC, and lipid profiles in TZ‐ingested rats compared to control.

The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC=0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC=0.80), as did a molecular fibrosis classifier (AUC=0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

Efficacy and safety of endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy in obese subjects with Non-Alcoholic SteatoHepatitis (NASH): study protocol for a randomized controlled trial (TESLA-NASH study)

BackgroundNon-alcoholic steatohepatitis (NASH) is frequently associated with obesity, and its standard treatment is weight loss with diet and exercise; a dy% weight reduction has been associated with improvement in liver histological and analytical abnormalities. However, less than 25% of subjects achieve this goal. Laparoscopic sleeve gastrectomy (LSG) represents the most common procedure of bariatric surgery, providing effective weight loss and improvement in comorbidities such as NASH, but it is associated with several postoperative complications. Endoscopic bariatric techniques are currently on the rise as a new tool in the fight against obesity, offering patients an alternative to more invasive surgery. However, their efficacy and safety compared with LSG is unclear.MethodsThe TESLA-NASH study is a randomized, controlled, open-label, unicentric clinical trial with a medical device. The aim of this study is to evaluate and compare the efficacy and safety of endoscopic sleeve gastroplasty (ESG) versus laparoscopic sleeve gastrectomy (LSG) in liver histology improvement of patients with obesity +/− metabolic syndrome and NASH. A total of 30 patients will be randomized 1:1 to the experimental or control group.DiscussionLSG is an effective treatment for weight reduction and for the remission of hepatic alterations. However, LSG is associated with acute and chronic postoperative complications. Bariatric endoscopic techniques promise less invasive and more cost-effective approaches to the treatment of obesity and metabolic comorbidities. ESG represents one of the most promising novel endoscopic interventions and it is mainly proposed for patients with mild-to-moderate obesity, but there are still no guidelines that specify its applicability criteria. This clinical trial will help us apply different tactics to the treatment of obesity and NASH.Trial registrationClinicalTrials.gov NCT04060368. Registered on Nov 15, 2019.

Clinical effect of entecavir antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase and mild liver histological abnormalities

Objective To investigate the clinical effect of entecavir antiviral therapy in chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (PNALT) and mild liver histological abnormalities. Methods A retrospective analysis was performed for 181 patients with hepatitis B virus (HBV) infection who were admitted to The First Affiliated Hospital of Guangxi Medical University from January 2008 to January 2018, and according to the baseline ALT level, they were divided into study group (61 patients with PNALT at baseline), control group 1 [62 patients with an ALT level of (1-2)×upper limit of normal (ULN)], and control group 2 (58 patients with an ALT level of > 2×ULN). Entecavir antiviral therapy was given for at least 1 year, and clinical outcome was compared between the three groups. The life-table method was used to calculate the cumulative progression rates and annual incidence rates of virologic response, HBeAg serological response, and virologic breakthrough. An analysis of variance was used for comparison of continuous data between groups, and the SNK method was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. Results Among the 181 patients enrolled in this study, there were 124 male patients (68.5%) and 80 patients with positive HBeAg (44.2%), with a mean follow-up time of 3.63 years. The three groups had a mean annual incidence rate of virologic response of 74.37%, 71.89%, and 74.21%, respectively (χ2=2.91, P=0.371) and an annual incidence rate of virologic breakthrough of 3.48%, 5.17%, and 2.73%, respectively (χ2=1.72, P=0.097). For the patients with positive HBeAg, the three groups had a mean annual clearance rate of 9.79%, 37.16%, and 38.24%, respectively (χ2=1.37, P=0.01) and a mean annual HBeAg seroconversion rate of 9.10%, 31.35%, and 36.74%, respectively (χ2=5.61, P=0.021); the study group had significantly lower mean annual clearance rate and seroconversion rate of HBeAg than the control groups 1 and 2 (all P Conclusion CHB patients with PNALT level can obtain satisfactory virologic response after entecavir antiviral therapy, while immunological response needs to be further improved.

Protective Effect of Oligonol on Dimethylnitrosamine-Induced Liver Fibrosis in Rats via the JNK/NF-κB and PI3K/Akt/Nrf2 Signaling Pathways.

