Elevated ALT Levels Research Articles

Corchorus olitorius L. Leaf Extract Protects Rats from Acrylamide-Induced Hepatic Injury

Acrylamide is a water-soluble compound that forms during the high-temperature cooking of starchy foods and has carcinogenic, neurotoxic, and genotoxic properties. Also, short-term exposure to acrylamide has been shown to cause significant hepatic injury in laboratory animals, along with disruption of antioxidant defense mechanisms due to excessive ROS production. Therefore, dietary antioxidants are believed to be useful in combating the negative effects of acrylamide. Corchorus olitoris L., also known as molokhia in Arabic, is a leafy vegetable which is shown to possess potent antioxidant and organoprotective properties. In this study, rats were administered with an aqueous extract of molokhia leaves to see if it could protect them against acrylamide-induced hepatic damage. Hepatic injury markers included serum total protein, total bilirubin, ALT, AST, and ALP, while oxidative stress markers included MDA, GSH, CAT, and SOD after dosing with three levels of extract (100, 250, and 500 mg/kg) for 21 days. Results indicated that the extracts substantially reduced elevated levels of bilirubin, ALT, AST, ALP, and MDA to normal levels at all doses. The extracts also brought serum protein, GSH, CAT, and SOD levels back to normal. Although the restoration of serum hepatic enzyme levels was dose dependent, no specific dose dependent relationship was found for serum proteins, MDA, GSH, CAT, or SOD activities. The study's findings show that molokhia leaves extract protects against acrylamide-induced hepatic damage by virtue of its good radical scavenging and anti-lipiperoxidative properties conferred by phenolics, flavonoids, and alkaloids.

Heavy metals exposure is associated with early liver dysfunction among rural residents aged 40-75 years in southwest China.

Heavy metals exposure has been associated with liver dysfunction in recent reports, while the hepatoxicity of lead (Pb) and cadmium (Cd) has been well established. However, the combined effects of multi-metal in real-world scenario on liver dysfunction are still unclear. This cross-sectional study examined associations between 10 biomarkers of early liver injury and multiple heavy metals levels. The levels of heavy metals/metalloid (magnesium [Mg], calcium [Ca], iron [Fe], zinc [Zn], arsenic [As], Cd, copper [Cu], and Pb) were measured in blood and urinary sample collected from 725 participants in a Cd-polluted area and an unpolluted area in southwest China. The early liver dysfunction biomarkers included the liver enzymes (ALT, ALP, AST, and GGT), proteins (TP, ALB, and GLO), and bilirubin (TBIL, DBIL, and IBIL). Confounder-adjusted beta coefficients were determined using multiple linear regression model analysis for the group-classified and gender-classified samples. Our results showed that blood Fe, Cd, and Cu levels were found to be positively related to elevated ALT levels and blood Cu was positively associated with AST levels in the Cd-polluted area, while the highest blood Zn quartile in the polluted area and blood Mg quartile in the unpolluted area were associated with lower ALT levels. Our finding implies that industrial pollution results in heavy metals of Cd and Pb exposure and effects of Fe, Cd, Cu, and Pb in the Cd-polluted area may be the main contributors to increase the risk of liver dysfunction while Zn in the Cd-polluted area and Mg in the unpolluted area may be the protective factors.

Anticancer property of Selaginella bryopteris (L.) Bak. against hepatocellular carcinoma in vitro and in vivo

