Hepatic Aminotransferase Activity Research Articles

Modulation of the Nrf-2 and HO-1 signalling axis is associated with Betaine's abatement of fluoride-induced hepatorenal toxicities in rats.

Sodium fluoride (NaF) ingestion has several detrimental effects in humans and rodents. NaF mechanisms of toxicity include perturbation of intracellular redox homeostasis and apoptosis. Betaine (BET) is a modified amino acid with anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigates BET's effect on NaF-induced hepatorenal toxicities in rats. Experimental rats (n=30) were randomly assigned to groups (n=6) and treated by gavage for 28 days. Group I (2 mL of distilled water), Group II (NaF: 9 mg/kg) alone, Group III: (BET: 100 mg/kg), Group IV: (NaF: 9 mg/kg and BET 1: 50 mg/kg), and Group V: (NaF: 9 mg/kg and BET 2: 100 mg/kg). Our findings revealed significantly (p<0.05) increased hepatic transaminase activities alongside creatinine and urea levels following NaF-alone treatment in addition to increased oxidative status, lipid peroxidation, reactive oxygen and nitrogen species, decreased superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase, glutathione, and total sulfhydryl groups. The reduced levels of nuclear factor erythroid 2-related factor-2 and the activities of heme oxygenase-1, thioredoxin, and thioredoxin reductase in NaF-alone treated rats equally compromised cellular molecular responses to oxidative stress. Also, NaF increased (p<0.05) hepatorenal inflammatory biomarkers-nitric oxide, interleukin-10, myeloperoxidase, and xanthine oxidase. Furthermore, caspase-3 and caspase-9 were increased (p<0.05) in rats treated with NaF alone. Contrastingly, BET was observed to alleviate the harmful effects of NaF. Treatment with BET mitigated NaF-induced oxido-inflammatory responses and apoptosis in the experimental rat's hepatorenal system. The study demonstrates the potential of BET to abate NaF-induced hepatorenal toxicity.

Verification of the Morphofunctional Disorders Level of the Hepatorenal System during the Feline Tripelphosphate Urolithiasis

Introduction. The available information referring to the feline urolithiasis pathogenesis does not fully reflect the nature of changes taking place in the body, because it does not take into account the existing liver-kidney interrelationship. A systemic approach to studying this problem enables development of the targeted diagnostic strategies, increase of the subsequent therapeutic efficacy, as well as reduction of the possible clinical harm of polypragmasia. The aim of this article is to study the interrelationship between the nature of the hepatorenal system morphofunctional disorders and the level of metabolic processes in cats sick with struvite urolithiasis with the signs of cystolithiasis.Materials and Methods. The objects of the research were cats: the 1st experimental group consisted of the outbred female cats with tripelphosphate urolithiasis with signs of cystolithiasis, the 2nd experimental group — outbred castrated male cats with tripelphosphate urolithiasis with signs of cystolithiasis, the control group was mixed of the clinically healthy male and female animals. During the research, the results of the sick animals' clinical study, morphological and biochemical blood serum tests, hepatorenal system transabdominal ultrasonography were used, the urine macroscopic and biochemical examinations as well as urine sediment microscopy were carried out.Results. Against the background of hyperazotemia in sick animals (UREA — 14.70±1.30 mmol/L and 17.05±1.60 mmol/L; CREA — 173.90±6.06 μmol/L and 182.30±7.54 μmol/L; URIC ACID — 69.30±4.50 μmol/L and 73.48±4.83 μmol/L) and water-electrolyte metabolism disorder (Ca+2 — 2.89±0.05 mmol/L and 3.04±0.12 mmol/L; P+3 — 3.12±0.06 mmol/L and 3.20±0.09 mmol/L; iCa+2 — 1.39±0.03 mmol/L and 1.42±0.02 mmol/L; Cl- — 125.58±1.19 mmol/L and 129.90±1.06 mmol/L) there were observed: a disorder in the hepatobiliary system functioning due to elevation of the main hepatic transaminase activity (AST — 41.74±5.35 unit/L and 49.30±6.74 unit/L; ALT — 85.82±6.15 unit/L and 90.05±6.50 unit/L; ALКP — 45.61±3.10 unit/L and 48.16±2.86 unit/L; AAR — 0.49±0.03 and 0.54±0.02), elevation of total bilirubin level (BILT — 5,76±0,15 μmol/L and 6,08±0,24 μmol/L) and bilirubin direct (BILD — 1,40±0,03 μmol/L and 1,62±0,02 μmol/L), as well as elevation of the gamma-glutamyl transpeptidase (GGT — 6,67±1,01 unit/L and 7,90±0,90 unit/L) and lactate dehydrogenase (LDH — 215,47±10,30 unit/L and 219,04±9,27 unit/L) activity level. The acoustic shadowing of the hepatorenal system organs confirmed the signs of acute hepatitis against the background of cystolithiasis due to the existing anatomical relationship between kidneys and liver.Discussion and Conclusion. The results of the sick animals’ blood serum examination indicated the progression of the hematopoietic dysfunction during the tripelphosphate urolithiasis, which contributed to the development of the circulatory tissue hypoxia in the liver-kidney system. The development of the hyperazotemia contributed to the elevation of the main hepatic transaminase activity and building-up of the functional disorders in the hepato-biliary system of sick cats in response to the acute inflammatory process going on in the urogenital tract. The carbohydrate and lipid metabolism disorders indicated the liver metabolic activity disorder and its parenchymal damage on the background of urolithiasis. The electrolyte and water metabolism disorders, the development of the hyperproteinemia in test cats with the tripelphosphate urolithiasis contributed to the damage of the hepatorenal system organs due to development of the compensated metabolic acidosis and hyperchloremia.