Oligonol is a low molecular weight polyphenol product derived from lychee fruit by a manufacturing process. We investigated oligonol’s anti-fibrotic effect and the underlying mechanism in dimethylnitrosamine (DMN)-induced chronic liver damage in male Sprague–Dawley rats. Oral administration of oligonol (10 and 20 mg/kg body weight) ameliorated the DMN-induced abnormalities in liver histology and serum parameters in rats. Oligonol prevented the DMN-induced elevations of TNF-α, IL-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase expressions at the mRNA level. NF-κB activation and JNK phosphorylation in DMN-treated rats were ablated by oligonol. Oligonol reduced the enhanced production of hepatic malondialdehyde and reactive oxygen species and recovered protein SH, non-protein SH levels, and catalase activity in the DMN treated liver. Nrf2 translocation into the nucleus was enhanced, and PI3K and phosphorylated Akt levels were increased by administering oligonol. The level of hepatic fibrosis-related factors such as α-smooth muscle actin, transforming growth factor-β1, and type I collagen was reduced in rats treated with oligonol. Histology and immunohistochemistry analysis showed that the accumulation of collagen and activation of hepatic stellate cells (HSCs) in liver tissue were restored by oligonol treatment. Taken together, oligonol showed antioxidative, hepatoprotective, and anti-fibrotic effects via JNK/NF-κB and PI3K/Akt/Nrf2 signaling pathways in DMN-intoxicated rats. These results suggest that antioxidant oligonol is a potentially useful agent for the protection against chronic liver injury.

Effect of Zinc on Hepatic and Renal Tissues of Chronically Arsenic Exposed Rats: A Biochemical and Histopathological Study.

Consumption of arsenic-contaminated drinking water has become major global health concern. One of the major mechanism responsible for the toxicity of arsenicals is the generation of oxidative stress. Zinc, a nutritional antioxidant, plays key role in maintaining various cellular pathways. The present study was aimed at elucidating the effects of zinc supplementation on hepatic and renal tissue damage caused by arsenic exposure to rats. Rats were randomly divided into four experimental groups: control; As administered; Zn supplemented; combined zinc; and arsenic supplemented. Arsenic exposure resulted in significantly elevated accumulation of arsenic in the liver and kidney tissue. In the liver, exposure to arsenic reduced the levels of reduced glutathione (GSH), total glutathione (TG), redox ratio, and the activity of superoxide dismutase (SOD), whereas lipid peroxidation (LPO), inflammation markers, and nitric oxide (NO) levels were elevated with no significant change in catalase (CAT) activity. Arsenic exposure also enhanced the serum levels of liver functional indices and histological abnormalities in liver sections. In the kidney, a significant increase in NO levels and decrease in SOD activity was observed, with no significant changes in the rest of the parameters. The administration of zinc- to arsenic-intoxicated animals significantly improved their hepatic function parameters, arsenic burden, and histological changes which were associated with the restoration of enzymatic and non-enzymatic antioxidant defense system as compared to their intoxicated counterparts. In the kidney also, the NO levels and SOD activity were restored. This data reveals that zinc is effective in ameliorating the toxic effects inflicted by chronic arsenic toxicity.

Perfluorooctanoic acid-induced liver injury is potentially associated with gut microbiota dysbiosis

Perfluorooctanoic acid (PFOA), an environmental pollutant, is widely engaged in industrial products and tends to accumulate in the liver. Emerging evidence has suggested that the gut microbiome is a pivotal player in maintaining animal health and can potentially altered by xenobiotic. However, few studies explored whether PFOA-induced liver injury is associated with gut microbiota dysbiosis. In the present study, the effects of subacute and subchronic PFOA exposure on liver and gut microbiota in C57BL/6J mice were investigated. Our findings showed that both subacute and subchronic exposure to PFOA induced the liver inflammation, disrupted antioxidative homeostasis and caused liver histological abnormalities with detectable hepatomegaly, ultimately triggering liver injury. Besides, 16S rRNA sequencing analysis revealed that subacute PFOA exposure caused significant changes in the abundances of intestinal flora known to contribute to liver inflammation and oxidative stress, such as the Dehalobacterium and Bacteroides genera. Exposure to subchronic toxicity mainly induced the decrease in commensal probiotics including Lactobacillus and Bifidobacterium genera, which are potentially beneficial to liver damage, compared with that in the untreated group. They also resulted in disturbed functional capabilities of the microbial communities by a Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis. Additionally, the levels of short-chain fatty acids (SCFAs), especially butyric acid, were significantly reduced by PFOA administration. Collectively, our observations suggested that liver damage induced by both subacute and subchronic PFOA exposures probably partly related to the gut microbiota dysbiosis and provided a new insight into the role of PFOA in liver injury.