BackgroundHepatocellular carcinoma (HCC) is the most common and leading cause of cancer-related mortality worldwide. It has limited therapeutic options and side effects caused by current treatment methods. Selaginella bryopteris is used traditionally in the treatment of several health-related problems but mostly remains to be scientific validation. PurposeThis study investigated the effect of Selaginella bryopteris on a hepatic cancer cell line in vitro and in the NDEA-induced HCC rat model in vivo. MethodThe anticancer effect of S. bryopteris was evaluated in vitro using a human hepatocellular carcinoma HepG2 cell line. Gas chromatography-mass spectrometry (GC–MS) was carried out to analyze the phytoconstituents of S. bryopteris extract. Different techniques were used in this in vitro anticancer study to evaluate cell viability, alteration in nuclear morphology, mitochondrial membrane potential, and generation of reactive oxygen species (ROS). For an in vivo study, Sprague Dawley (SD) rats were induced with N- nitrosodiethylamine (200 mg/kg b.w. once, i.p.) and carbon tetrachloride (3 mL/kg/week b.w., s.c.) up to six weeks. The induced animals were treated with S. bryopteris extract (100 and 200 mg/kg) and silymarin (100 mg/kg) for 28 days. The level of liver function parameters and antioxidant enzymes were assessed. A reverse transcriptase-polymerase chain reaction was used to evaluate the gene expression patterns of p53, Bax, caspase-3, caspase-9, and Bcl-2 mRNAs. ResultsIn a liver cancer cell line (HepG2), Selaginella bryopteris extract (SBE) induced apoptosis through altering mitochondrial membrane potential, nuclear condensation, and the production of reactive oxygen species. The elevated level of ALT, AST, GGT, and TBL in HCC-induced rats were declined significantly by SBE administration. SBE enhanced antioxidant activity (GST, Catalase, SOD, GPX), antioxidant molecule (GSH), and reduced the level of stress marker (MDA) in NDEA induced animals. The effects of SBE against HCC were also demonstrated by the up-regulated expression of pro-apoptotic genes (p53, caspase-3, caspase-9, Bax) and the down-regulated expression of anti-apoptotic (Bcl-2) gene by qRT-PCR analysis in liver tissue. Histological analysis revealed that the extract improved the liver architecture. The major bioactive compounds detected by GC–MS analysis were imidazole, amentoflavone, gallic acid, catechine, palmitic acid, lupeol, l-Fucitol, and myo-inositol. SBE was found to be safe in an acute toxicity test. As a result, our findings indicate that S. bryopteris extract may have anti-HCC potential. ConclusionsIn vitro and in vivo, Selaginella bryopteris extract has significant antiproliferative action against HCC. S. bryopteris extract can be used as a safe and natural potential drug candidate against hepatocellular carcinoma.

'Silymarin' a Potential Treatment Targeting Hepatic Fibrosis of Schistosomiasis

Background: Despite all treatment and control efforts, schistosomiasis still thrives in humanity. It is endemic in 78 countries that are anchored by poverty and diseases. Until now, the broad-spectrum praziquantel (PZQ) drug is the only effective treatment of choice. However, reports documented some side effects for PZQ like haemorrhage in lung tissues, resistance, and inefficacy to treat fibrotic tissues. Therefore, alternative drugs that help in reducing the undesired effects of schistosomiasis are required. This study examined the efficacy of Silymarin in interfering with the fibrogenesis process using a mouse model. Silymarin is a herbal extract known to have flavonoids and polyphenols that help in reducing the inflammatory reaction, stimulating hepatocyte regeneration, and inhibiting the fibrogenesis process.
 Methods: A total of thirty adult tBALB/c male mice were divided into negative, chronically infected control and treated groups. All were killed after 18 weeks from the initial infection. Different histopathological investigations and liver function tests were carried out to detect the difference between the groups.
 Results: Administration of Silymarin exhibited a significant improvement in all associated histopathology with a considerable decline in the area percentage of collagen fibers. It restored the elevated level of serum ALT as well.
 Conclusion: Silymarin as a treatment for chronic hepatopathies will only be successful if started during the acute phase of the disease.

Liver Function Derangement and Bleeding Morbidity in Dengue Fever and Dengue Haemorrhagic Fever in a tertiary Hospital in Bangladesh

