Hepatic Histology Research Articles

WED-150 - Systematic review and meta-analysis: the proportion of chronic hepatitis B patients with different alanine transaminase upper limits and significant hepatic histology

WED-150 - Systematic review and meta-analysis: the proportion of chronic hepatitis B patients with different alanine transaminase upper limits and significant hepatic histology

Effect of Tiger Shrimp Shell Extract (Penaeus monodon) on Monosodium Glutamate-Induced Mice

Background: The shell is a part of the tiger shrimp (Penaeus monodon) body that often becomes waste and has not been utilized properly, but it contains secondary antioxidants that can prevent oxidative stress in the form of astaxanthin. Although several studies have examined the function of astaxanthin as an antioxidant, the role of it in tiger shrimp shells against hepar mice induced by monosodium glutamate (MSG) is not well knownObjective: to determine the effect of tiger shrimp shell extract in graded doses on the histopathological picture of hepatic mice induced by MSG.Methods: Extraction of tiger shrimp shell was carried out with palm head oil solvent and analyzed with Ultraviolet-Visible spectrophotometer (UV-Vis). This study used 25 male mice classified into 5 groups. One group was negative control without any need and 4 other groups were induced with MSG 0.84 g/kgBB. Three of the MSG-induced groups were induced with tiger shrimp shell extract at doses of 50 mg/kgBB, 100 mg/kgBB, and 200 mg/kgBB. The treatment was given for 35 days. Mice were terminated on the 42nd day and hepatic histopathology was observed with Manja Roenigk score.Results: The group induced with tiger shrimp shell extract in graded doses showed a better picture of hepatic histology structure compared to the group that was only induced with MSG. Statistical tests using the Kruskal Wallis test showed a significant difference between each group with a P value of 0.005.Conclusion: Feeding of tiger shrimp shell extract in graded doses can prevent hepatic damage to MSG-induced mice.

Effects of dietary copper (Cu) on growth performance, body composition, mineral content, hepatic histology and Cu transport of the GIFT strain of Nile tilapia (Oreochromis niloticus)

This study determined the influence of dietary copper (Cu) levels on growth and feed utilization, body composition, mineral content, liver histology and intestinal Cu transport, and identify dietary Cu requirement of the GIFT strain of Nile tilapia (Oreochromis niloticus). Six diets were prepared with Cu sulfate addition at levels of 0 (control), 5, 10, 20, 40, and 80 mg/kg, respectively. Analytical dietary Cu contents were 1.55, 2.97, 4.51, 7.25, 11.30, and 19.24 mg Cu/kg diet, respectively. Each experimental diet was fed to three replicates of GIFT tilapia (25 fish per tank, initial body weight 4.34 ± 0.01 g) in a recirculating freshwater system for eight weeks. GIFT tilapia fed 4.51 mg Cu/kg diet had higher growth performance and feed utilization. Cu contents in the whole-body, the liver and intestinal tract increased with dietary Cu levels. Moreover, dietary Cu addition also affected whole-body Mg content significantly, but did not affect whole body crude protein, lipid, zinc (Zn), iron (Fe), and calcium (Ca) content. GIFT tilapia fed with 4.51 mg Cu/kg diet had lower liver vacuoles relative area. Furthermore, dietary Cu addition also significantly influenced mRNA expression of genes involved in intestinal Cu transport, such as copper transporter 1 (ctr1), copper transporter 2 (ctr2), antioxidant 1 copper chaperone (atox1), cytochrome c oxidase copper chaperone (cox17) and copper-transporting ATPase alpha (atp7a). The regression analysis of weight gain and whole-body Cu retention against the dietary Cu levels suggested that 4.23 to 4.57 mg Cu/kg diet was optimal for GIFT tilapia. Statement of relevanceOur study determined the optimal dietary Cu requirement of GIFT strain of tilapia, which provided good references for dietary Cu addition for the fish species, and accordingly was helpful for its feed formulation and aquaculture production. Our study also demonstrated that dietary Cu addition influenced mRNA expression of genes involved in Cu transport, which provides a good basis for exploring Cu metabolism in fish.