A ten-year retrospective California Poison Control System experience with possible amatoxin mushroom calls

Introduction Mushrooms containing amatoxin are found worldwide and represent a challenging poisoning for the clinician and consulting poison center. This study evaluates the experience of a large poison system with possible amatoxin-containing mushroom ingestion calls. Methods A 10-year retrospective review of the California Poison Control System database was performed for amatoxin mushroom ingestion calls resulting in hospitalization. Cases found were abstracted and data statistically analyzed for association with a composite endpoint of death, liver transplant, and/or the need for dialysis. Results Amatoxin-containing mushroom calls are infrequent with the vast majority (98.4 percent) coming from Northern California during the rainier first and fourth quarters (October through March) of the year. Elevated initial aminotransferase activities and international normalized ratios were predictive of the composite negative outcome. The mortality plus liver transplant and hemodialysis composite rate was 8.2 percent, consistent with current literature. Conclusion The California Poison Control System has relatively few amatoxin-containing mushroom ingestion calls that result in hospitalization but those that are reported mostly occur in Northern California. Treatment bias towards the sickest patients may explain the association of intravenous fluid use or treatment with acetylcysteine or silibinin with meeting the composite outcome. The initial presence of elevated hepatic aminotransferase activity and international normalized ratios are poor prognostic indicators and are likely reflective of late presentation, an advanced toxic phase of amatoxin poisoning, and/or delays in time to obtain poison center consultation.

Comparative analysis of signalling pathways in tissue protein metabolism in efficient and non-efficient beef cattle: acute response to an identical single meal size

Protein turnover has been associated to residual feed intake (RFI) in beef cattle. However, this relationship may be confounded by feeding level and affected by the composition of the diet being fed. Our aim was to assess postmortem the protein metabolism signalling pathways in skeletal muscle and liver of 32 Charolais young bulls with extreme RFI phenotypes. Bulls were fed two contrasting diets during the whole fattening period but were subjected to a similar and single nutritional stimulus, induced by their respective concentrate, just prior to slaughter. The key targets were protein degradation (autophagy and ubiquitin) and synthesis signalling pathways through western-blot analysis, as well as hepatic transaminase activity. To ensure a precise assessment of all animals at the same postprandial time, they were provided with a test meal (2.5 kg of either a high-starch and high-protein concentrate or high-fibre and low-protein concentrate) 3 hours prior to slaughter, irrespective of their RFI grouping. Blood and tissues were sampled at the slaughterhouse (3 h and 3 h30 postprandially, respectively). In response to an identical single meal size, efficient RFI animals showed higher (P < 0.05) postprandial plasma β-hydroxybutyrate concentrations and insulinemia (only with the high-starch concentrate) than non-efficient animals. Moreover, efficient RFI bulls had lower muscle (P = 0.04) and liver (P = 0.08) ubiquitin protein abundance (degradation pathway) and tended to have lower alanine transaminase activity in the liver (P = 0.06) compared to non-efficient bulls, regardless of diet. A positive correlation between protein degradation potential and amino acid catabolism was identified in this study (r = 0.52, P = 0.004), which was interpreted as being biologically linked to the RFI phenotype. Efficient RFI bulls also had a faster potential for protein synthesis in the muscle, as indicated by their greater ratio of phosphorylated to total form of ribosomal protein S6 kinase (P = 0.05), regardless of diet. Results on protein synthesis pathway in muscle and plasma metabolite concentrations suggested that efficient RFI cattle may have a faster nutrient absorption and insulin responsiveness after feeding than inefficient cattle. We did not find significant differences in hepatic protein synthesis pathways between the two RFI groups (P > 0.05). Our findings suggest that, in response to an identical single meal size, efficient RFI animals exhibited lower activation of tissue protein degradation pathways and faster muscle protein synthesis activation compared to their inefficient counterparts. This pattern was observed regardless of the composition of the tested meals.