Background: Dengue is a major international health concern that is prevalent in tropical and sub tropical countries. Study of dengue infection and its Liver complications are scarce from countries like India. This study was done to assess the frequency and spectrum of liver dysfunction and bleeding morbidity in Dengue infection patients. Methods: A Cross sectional prospective observational study was performed in the of Department of Medicine Sir Salimullah Medical College Mitford Hospital. All the inpatients who were diagnosed with dengue infection between July 2015 to July 2016 were included in this study. A total of 70 patients were included in the study. Results: Patients were classified as classical dengue fever (DF) 61.5.% dengue haemorrhagic fever (DHF) 38.5%. The mean age was 28.607±10.45 years in DF group and 26.78±11.78 years in DHF group and male: female ratio was 3:1. Deranged serum glutamic-oxaloacetic transaminase (SGOT) and/or Serum glutamic pyruvic transaminase (SGPT) was present in most of the patients. Elevation of ALT level occured more in DHF group patient (81%) than DF group (46%). Out of 70 patient 28(40%) patient were within normal value. 42 (60%) patient had elevated ALT level which is statistically significant (p value-<0.05)..The degree of rise of SGOT, SGPT,and Bilirubin was significantly more in DHF and DSS, as compared to DF. About bleeding morbidity, purpura was a mentionable finding 29(41%) but gum bleeding 15(21%), echymosis 14(20%), are less in both DF and DHF group. Major bleeding like hematomesis 5 (7%), melaena 4 (5%) and haematuria 1 (1%) also occured in both group of patients. Conclusion: Liver dysfunction in the form of raised SGPT was seen in almost all patients. Preferentially high SGOT may serve as an early indicator of dengue infection while high values of bilirubin, SGOT, SGPT,may be an indicator of severe disease and poor prognosis. Bangladesh J Medicine July 2022; 33(1) : 44-51

An Antioxidant Enzyme Therapeutic for Sepsis.

Sepsis is a systemic inflammatory response syndrome caused by infections that may lead to organ dysfunction with high mortality. With the rapid increase in the aging population and antimicrobial resistance, developing therapeutics for the treatment of sepsis has been an unmet medical need. Excessive production of reactive oxygen species (ROS) during inflammation is associated with the occurrence of sepsis. We report herein a treatment for sepsis based on PEGylated catalase, which can effectively break down hydrogen peroxide, a key component of ROS that is chemically stable and able to diffuse around the tissues and form downstream ROS. PEGylated catalase can effectively regulate the cytokine production by activated leukocytes, suppress the elevated level of AST, ALT, TNF-α, and IL-6 in mice with induced sepsis, and significantly improve the survival rate.

Fasting augments pyrrolizidine alkaloid-induced hepatotoxicity.

Pyrrolizidine alkaloids (PAs) are phytotoxins widely present in various natural products and foodstuffs. The present study aims to investigate the effects of fasting on PA-induced hepatotoxicity and the underlying biochemical mechanisms. The results of hepatotoxic study showed that 15-h overnight fasting significantly exacerbated the hepatotoxicity of retrorsine (RTS, a representative toxic PA) in fasted rats compared to fed rats, as indicated by remarkably elevated plasma ALT and bilirubin levels and obvious liver histological changes. Further toxicokinetic studies revealed that fasting significantly enhanced cytochromes P450 enzymes (CYPs)-mediated metabolic activation of RTS leading to increased formation of pyrrole-protein adducts and thus decreased the in vivo exposure and excretion of both parent RTS and its N-oxide metabolite. Metabolic studies demonstrated that fasting induced enzyme activities of CYP1A2, CYP2B6 and CYP2E1 that participated in catalyzing RTS to its reactive pyrrolic metabolites. Moreover, fasting also dramatically decreased hepatic glutathione (GSH) content, which restricted the detoxification of GSH by neutralizing the reactive pyrrolic metabolite of RTS, further contributing to the enhanced hepatotoxicity. The present findings may have an impact on future PA toxicity tests with different dietary styles and/or risk assessment of metabolite-mediated toxins by considering the profound effects of fasting.