Abstract 674: Transgelin Deficiency Is Associated With Elevated Low-density Lipoprotein Cholesterol And Atherogenesis In Mice.

Genetic hyperlipidemias are a major risk factor for atherosclerotic cardiovascular disease due to life-long exposure to elevated plasma lipids. However, the causality of hyperlipidemia is not known in a large proportion of patients, suggesting that unknown genes remain to be discovered. Applying a CRISPR/Cas9 screen, we recently identified transgelin (TAGLN), an actin binding protein, as a new gene involved in LDL metabolism. TAGLN supports LDL endocytosis presumably by interacting with actin filaments during LDL endocytosis; however, if TAGLN impacts on plasma lipid levels and atherogenesis in vivo is unknown. Aim: To investigate TAGLN’s impact on lipid profile and atherosclerosis development in a Tagln -knockout (KO) mouse model. Methods: Tagln -KO (n=18) and wild-type (WT) (n=18) mice were fed a high-fat diet (42% Cal from fat) for 12 weeks. We collected plasma for lipoprotein analysis, liver specimens for histopathology and lipid extraction/quantification, and aortas for quantifying atherosclerotic plaque area. Results: Tagln -KO mice showed higher total cholesterol than WT mice (20% increase, mean±SD: 299±51 vs. 251±59 mg/dL, p=0.014), without changes in triglyceride levels (p=0.36). Lipoprotein subfraction analysis by FPLC revealed an increase in the lipids associated with the LDL fraction of Tagln -KO mice. Although no differences were observed in hepatic histology or triglyceride content, Tagln -KO animals showed an increase in the hepatic content of total cholesterol (mean±SD: 376±65 vs. 317±70 μg/100 mg, p=0.012). Finally, Tagln -KO mice developed about twice more atherosclerotic lesion area than WT mice (Median(IQR): 0.997(0.347-1.451) vs 0.428(0.336-0.859), p=0.015). Conclusions: In line with a reduction in LDL uptake in hepatocytes, shown by our previous in vitro data, TAGLN deficiency was associated with hypercholesterolemia and high LDL cholesterol in mice, likely due to decreased hepatic LDL clearance. Despite the modest hypercholesterolemia, Tagln -KO mice showed disproportionally increased atherosclerosis, suggesting that TAGLN may regulate other atherogenic mechanisms, beyond LDL cholesterol.

Kaempferol Suppresses Carbon Tetrachloride-Induced Liver Damage in Rats via the MAPKs/NF-κB and AMPK/Nrf2 Signaling Pathways.

Oxidative stress plays a critical role in the development of liver disease, making antioxidants a promising therapeutic approach for the prevention and management of liver injuries. The aim of this study was to investigate the hepatoprotective effects of kaempferol, an antioxidant flavonoid found in various edible vegetables, and its underlying mechanism in male Sprague-Dawley rats with carbon tetrachloride (CCl4)-induced acute liver damage. Oral administration of kaempferol at doses of 5 and 10 mg/kg body weight resulted in the amelioration of CCl4-induced abnormalities in hepatic histology and serum parameters. Additionally, kaempferol decreased the levels of pro-inflammatory mediators, TNF-α and IL-1β, as well as COX-2 and iNOS. Furthermore, kaempferol suppressed nuclear factor-kappa B (NF-κB) p65 activation, as well as the phosphorylation of Akt and mitogen-activated protein kinase members (MAPKs), including extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 in CCl4-intoxicated rats. In addition, kaempferol improved the imbalanced oxidative status, as evidenced by the reduction in reactive oxygen species levels and lipid peroxidation, along with increased glutathione content in the CCl4-treated rat liver. Administering kaempferol also enhanced the activation of nuclear factor-E2-related factor (Nrf2) and heme oxygenase-1 protein, as well as the phosphorylation of AMP-activated protein kinase (AMPK). Overall, these findings suggest that kaempferol exhibits antioxidative, anti-inflammatory, and hepatoprotective effects through inhibiting the MAPK/NF-κB signaling pathway and activating the AMPK/Nrf2 signaling pathway in CCl4-intoxicated rats.