A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis

Previous studies demonstrated that autophagy is protective in hepatocytes and macrophages, but detrimental in hepatic stellate cells in chronic liver diseases. The role of autophagy in liver sinusoidal endothelial cells (LSECs) in non-alcoholic steatohepatitis (NASH) is unknown. Our aim was to analyze the potential implication of autophagy in LSECs in NASH and liver fibrosis. We analyzed autophagy in LSECs from patients using transmission electron microscopy. We determined the consequences of a deficiency in autophagy: (a) on LSEC phenotype, using primary LSECs and an LSEC line; (b) on early stages of NASH and on advanced stages of liver fibrosis, using transgenic mice deficient in autophagy specifically in endothelial cells and fed a high-fat diet or chronically treated with carbon tetrachloride, respectively. Patients with NASH had half as many LSECs containing autophagic vacuoles as patients without liver histological abnormalities, or with simple steatosis. LSECs from mice deficient in endothelial autophagy displayed an upregulation of genes implicated in inflammatory pathways. In the LSEC line, deficiency in autophagy enhanced inflammation (Ccl2, Ccl5, Il6 and VCAM-1 expression), features of endothelial-to-mesenchymal transition (α-Sma, Tgfb1, Col1a2 expression) and apoptosis (cleaved caspase-3). In mice fed a high-fat diet, deficiency in endothelial autophagy induced liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, Vcam-1), liver cell apoptosis (cleaved caspase-3) and perisinusoidal fibrosis. Mice deficient in endothelial autophagy treated with carbon tetrachloride also developed more perisinusoidal fibrosis. A defect in autophagy in LSECs occurs in patients with NASH. Deficiency in endothelial autophagy promotes the development of liver inflammation, features of endothelial-to-mesenchymal transition, apoptosis and liver fibrosis in the early stages of NASH, but also favors more advanced stages of liver fibrosis. Autophagy is a physiological process controlling endothelial homeostasis in vascular beds outside the liver. This study demonstrates that autophagy is defective in the liver endothelial cells of patients with non-alcoholic steatohepatitis. This defect promotes liver inflammation and fibrosis at early stages of non-alcoholic steatohepatitis, but also at advanced stages of chronic liver disease.

2444 Beyond Weight Loss: Bariatric Surgery as Treatment for NAFLD in the Post-Transplant Patient

INTRODUCTION: Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG), has previously demonstrated reversal of abnormal liver histology in non-alcoholic fatty liver disease (NAFLD). However, bariatric surgery following orthotopic liver transplant (OLT) performed for non-alcoholic steatohepatitis (NASH) cirrhosis is less well studied, with only a few retrospective studies cited in the literature. We present the case of bariatric surgery performed in a patient status post OLT with successful reversal of NAFLD. CASE DESCRIPTION/METHODS: The patient is a 69-year-old female with past medical history of metabolic syndrome (diabetes, hypertension, dyslipidemia, obesity) and cirrhosis secondary to NASH and alcohol who underwent deceased donor OLT. Eighteen months postoperatively, the patient had gained 20 pounds and required multiple medications to control her blood pressure and diabetes. Subsequent abdominal ultrasound with doppler demonstrated hepatic steatosis, patent transplant vasculature and no ascites. Despite dietary and lifestyle modifications, the patient could not lose weight. She continued to have elevated transaminases (up to aspartate aminotransferase 58, alanine aminotransferase 82) prompting suspicion for recurrent NASH. The patient was ultimately referred for LSG. Her BMI prior to LSG was 37; seven weeks postoperatively it decreased to 32. Her liver function test normalized, and she no longer required Metformin. DISCUSSION: NAFLD is the most common chronic liver disorder in developed countries, and NASH cirrhosis is the second most common cause for liver transplant in the United States. Approximately 3-5% of the population in the United States lives with NASH, and this number is expected to rise with the obesity epidemic. Further troubling is NASH and cryptogenic cirrhosis seen in post-OLT patients, with one study citing 39% of those transplanted for NAFLD-related cirrhosis show steatosis on biopsy six months after transplant. Bariatric surgery, both RYGB and LSG, can reverse NAFLD histology, and only recently have retrospective reviews examined bariatric surgery as a successful means of halting and reversing NAFLD in the post-transplant patient. As with the case of our patient, bariatric surgery can provide an effective means of treating NAFLD in the post-OLT patient with metabolic syndrome. More research is currently needed to establish optimal patient selection criteria and long term efficacy in this regard.

Holothuria Leucospilota Polysaccharides Ameliorate Hyperlipidemia in High-Fat Diet-Induced Rats via Short-Chain Fatty Acids Production and Lipid Metabolism Regulation.

Holothuria leucospilota polysaccharides (HLP) are expected to become potential resources for the treatment of hyperlipidemia because of their various bioactivities. In the study, the treatment of HLP on improving hyperlipidemia in rats was explored. Oral administration of HLP at 100 or 200 mg/kg body weight effectively alleviated serum lipid levels and liver histological abnormalities in high-fat-diet rats. HLP regulated abnormal mRNA, lipogenesis-related hormones and inflammatory cytokines (tumor necrosis factor-α, interleukin-6 and interleukin-12) levels. HLP improved the ability of gut microbiota to produce short-chain fatty acids (SCFAs). SCFAs have been found to ameliorate liver lesions. Therefore, HLP alleviated hyperlipidemia by improving the levels of SCFAs to regulate lipid metabolism. These results indicated that HLP could be used as beneficial polysaccharides to alleviate hyperlipidemia.