An Observational Study to Determine Severity and Complications Associated with Non-Alcoholic Fatty Liver Disease with Special Emphasis on Riskfactors

Introduction: The clinical spectrum of NAFLD is wide extending and ranges from NAFL to NASH, advanced fibrosis, cirrhosis, HCC. It has emerged as the most prevalent chronic liver disease worldwide in adults and children's. NAFLD is commonly linked with MS such as obesity, DM, H0TN, hypercholesterolemia. Methods: This is an observational study conducted to determine risk factor, severity and complication associated with NAFLD. Data was collected from outpatient and inpatients of gastroenterology department and also through patient or care taker interview. Result: A total of 112 cases of liver disease were observed among them 61 cases were found with NAFLD. Majority of cases were examined with Grade I fatty liver. Males were more prone to develop NAFLD and the most highest prevalence was found in the age group 51-70yrs. DM is the main RF and PHTN is the common complication observed. Beta blocker, ARB, statins, are frequently observed prescribed drugs to manage risk factors and complication. Hepatoprotective drugs like ursodeoxycholic acid, SAMe are given. Conclusion: The study concluded that the prevalence of Grade I fatty liver was high followed by CLD. Further, patients with NAFLD were predominantly middle aged men, most of whom were overweight and obese. Prevalence of NAFLD appears to be substantially higher than that predicted on basis of elevated ALT levels. Male sex, BMI, abnormal transaminase level, and MS were independently associated with ultrasonographic severe fatty change. Early detection, as well as steps to prevent the condition through lifestyle modification may halt the progression of a benign disease to advanced illness. Sedentary behavior or physical inactivity is a developing issue quietly putting individuals at elevated risk.

Development of herpetrione nanosuspensions stabilized by glycyrrhizin for enhancing bioavailability and synergistic hepatoprotective effect

The objective of this study was to develop novel herpetrione (HPE) nanosuspensions stabilized by glycyrrhizin (HPE NSs/GL) for enhancing bioavailability and hepatoprotective effect of HPE. HPE NSs/GL were prepared by wet media milling method and then systemically evaluated by particle size analysis, scanning electronic microscopy (SEM), X-ray powder diffraction (XRPD), dissolution test, pharmacokinetics, and hepatoprotective effect. HPE-NSs stabilized by poloxamer 407 (HPE NSs/P407) were also prepared and used as a reference for comparison. HPE NSs/GL and HPE-NSs/P407 with similar particle sizes around 450 nm and PDI less than 0.2 were successfully prepared and both of them appeared to be spherical under SEM. The XRPD results demonstrated that HPE in both HPE NSs/GL and HPE NSs/P407 was presented in the amorphous state and the addition of GL or P407 and the milling process didn’t alter the physical state of HPE. The dissolution and pharmacokinetic studies demonstrated that HPE NSs/GL exhibited significant enhancement in drug dissolution (72.44% within 24 h) and AUC0–t (24.91 ± 3.3 mg/L·h) as compared to HPE coarse suspensions (HPE CS, 34.19% & 13.07 ± 1.02 mg/L·h), but was similar with those of HPE NSs/P407 (80.06% & 26.75 ± 4.06 mg/L•h). Moreover, HPE NSs/GL exhibited significantly better hepatoprotective effect as compared to HPE CS and HPE NSs/P407 as indicated by the lowering of the elevated serum ALT and AST levels and the improvement of the hepatic morphology and architecture, which might be attributed to the improved bioavailability of HPE, and synergistic hepatoprotective effect of GL via alleviating inflammation evidenced by the significant decreased hepatic levels of inflammatory cytokines IL-1β, IL-6 and TNF-α. It could be concluded that GL might be an effective stabilizer for preparing HPE NSs, and HPE NSs/GL is a potential formulation strategy for improving oral bioavailability and hepatoprotective effect of HPE.

Association between serum alanine and aspartate aminotransferase and blood pressure: a cross-sectional study of Chinese freshmen