Tigecycline induced liver toxicity in a renal transplant recipient with hepatic histology imitating sepsis

Background: Tigecycline has an expanded broad-spectrum antibacterial activity including multi-drug resistant pathogens. A case of a renal transplant recipient with tigecycline- induced acute liver injury is presented.

Aqueous extract of Daucus carota exerts a protective effect on the Renal, Hepatic and Duodenal mucosal histology in Diclofenac Induced Tissue Injury

Objective: The use of ethnobiology in treatment of many diseases especially in rural residents with limited access to medical technology, treatment and equipment is beneficial and necessary. Daucus carota (DC) root extract was used as pre-treatment in adult Wistar rats exposed to diclofenac sodium (DF) to investigate a protective effect on the histology of liver, kidney and duodenum. Materials and Method: Twenty-five adult Wistar rats were used for this study and were randomly divided into 5 groups of 5 rats each, which included: Group A - Normal control; Group B – 50mg/kg DF control; Group C – 50mg/kg DC + 50mg/kg DF, Group D – 100mg/kg DC + 50mg/kg DF; and, Group E – 140mg/kg DC + 50mg/kg DC. Results and Discussion: The results showed a reduction in damage to the hepatocytes, maintenance of sinusoidal integrity and reduction in the number of inflammatory cells in the hepatic parenchyma, In the kidney tissue, the extract preserved the glomerular capillary tuft, renal tubular epithelial cells, conserved Bowman’s space and lining epithelium of the capsule in a dose dependent manner. The intestinal mucosa in groups treated with higher doses of the extract were completely preserved and intact with minimal erosion of epithelial lining along with preservation of lamina propria and intestinal glands. Conclusion: Pre-administration of DC, preferably at concentrations of 100mg/kg and 140mg/kg reduced hepatotoxicity, renal tissue and mucosal layer damage in the duodenum following administration of DF. This preservation of tissues improved as concentration of the extract increased verifying that its efficiency was dose dependent.

The combined effect of Raspberry Ketone with Resveratrol against oxidative stress and steatohepatitis in rats: Pharmacokinetic and pharmacodynamic studies.

Raspberry Ketone (RK) and Resveratrol (RSV) are natural phenolic antioxidants and anti-inflammatory agents. However, its combined pharmacokinetic and pharmacodynamics potentials are not reported. The study aims to assess the combined effect of RK with RSV to protect rats from carbon-tetrachloride (CCl4) induced oxidative stress and NASH. The toxicant CCl4 was employed at a concentration of 1 mL/kg as a 1:1 (v/v) mixture with olive oil twice weekly for 6 weeks to induce liver toxicity. Animal treatment was followed for 2 weeks. Silymarin was used as a standard control drug to compare the hepatoprotective effect of RK and RSV. Hepatic histology, oxidative stress, MMP, reduced glutathione (GSH), plasma levels of SGOT, SGPT, and lipid profile (total cholesterol and triglycerides) were measured. Anti-inflammation genes (IL-10), and fibrotic genes (TGF-β) were also examined in liver tissue. Oral administration of combined RK with RSV (50 + 50 mg/kg for 2 weeks) showed significantly more hepatoprotection by significantly decreasing elevated plasma markers and lipid profile than alone RK and RSV (100 mg/kg daily for 2 weeks). It also significantly alleviated the hepatic lipid peroxidation, restoring the activities of GSH levels in the liver. RT-PCR and Immunoblotting studies confirmed that significantly upregulation of anti-inflammation genes and protein expression (MMP-9) ameliorated the disease. Pharmacokinetic studies confirmed more synergistic stability in simulated gastric-intestinal fluids (FaSSGF, FaSSIF) and rat liver microsomes (CYP-450, NADPH oxidation & glucuronidation. Moreover, coadministration of drugs augmented the relative bioavailability, Vd/ F (L/Kg), and MRT0-∞( h), which leads to more efficacy. This pharmacokinetic and pharmacodynamic reveals a new adjuvant therapy for the treatment of steatohepatitis.