Integrated Analysis of Gut Microbiome and Liver Metabolome to Evaluate the Effects of Fecal Microbiota Transplantation on Lipopolysaccharide/D-galactosamine-Induced Acute Liver Injury in Mice

Acute liver failure (ALF) refers to the occurrence of massive hepatocyte necrosis in a short time, with multiple complications, including inflammatory response, hepatic encephalopathy, and multiple organ failure. Additionally, effective therapies for ALF are lacking. There exists a relationship between the human intestinal microbiota and liver, so intestinal microbiota modulation may be a strategy for therapy of hepatic diseases. In previous studies, fecal microbiota transplantation (FMT) from fit donors has been used to modulate intestinal microbiota widely. Here, we established a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-gal) induced ALF to explore the preventive and therapeutic effects of FMT, and its mechanism of action. We found that FMT decreased hepatic aminotransferase activity and serum total bilirubin levels, and decreased hepatic pro-inflammatory cytokines in LPS/D-gal challenged mice (p < 0.05). Moreover, FMT gavage ameliorated LPS/D-gal induced liver apoptosis and markedly reduced cleaved caspase-3 levels, and improved histopathological features of the liver. FMT gavage also restored LPS/D-gal-evoked gut microbiota dysbiosis by modifying the colonic microbial composition, improving the abundance of unclassified_o_Bacteroidales (p < 0.001), norank_f_Muribaculaceae (p < 0.001), and Prevotellaceae_UCG-001 (p < 0.001), while reducing that of Lactobacillus (p < 0.05) and unclassified_f_Lachnospiraceae (p < 0.05). Metabolomics analysis revealed that FMT significantly altered LPS/D-gal induced disordered liver metabolites. Pearson's correlation revealed strong correlations between microbiota composition and liver metabolites. Our findings suggest that FMT ameliorate ALF by modulating gut microbiota and liver metabolism, and can used as a potential preventive and therapeutic strategy for ALF.

Critical Hypermagnesemia in Preeclamptic Women Undera MagnesiumSulfate Regimen: Incidence and Associated Risk Factors.

Magnesium sulfate is used as prophylaxis and treatment of severe preeclampsia/eclampsia, albeit its safety and toxicity are a concern. We designed this study to estimate the incidence of critical hypermagnesemia in severely preeclamptic women undera magnesiumsulfate regimen at 8h following its administration and to identify the associated risk factors as the primary outcomes. Also, secondary outcomes were to compare baseline characteristics, laboratory findings, and maternal-neonatal complications stratified by the baseline serum magnesium (Mg2+) in those women, and to assess the degree of agreement between patellar reflex and serum Mg2+ concentration 8h following magnesiumsulfate administration. We conducted a retrospective study including severely preeclamptic women receiving magnesium sulfate from June 2016 to May 2021. We enrolled 429 women in the study. Two-hundred sixty-one (60.8%) of the included women developed critical hypermagnesemia. Preeclamptic women with high baseline serum Mg2+ concentration demonstrated significantly affected renal functions, hepatic transaminase activities, and low platelet count as well as more reported maternal complications compared to those with low baseline serum Mg2. Multivariable logistic regression revealed that a lower gestational age, a higher uric acid concentration, and a higher baseline serum Mg2+ concentration were independently associated with an increased risk of critical hypermagnesemia. The agreement between deep tendon reflex assessment and serum Mg2+ concentration was slight although not significant. The maternal-neonatal outcomes were non-significant in women with critical hypermagnesemia. More vigilant monitoring through assessment of both serum Mg2+ concentration and deep tendon reflex should be considered especially in high-risk women.