BackgroundHigh blood pressure is a well-recognized risk factor for cardiovascular events, and the incidence of hypertension is increasing among young people. This study investigated the relationship between ALT and AST levels and hypertension among freshmen in China.MethodsThis cross-sectional study was conducted in the Anhui Province from September to November 2018. A total of 3114 freshmen underwent a physical examination including testing of biochemical indicators and a standardized questionnaire.ResultsThe overall prevalence of elevated ALT and AST were 6.8% and 2.3% among freshmen. The mean ALT and AST levels were higher in males (22.59 ± 21.98 vs.12.62 ± 10.30 U/L; 23.55 ± 12.24 vs. 20.02 ± 5.75 U/L, respectively). The prevalence of hypertension was significantly higher in men (16.1%) than in women (1.9%). The mean values of BMI, SBP, DBP, TC, TG, and LDL-C were found to be increased with elevated levels of serum ALT and AST in the quartiles (P for trend < 0.05). After adjusting for covariates, the risk of hypertension was significantly higher in the highest ALT quartile than in the lowest quartile (OR (95% CI) of 1.681 (1.028, 2.751) in males; 2.802 (1.102, 7.124) in females). A strong linear relationship was found between serum ALT levels and the odds of hypertension after adjustment for potential confounders only in total population and females (P for trend < 0.05).ConclusionsThese findings suggest that ALT level is significantly associated with hypertension both in male and female freshmen.

A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

Elevated liver enzymes of newly diagnosed pediatric celiac patients-a prospective-observational study.

Celiac disease clinical presentation is constantly changing. We set to determine the prevalence of elevated transaminases in newly diagnosed celiac patients and to evaluate this sub-group of patients for associated clinical and laboratory findings and assess their natural course of disease following therapeutic diet initiation. We conducted a prospective-observational study of all newly diagnosed pediatric celiac patients, between August 2016 and April 2018, in a pediatric gastroenterology clinic. Clinical data, anthropometrics, and blood test results were recorded at diagnosis and at 3, 6, and 12months, respectively, of follow-up. We compared patients with normal and elevated transaminases at diagnosis. ALT threshold was set at 24 U/l. Of 125 newly diagnosed celiac patients, 31 (24.8%) had elevated ALT at diagnosis; two (1.6%) with over 3 × ULN. Patients with elevated ALT at diagnosis were significantly younger (mean age 5.5 (SD 3.4) vs. 7.3 (SD 3.7) years, p < 0.01) and more commonly presented with diarrhea (32.3% vs. 14.9%, p = 0.03). Eighty percent of patients with elevated ALT levels normalized their ALT within 3months and all within 1year. Following gluten-free diet initiation, patients with elevated ALT had similar clinical course, growth, serology normalization rate, and laboratory results, compared to patients with normal ALT over a 1-year follow-up. A single patient was simultaneously co-diagnosed with celiac disease and autoimmune hepatitis.Conclusion: Clinically significant ALT abnormalities are rare among newly diagnosed pediatric celiac patients. Significant elevations failing to normalize on a gluten-free diet should raise concern of a concomitant primary liver disease and warrant further investigations. What is Known: • Elevated liver enzymes may be an extra-intestinal manifestation of celiac disease. • Reported prevalences of ALT elevations among children with a new diagnosis of celiac disease ranges between 5 and 40%. What is New: • ALT elevations are present in 25% of children with a new diagnosis of celiac disease. • Significant elevations (>3 × ULN) are rare (1.6%). • Elevated liver enzymes are associated with earlier age at diagnosis. • The natural history of patients with elevated liver enzymes at diagnosis is comparable to those without.

Predictors of severity and development of critical illness of Egyptian COVID-19 patients: A multicenter study.

We conducted the present multicenter, retrospective study to assess the epidemiological, clinical, laboratory, and radiological characteristics associated with critical illness among patients with COVID-19 from Egypt. The present study was a multicenter, retrospective study that retrieved the data of all Egyptian cases with confirmed COVID-19 admitted to hospitals affiliated to the General Organization for Teaching Hospitals and Institutes (GOTHI) through the period from March to July 2020. The diagnosis of COVID-19 was based on a positive reverse transcription-polymerase chain reaction (RT-PCR) laboratory test. This retrospective study included 2724 COVID-19 patients, of whom 423 (15.52%) were critically ill. Approximately 45.86% of the critical group aged above 60 years, compared to 39.59% in the non-critical group (p = 0.016). Multivariate analysis showed that many factors were predictors of critically illness, including age >60 years (OR = 1.30, 95% CI [1.05, 1.61], p = 0.014), low oxygen saturation (OR = 0.93, 95% CI [0.91, 0.95], p<0.001), low Glasgow coma scale (OR = 0.75, 95% CI [0.67, 0.84], p<0.001), diabetes (OR = 1.62, 95% CI [1.26, 2.08], p<0.001), cancer (OR = 2.47, 95% CI [1.41, 4.35], p = 0.002), and serum ferritin (OR = 1.004, 95% CI [1.0003, 1.008], p = 0.031). In the present report, we demonstrated that many factors are associated with COVID-19 critical illness, including older age groups, fatigue, elevated temperature, increased pulse, lower oxygen saturation, the preexistence of diabetes, malignancies, cardiovascular disease, renal diseases, and pulmonary disease. Moreover, elevated serum levels of ALT, AST, and ferritin are associated with worse outcomes. Further studies are required to identify independent predictors of mortality for patients with COVID-19.