Acadesine supplementation in a soybean oil-based diet remodels hepatic lipid and glucose metabolism in juvenile large yellow croaker (Larimichthys crocea)

Dietary high soybean oil (SO) inclusion leads to excessive hepatic lipid accumulation and metabolism disorder in fish species. This study was conducted to investigate the effects of adenosine 5’-monophosphate-activated protein kinase (AMPK) pathway activation by acadesine (AICAR) on hepatic histology and metabolism-related gene expression of juvenile large yellow croakers (Larimichthys crocea) fed with SO-based diet. In this study, fish (initial body weight 3.89 ± 0.02 g) were fed fish oil (FO)-based, SO, or SOA (SO diet supplemented with 100 mg kg−1 AICAR) diets with three replicates of each treatment for 70 days. In general, the replacement of dietary FO with SO led to excessive hepatic lipid accumulation and a glucose metabolism disorder. Histological sections and biochemical analysis of hepatic tissue consistently revealed that AICAR supplementation could partly ameliorate SO-induced excessive hepatic lipid accumulation, probably by suppressing the expression of genes related to fatty acid uptake and lipogenesis while enhancing the expression of lipolysis-related genes. Nevertheless, AICAR regulated lipid metabolism in muscle tissue in an inverse pattern to that in hepatic tissue, indicating that muscle tissue could attempt to mitigate lipid accumulation by improving lipolysis in response to the dietary inclusion of SO. Dietary AICAR partly improved glucose metabolism by reducing the expression of genes related to gluconeogenesis in hepatic tissue while increasing the expression of genes related to glucose uptake and glycolysis in muscle tissue. Collectively, dietary AICAR mitigated excessive hepatic lipid accumulation and glucose metabolism disorder. The amelioration of hepatic lipid accumulation by AICAR is likely caused by increasing lipid catabolism and decreasing lipid anabolism. The improved glucose metabolism by AICAR may be ascribed to decreased hepatic gluconeogenesis, as well as increased muscle glucose uptake and utilization.

Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice

Hepatic stellate cell (HSC) activation via the autophagy pathway is a critical factor in liver fibrogenesis. This study tests the hypothesis that chloroquine (CQ) treatment can prevent autophagy and HSC activation in vitro and in vivo in bile-duct-ligated (BDL) mice. Sham-operated and BDL mice were treated with either PBS or CQ in two 60 mg/kg doses the day (D) before and after surgery. On day 2 (2D), HSCs were isolated, and their biological activities were evaluated by measuring intracellular lipid content, α-sma/collagen, and expression of autophagy lc3, sqstm1/p62 markers. The treatment efficacy on liver function was evaluated with serum albumin, transaminases (AST/ALT), and hepatic histology. Primary HSCs were treated in vitro for 24 h with CQ at 0, 2.5, 5, 10, 30, and 50 µM. Autophagy and HSC activation were assessed after 2D of treatment. CQ treatment improved serum AST/ALT, albumin, and bile duct proliferation in 2D BDL mice. This is associated with a suppression of HSC activation, shown by higher HSC lipid content and collagen I staining, along with the blockage of HSC autophagy indicated by an increase in p62 level and reduction in lc3 staining. CQ 5 µM inhibited autophagy in primary HSCs in vitro by increasing p62 and lc3 accumulation, thereby suppressing their in vitro activation. The autophagy inhibitor CQ reduced HSC activation in vitro and in vivo. CQ improved liver function and reduced liver injury in BDL mice.

Aflatoxin-B1-Exposure-Induced Hepatic Injury Could Be Alleviated by Polydatin through Reducing Oxidative Stress, Inhibiting Inflammation and Improving Mitophagy.