The effects of intermittent hypoxia on hepatic expression of fatty acid translocase CD36 in lean and diet-induced obese mice

BackgroundBoth obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are prevalent within obese individuals. We aimed to investigate the effects of intermittent hypoxia (IH), a clinical feature of OSA, on hepatic expression of fatty acid translocase (CD36) in relation to liver injury in lean and diet-induced obese mice. MethodsFour-week-old male C57BL/6J mice were randomized to standard diet (SD) or high fat (HF) diet groups. At 13-week-old, all mice were exposed to either air or IH (IH30; thirty hypoxic episodes per hour) for four weeks. We assessed liver injury through lipid profile, oxidative and inflammatory stress, histological scoring and hepatic CD36 expression. ResultsIn lean mice, IH elevated serum and hepatic triglyceride and free fatty acid (FFA) levels, in line with upregulation of hepatic CD36 expression and myeloperoxidase (MPO)-positive cells in support of inflammatory infiltrates along with increase in serum malondialdehyde (MDA), C-X-C motif chemokine ligand 1(CXCL-1) and monocyte chemoattractant protein-1 (MCP-1). In diet-induced obese mice, an increase in hepatic alanine transaminase (ALT) activity, serum and hepatic levels of lipid parameters and inflammatory markers, serum MDA level, hepatic expressions of CD36 and α-smooth muscle actin (α-SMA), and MPO-positive cells was observed. IH potentiated hepatic ALT activity, serum CXCL-1 and hepatic interleukin-6 (IL-6), in line with inflammatory infiltrates, but paradoxically, reduced hepatic FFA level and hepatic CD36 expression, compared to obese mice without IH exposure. However, IH further augmented diet-induced liver steatosis and fibrosis as shown by histological scores. ConclusionThis study contributes to support that IH featuring OSA may lead to liver injury via differential regulation of hepatic CD36 expression in lean and diet-induced obese mice.

Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway

AimsHepatocyte necroptosis is a critical event in the progression of non-alcoholic fatty liver disease (NAFLD). Obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic intermittent hypoxia (CIH) may be linked with the pathogenesis and the severity of NAFLD. However, the potential role of necroptosis in OSAHS-associated NAFLD has not been evaluated. The present study investigated whether IH could affect NAFLD progression through promoting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis, oxidative stress, and inflammatory response, and further elucidated the underlying molecular mechanisms. Main methodsLO2 cells were treated with palmitic acid (PA) and subjected to IH, and necroptosis, oxidative stress, and inflammation were assessed. The high-fat choline-deficient (HFCD)-fed mouse model was also used to assess the effects of CIH in experimental NAFLD in vivo. Key findingsIn this study, we found that RIPK3-mediated necroptosis was activated both in the PA plus IH-treated LO2 cells and liver of HFCD/CIH mice, and which could trigger oxidative stress and inflammatory response by decreasing Nrf2 and increasing p-P65. RIPK3 downregulation significantly reduced hepatocyte necroptosis, and ameliorated oxidative stress and inflammation through modulating Nrf2/NFκB pathway in vitro and vivo. Similarly, pretreatment with TBHQ, an activator of Nrf2, effectively blocked the generation of oxidative productions and inflammatory cytokines. In addition, RIPK3 inhibitor GSK-872 or TBHQ administration obviously alleviated hepatic injury, including histology, transaminase activities, and triglyceride contents in vivo. SignificanceIH aggravates NAFLD via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway, and which should be considered as a potential therapeutic strategy for the treatment of NAFLD with OSASH.