Serum cytokine/chemokine profiles predict hepatitis B reactivation in HBV/HCV co-infected subjects receiving direct-acting antiviral agents

Direct-acting antiviral agents (DAAs) have revolutionized the paradigm for HCV treatment. However, patients with HBV and HCV co-infection receiving DAAs are at significant risk of HBV reactivation, with limited literature addressing the roles of serum chemokines/chemokines. We aimed to explore the profiles and predictive value of serum cytokines/chemokines regarding HBV reactivation in this clinical setting. From 2017 to 2019, 25 patients with HBV and HCV co-infection scheduled for DAA therapy were prospectively enrolled. At enrolment and after DAA treatment, serial serum cytokine/chemokine levels were examined. The baseline and dynamic levels were compared between those with versus without HBV virologic (defined by an increase of serum HBV DNA to >10 times) and clinical reactivation (defined by>1.5-fold elevated ALT level than nadir and >100U/L; or>2-fold increase from nadir and greater than the upper normal limit, in addition to virologic reactivation). There were 20 patients (80%) experiencing HBV virologic reactivation and 6 patients (24%) experiencing clinical reactivation. Patients with clinical reactivation had higher pre-treatment TNF-alpha (27.93 versus 18.85pg/mL, P=0.015), lower week-4 IFN-gamma (1.07 versus 8.74pg/mL, P=0.020) levels and significant declines of CCL2 and TNF-alpha (P<0.05). Single or combination of these cytokines helped predict clinical reactivation (all P<0.05). Higher serum TNF-alpha at baseline and lower IFN-gamma at week 4 were associated with mild clinical reactivation of HBV in patients with HBV/HCV co-infection receiving DAAs. Combination of these cytokines reliably predicted HBV reactivation early.

Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration.

Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively. In the current study, we interrogated the effects of endogenous n3-PUFA enrichment in a mouse model which recapitulates features of early human AH using transgenic fat-1 mice which endogenously convert n6-PUFAs to n3-PUFAs. Male wild type (WT) and fat-1 littermates were provided an ethanol (EtOH, 5% v/v)-containing liquid diet for 10 days, then administered a binge of EtOH (5 g/kg) by oral gavage on the 11th day, 9 h prior to sacrifice. In WT mice, EtOH treatment resulted in liver injury as determined by significantly elevated plasma ALT levels, whereas in fat-1 mice, EtOH caused no increase in this biomarker. Compared to their pair-fed controls, a significant EtOH-mediated increase in liver neutrophil infiltration was observed also in WT, but not fat-1 mice. The hepatic expression of several cytokines and chemokines, including Pai-1, was significantly lower in fat-1 vs WT EtOH-challenged mice. Cultured bone marrow-derived macrophages isolated from fat-1 mice expressed less Pai-1 and Cxcl2 (a canonical neutrophil chemoattractant) mRNA compared to WT when stimulated with lipopolysaccharide. Further, we observed decreased pro-inflammatory M1 liver tissue-resident macrophages (Kupffer cells, KCs), as well as increased liver T regulatory cells in fat-1 vs WT EtOH-fed mice. Taken together, our data demonstrated protective effects of endogenous n3-PUFA enrichment on liver injury caused by an acute-on-chronic EtOH exposure, a paradigm which recapitulates human AH, suggesting that n3-PUFAs may be a viable nutritional adjuvant therapy for this disease.