Aflatoxin B1 (AFB1) is a toxic food/feed pollutant, exerting extensive deleterious impacts on the liver. Oxidative stress and inflammation are considered to be vital contributors to AFB1 hepatotoxicity. Polydatin (PD), a naturally occurring polyphenol, has been demonstrated to protect and/or treat liver disorders caused by various factors through its antioxidant and anti-inflammatory properties. However, the role of PD in AFB1-induced liver injury is still elusive. Therefore, this study was designed to investigate the protective effect of PD on hepatic injury in mice subjected to AFB1. Male mice were randomly divided into three groups: control, AFB1 and AFB1-PD groups. The results showed that PD protected against AFB1-induced hepatic injury demonstrated by the reduced serum transaminase activity, the restored hepatic histology and ultrastructure, which could be attributed to the enhanced glutathione level, the reduced interleukin 1 beta and tumor necrosis factor alpha concentrations, the increased interleukin 10 expression at transcriptional level and the up-regulated mRNA expression related to mitophagy. In conclusion, PD could alleviate AFB1-induced hepatic injury by reducing oxidative stress, inhibiting inflammation and improving mitophagy.

Blackberry-Loaded AgNPs Attenuate Hepatic Ischemia/Reperfusion Injury via PI3K/Akt/mTOR Pathway

To achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms. IRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed. Pre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors. BBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.

Low Dose of BPA Induces Liver Injury through Oxidative Stress, Inflammation and Apoptosis in Long–Evans Lactating Rats and Its Perinatal Effect on Female PND6 Offspring

Bisphenol A (BPA) is a phenolic compound used in plastics elaboration for food protection or packaging. BPA-monomers can be released into the food chain, resulting in continuous and ubiquitous low-dose human exposure. This exposure during prenatal development is especially critical and could lead to alterations in ontogeny of tissues increasing the risk of developing diseases in adulthood. The aim was to evaluate whether BPA administration (0.036 mg/kg b.w./day and 3.42 mg/kg b.w./day) to pregnant rats could induce liver injury by generating oxidative stress, inflammation and apoptosis, and whether these effects may be observed in female postnatal day-6 (PND6) offspring. Antioxidant enzymes (CAT, SOD, GR, GPx and GST), glutathione system (GSH/GSSG) and lipid-DNA damage markers (MDA, LPO, NO, 8-OHdG) were measured using colorimetric methods. Inducers of oxidative stress (HO-1d, iNOS, eNOS), inflammation (IL-1β) and apoptosis (AIF, BAX, Bcl-2 and BCL-XL) were measured by qRT-PCR and Western blotting in liver of lactating dams and offspring. Hepatic serum markers and histology were performed. Low dose of BPA caused liver injury in lactating dams and had a perinatal effect in female PND6 offspring by increasing oxidative stress levels, triggering an inflammatory response and apoptosis pathways in the organ responsible for detoxification of this endocrine disruptor.

Dietary Fat Exacerbates Liver Disease in Bile Duct-Ligated Rats

Previous studies have suggested that the mortality of bile duct-ligated (BDL) rats is related to the amount of dietary fat consumed. We investigated the influence of dietary fat concentration on liver disease in BDL rats. Groups of rats were fed for 4 wk either a low fat diet (LF, 0.92 kJ/g; 3% of total energy from fat), a high fat diet (HF, 1.07 kJ/g; 30% fat), a high fat diet with energy density equivalent to that of the LF diet (HFIB, 0.92 kJ/g; 30% fat) or a diet based on the composition of commercial nonpurified diets (COMP, 0.90 kJ/g; 10% fat). Energy intake, body weight gain, plasma biochemical indices and hepatic histology were compared in BDL and sham-operated control rats. Bile duct-ligated animals consuming the LF diet showed a faster recovery of energy intake and greater body weight gain following surgery than did BDL animals fed the other three diets. Plasma alkaline phosphatase activity was significantly greater in BDL animals fed either of the high fat diets than in those fed the LF or COMP diet starting 1 and 2 wk, respectively, after surgery. Hepatic fibrosis and bile duct proliferation at d 28 post-ligation were greater in rats fed a 30% fat (HF) diet than in rats fed the 3% fat (LF) diet. These results suggest that dietary fat concentration can influence the severity of liver dysfunction in extrahepatic biliary obstruction.

Therapeutic effects of atorvastatin on doxorubicin-induced hepatotoxicity in rats via antioxidative damage, anti-inflammatory, and anti-lipotoxicity.

Doxorubicin (DOX), is a high efficiency anthracycline antitumor drug. However, the clinical application of DOX is limited mainly by dose-related adverse drug reactions. Currently, the therapeutic effects of Atorvastatin (ATO) on DOX-induced hepatotoxicity were studied in vivo. The results indicated that DOX impaired hepatic function, as measured by an increased levels of liver weight index and serum concentrations of aspartate transaminase and alanine transaminase, as well as alteration of hepatic histology. In addition, DOX increased the serum levles of triglyceride(TG) and nonestesterified fatty acid. ATO prevented these changes. Mechanical analysis revealed that ATO restored the changes of malondialdehyde, reactive oxygen radical species, glutathione peroxidase and manganese superoxide dismutase. Additionally, ATO inhibited the increased expression levels of nuclear factor-kappa B and interleukin 1β, hence suppressing inflammation. Meanwhile, ATO inhibited cell apoptosis by dramatically decreasing the Bax/Bcl-2 ratio. In addition, ATO mitigated the lipidtoxicity by inhibiting the adipolysis of TG and accelerating hepatic lipid metabolism. Taken together, the results suggest ATO has therapeutic effect on DOX-induced hepatotoxicity via inhibition of oxidative damage, inflammatory and apoptosis. In addition, ATO attenuates DOX-induced hyperlipidemia via modulation of lipid metabolism.

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Evaluation of the Possible Protective Role of Nobiletin against Arsenic-Induced Liver Damage in Male Albino Rats.

Arsenic (As) is a toxic contaminant present in organic and inorganic forms in the environment. Nobiletin (NOB) is a polymethoxy flavone that has recently gained substantial consideration due to its curative impacts. The present experiment was conducted to assess the hepatoprotective efficiency of NOB on As-generated hepatotoxicity. Twenty-four adult rats were equally distributed into four groups and designated as control, As (50 mg/kg)-treated, As + NOB (50 mg/kg and 25 mg/kg, respectively), and NOB (25 mg/kg)-treated groups. After 30 days, experimental animals were decapitated, then blood and tissue samples were collected for further analysis. The group treated with As showed a significant decrease in the activity of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione (GSH), glutathione reductase (GSR), and total antioxidant status (TAS), and a substantial increase in the accumulation of As in liver tissues, levels of total oxidant status (TOS), hydrogen peroxide (H2O2), and lipid peroxidation (TBARS). Significant increases in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) levels were observed in As-treated rats. Moreover, nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6, and cyclo-oxygenase (COX)-2 activity, as well as the levels of pro-apoptotic markers (Bax, Caspase-3, and Caspase-9) were increased on exposure to As. In contrast, the anti-apoptotic marker (Bcl-2) level was significantly decreased. As administration showed a significant disturbance in hepatic tissue histology. However, cotreatment of NOB with As considerably increased the antioxidant enzyme activity, with a noteworthy reduction in the deposition of As in hepatic tissues, TBARS, and H2O2 levels. NOB-administrated rats showed considerable recovery in terms of inflammation, apoptosis, and histological damage. Hence, NOB can be considered a useful curative compound due to its medicinal properties against As-prompted hepatotoxicity.

Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis.