Mitochondrial dysfunction in mouse livers depleted of iron chaperone PCBP1

Iron is an essential nutrient that forms cofactors required for the activity of hundreds of cellular proteins. However, iron can be toxic and must be precisely managed. Poly r(C) binding protein 1 (PCBP1) is an essential, multifunctional protein that binds both iron and nucleic acids, regulating the fate of both. As an iron chaperone, PCBP1 binds cytosolic iron and delivers it to iron enzymes for activation and to ferritin for storage. Mice deleted for PCBP1 in the liver exhibit dysregulated iron balance, with lower levels of liver iron stores and iron enzymes, but higher levels of chemically-reactive iron. Unchaperoned iron triggers the formation of reactive oxygen species, leading to lipid peroxidation and ferroptotic cell death. Hepatic PCBP1 deletion produces chronic liver disease in mice, with steatosis, triglyceride accumulation, and elevated plasma ALT levels. Human and mouse models of fatty liver disease are associated with mitochondrial dysfunction. Here we show that, although deletion of PCBP1 does not affect mitochondrial iron balance, it does affect mitochondrial function. PCBP1 deletion affected mitochondrial morphology and reduced levels of respiratory complexes II and IV, oxygen consumption, and ATP production. Depletion of mitochondrial lipids cardiolipin and coenzyme Q, along with reduction of mitochondrial oxygen consumption, were the first manifestations of mitochondrial dysfunction. Although dietary supplementation with vitamin E ameliorated the liver disease in mice with hepatic PCBP1 deletion, supplementation with coenzyme Q was required to fully restore mitochondrial lipids and function. In conclusion, our studies indicate that mitochondrial function can be restored in livers subjected to ongoing oxidative damage from unchaperoned iron by supplementation with coenzyme Q, a mitochondrial lipid essential for respiration that also functions as a lipophilic radical-trapping agent.

Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury.

Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elusive. Here we focused on the potential roles of orphan nuclear receptor (NR) RORγ in lipid programming, and aimed to explore its action on cholesterol regulation in the liver of mycotoxin-exposed piglets. We found that liver tissues were damaged in the mycotoxin-exposed piglets compared to the healthy controls, revealed by histological analysis, elevated seral ALT, AST and ALP levels, and increased caspase 3/7 activities. Consistent with the transcriptomic finding of down-regulated cholesterol metabolism, we demonstrated that both cholesterol contents and cholesterol biosynthesis/transformation gene expressions in the mycotoxin-exposed livers were reduced, including HMGCS1, FDPS, SQLE, EBP, FDFT1 and VLDLR. Furthermore, we reported that RORγ binds to the cholesterol metabolic genes in porcine hepatocytes using a genome-wide ChIP-seq analysis, whereas mycotoxin decreased the RORγ binding occupancies genome-wide, especially at the cholesterol metabolic pathway. In addition, we revealed the enrichment of co-factors p300 and SRC, the histone marks H3K27ac and H3K4me2, together with RNA Polymerase II (Pol-II) at the locus of HMGCS1 in hepatocytes, which were reduced by mycotoxin-exposure. Our results provide a deep insight into the cholesterol metabolism regulation during mycotoxin-induced liver injury, and propose NRs as therapeutic targets for anti-mycotoxin treatments.

Study Comparing the Liver Enzymes in Hypertensive and Normotensive Patients with Type 2 Diabetes

Objective: There were few clinical trials which indicate altered liver biochemical findings in diabetic patients, but through investigation to compare the liver enzymes in-between hypertensive and normotensive patients with type 2 diabetes was not evaluated. Thus main objective of current study was to compare the liver enzymes in hypertensive and normotensive patients with type 2 diabetes. Materials and Methods: This was a retrospective observational study conducted in a tertiary medical teaching hospital in Kolkata. Hospital OPD reports and patients clinical case records were used to fetch the required data in a predesigned clinical record pro forma. Result: Total 180 patients were participated in this observational retrospective trial where 33% patient were normotensive but having T2DM and 67% patients were hypertensive with T2DM. There were no statistically significant differences between the study variables among both the groups. However elevated level of GGT, ALT and AST were observed in T2DM normotensive patients as compare to T2DM hypertensive patients. abnormal liver functions were recorded in patients with uncontrolled diabetes as compared to patients with good control (p&lt;0.05). Conclusion: The current study concluded that elevated liver enzymes like bilirubin, GGT, SGOT and SGPT were common among diabetes mellitus patients and comparable with patients with hypertensive as well as normotensive patients with diabetes mellitus. Keywords: Liver enzymes, T2DM, hypertension.

Hepatoprotective effects of phytochemicals berberine and umbelliferone against methotrexate-induced hepatic intoxication: experimental studies and in silico evidence.

Chemotherapeutic drugs are used effectively to manage wide types of malignancies, but their therapeutic use is limited due to their associated hepatic intoxication. The current study sheds light on the effect of phytochemicals berberine (BBR) and umbelliferone (UMB) on methotrexate (MTX)-induced hepatic intoxication. Forty-eight rats were allocated to normal, BBR (50 mg/kg orally for 10 days), UMB (30 mg/kg orally for 10 days), MTX (20 mg/kg at the 5th day), BBR+MTX, and UMB+MTX. With regard to MTX, the results of this investigation reveal potent amelioration of MTX hepatotoxicity by BBR and UMB through reduction of the elevated serum levels of ALT, ALP, AST, and LDH confirmed by the attenuation of histopathological abrasion in liver tissues. BBR and UMB markedly restored antioxidant status. More importantly, BBR resulted in reducing P38 mitogen-activated protein kinase (P38MAPK), nuclear factor kappa-B (NF-κB), and Kelch-like ECH-associated protein 1 (Keap-1) genes and enhanced mRNA expression of Nrf-2 (P < 0.05). Interestingly, in silico studies via molecular docking pinpointed the binding modes of BBR and UMB to the binding pocket residues of P38MAPK, NF-κB, and Keap-1 and demonstrated a promising inhibition of Keap-1, P38MAPK, and NF-κB. BBR and UMB reduced the expression of pro-apoptotic protein Bax and apoptotic protein caspase-3 as well as increased the expression of anti-apoptotic protein Bcl-2. Therefore, BBR and UMB may denote promising therapeutic agents that can avert hepatic intoxication in patients receiving MTX.

Effects of Sodium Valproate Monotherapy on Blood Liver Enzyme Levels in Patients with Epilepsy: A Meta-Analysis.

We conducted this meta-analysis to assess the effects of sodium valproate (VPA) monotherapy on blood liver enzymes in patients with epilepsy. PubMed, Web of Science, EBSCO, Cochrane Library, Wanfang, China national knowledge infrastructure databases were searched. Nine studies were included. Results showed: (1) The overall SMD for blood AST, ALT, and GGT levels of VPA monotherapy group versus control group were 0.70 (95% CI=0.31 to 1.09, Z=3.52, p=0.0004), 0.47 (95% CI=- 0.01 to 0.95, Z=1.91, p=0.06), 0.44 (95% CI=0.29 to 0.60, Z=5.55, p<0.00001), respectively. (2) In subgroup meta-analysis, increased blood AST and GGT levels were observed in epileptic minors (AST: total SMD=0.85, 95% CI=0.40 to 1.30, Z=3.69, p=0.0002; GGT: total SMD=0.46, 95% CI=0.29 to 0.63, Z=5.25, p<0.00001). Elevated blood ALT level was observed in Asian patients receiving VPA monotherapy (total SMD=0.70, 95% CI=0.51 to 0.90, Z=7.01, p<0.00001), and the early stage of VPA monotherapy (total SMD=0.93, 95% CI=0.57 to 1.29, Z=5.09, p<0.00001). Overall, our results indicated that blood AST and GGT were significantly increased in epileptic minors receiving VPA monotherapy. The elevation of blood ALT was observed in Asian patients and the early stage of VPA monotherapy. However, due to the small number of included studies, our results should be considered with caution.