In cirrhotic nonalcoholic steatohepatitis (NASH) clinical trials, primary efficacy endpoints have been hepatic venous pressure gradient (HVPG), liver histology and clinical liver outcomes. Important histologic features, such as septa thickness, nodules features and fibrosis area have not been included in the histologic assessment and may have important clinical relevance. We assessed these features with a machine learning (ML) model. NASH patients with compensated cirrhosis and HVPG ≥6 mm Hg (n=143) from the Belapectin phase 2b trial were studied. Liver biopsies, HVPG measurements and upper endoscopies were performed at baseline and at end of treatment (EOT). A second harmonic generation/two-photon excitation fluorescence provided an automated quantitative assessment of septa, nodules and fibrosis (SNOF). We created ML scores and tested their association with HVPG, clinically significant HVPG (≥10 mm Hg) and the presence of varices (SNOF-V). We derived 448 histologic variables (243 related to septa, 21 related to nodules and 184 related to fibrosis). The SNOF score (≥11.78) reliably distinguished CSPH at baseline and in the validation cohort (baseline + EOT) [AUC=0.85 and 0.74, respectively]. The SNOF-V score (≥0.57) distinguished the presence of varices at baseline and in the same validation cohort [AUC=0.86 and 0.73, respectively]. Finally, the SNOF-C score differentiated those who had >20% change in HVPG against those who did not, with an AUROC of 0.89. The ML algorithm accurately predicted HVPG, CSPH, the development of varices and HVPG changes in patients with NASH cirrhosis. The use of ML histology model in NASH cirrhosis trials may improve the assessment of key outcome changes.

IMPACT OF DIETARY SUPPLEMENTAL ASCORBIC ACID ON ORGAN WEIGHT, VILLI MORPHOMETRY, ORGANOLEPTIC ATTRIBUTES AND ORGAN HISTOLOGY OF WEANED PIGS

This study aimed at evaluating the impact of dietary supplemental ascorbic acid on organ weight, villi morphometry, organoleptic attributes, and organ histology of weaned pigs using thirty-two Large white-Landrace crossbred with an average weight of 12.32±0.59 kg. The pigs were grouped into four treatments with eight replicates each. Diet C0 was the basal diet (control). Diets C1, C2, and C3 contained the basal diet with 1g/kg, 2g/kg and 3g/kg of ascorbic acid respectively for seven weeks. The weight of liver, kidney, spleen, heart, and lungs were significantly different (p<0.05) with pigs offered ascorbic acid-supplemented diet having higher values. Also, the villus height, villus width and muscle thickness were significantly influenced (p<0.05) with pigs fed diet C3 having the highest value for villus height and width. The organoleptic properties did not differ significantly (p>0.05). The jejunum villi histology showed that pigs fed diets C0 and C1 were essentially normal while those fed diets C2 and C3 had moderate enteritis. No observable lesions were recorded in the structure of the nephron. Moreover, the hepatic histology of pigs fed diet C1 was essentially normal while those fed diets C2 and C3 showed normal hepatocytes but with moderate sinusoidal congestion. It can be concluded that ascorbic acid supplementation caused increased organ weight, aided villus height and width, and reduced muscle thickness with moderate sinusoidal congestion at up to 3g/kg with no deleterious effects on organoleptic attributes.

The m6A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m6A dependent manner.

Background and Aims: N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various biological processes. However, its roles in fulminant hepatitis remain largely unknown. In the current study, YTHDF1 expression was found to be significantly downregulated in the livers among patients, as well as murine models with fulminant hepatitis versus normal controls. Thus, we hypothesized that YTHDF1 protects against fulminant hepatitis and investigated the underlying molecular mechanisms. Methods: Fulminant hepatitis was induced by D-GalN/LPS in conventional YTHDF1 knockout (YTHDF1-/-) mice, hepatocyte-specific YTHDF1 overexpression (AAV8- YTHDF1) mice, and corresponding control mice. Primary hepatocytes were cultured and subjected to LPS insult in vitro. Hepatic histology, cell death, oxidative stress and mitochondrial function were examined to assess liver damage. The molecular mechanisms of YTHDF1 function were explored using multi-omics analysis. Results: Ablation of YTHDF1 exacerbated hepatic apoptosis and reactive oxygen species (ROS) production and increased the number of aberrant mitochondria, while YTHDF1 overexpression resulted in the opposite effects. Multiomics analysis identified MFG-E8 as the direct target of YTHDF1. YTHDF1 augmented the translation of MFG-E8 in an m6A-dependent manner without effect on its mRNA expression, thereby restoring mitochondrial function. Additionally, administration of MFG-E8 almost completely reversed the YTHDF1 deficiency-mediated exacerbation of liver injury. Conclusions: The current study suggested that the m6A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m6A-dependent manner.