Impacts of dietary protein on growth performance, feed utilization, amino acid profile, activities of digestive and amino acid metabolizing enzymes of the soft‐shelled turtle ( Pelodiscus sinensis )

The impacts of dietary protein on growth, body proximate composition, feed utilization, amino acid profile, digestive enzyme activity and amino acid metabolizing enzymes in soft-shelled turtles (Pelodiscus sinensis) (initial weight: 4.02 ± 0.06 g) were measured during an 8-week feeding trail. Six diets containing 8%, 18%, 28%, 38%, 48% and 60% (control group) fishmeal were formulated, which contained 14.38%, 20.41%, 26.19%, 32.23%, 37.63% and 45.23% protein respectively. Weight gain, mean feed intake, skirt ratio, pepsin activity of stomach, total amino acid of the muscle and crude protein levels of the whole body improved as dietary protein content increased from 14.38% to 26.19% but remained stable thereafter. The hepatosomatic index, feed conversion ratio, intestinal alpha-amylase activity, moisture content of the whole body and serum alanine transaminase and aspartate aminotransferase activity decreased with increasing protein content up to 26.19% and then plateaued. The protein productive value and protein efficiency ratio decreased as protein content increased. Intestinal lipase activity and crude lipid levels of the whole body were unaffected by dietary protein level. Hepatic alanine transaminase and aspartate aminotransferase activity first significantly increased with increasing protein but remained stable at protein content ≥26.19%. The optimum dietary protein level for soft-shelled turtles was in the range of 27.36%–28.46% based on weight gain, ALT activity and AST activity results.

Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Physalin B (PB), a withanolide isolated from Physalis species (Solanaceae), exhibits a broad spectrum of biological activities, however, the potential role of PB in NASH has not been evaluated. The present study investigated the protective effects of PB against NASH and further elucidated the mechanisms of PB in hepatic autophagy and oxidative stress in vitro and in vivo. We conducted a series of experiments using methionine-choline deficient (MCD) diet induced NASH mice and cultured L02 cells. Serum markers of liver injury, morphology, and the histology of liver tissues were investigated. Western blot assays and quantitative real-time PCR were used to investigate the hepatoprotective effect of PB. PB significantly ameliorated hepatic injury, including hepatic index, transaminase activities, histology, and inflammation in MCD-induced mice. Moreover, PB markedly increased the expression of P62 and the ratio of LC3Ⅱ/Ⅰ in vitro and in vivo. Furthermore, PB promoted the interaction between endogenous KEAP1 and P62, reduced the interaction between KEAP1 and NRF2, activated the nuclear translocation of NRF2 and NRF2 target gene expression, and ultimately attenuated oxidative stress. In addition, knockdown of P62 blocked PB-mediated activation of NRF2 in L02 cells. These results clearly indicated that PB ameliorated NASH by stimulating autophagy and P62-KEAP1-NRF2 antioxidative signaling, suggesting that PB is expected to become a novel therapeutic drug for NASH.

Relative protective activities of quercetin, quercetin-3-glucoside, and rutin in alcohol-induced liver injury.

Alcoholic liver diseases has been known to be one of the major health risks worldwide. The purpose of this study was aimed to demonstrate the relative protective effect of quercetin, quercetin-3-glucoside, and rutin on alcohol-induced damage in hepatocytes. The hepatotoxicity, antioxidant enzymatic defense mechanisms, and pro-inflammatory mediators were examined for evaluating the hepatoprotective effects of quercetins in hepG2 cells. The results revealed that quercetin and its glucoside derivatives significantly prevented ethanol-induced hepatotoxicity by decreasing hepatic aminotransferase activities and inflammatory response in HepG2 cells. Moreover, the quercetins significantly induced detoxifying enzymes via the nuclear accumulation of the NF-E2-related factor 2 (Nrf2) and induction of antioxidant response element (ARE) gene. These hepatoprotective activities were observed to be more effective with quercetin aglycone than quercetin glucosides. From the above findings, the present study imply that quercetin aglycone may have a vital function in the therapeutic and preventive strategies of alcoholic liver diseases. PRACTICAL APPLICATIONS: Quercetin is commonly present in fruits and vegetables as aglycone and glucoside-derived forms. In the present study, quercetin and its glycosides was shown to alleviate oxidative stress, glutathione depletion, and pro-inflammatory cytokines in alcohol-induced HepG2 cells via the Nrf2/ARE antioxidant pathway. Moreover, quercetin aglycone had better protective effects against alcohol-induced liver damage in vitro, compared to its glycosylated form. The present study proposed that quercetin aglycone may be a more efficient hepatoprotective agent than its glucoside derivatives such as rutin in the amelioration of alcohol-induced liver diseases.

Evaluation of antioxidant and hepatoprotective property of ethanolic extract of curculigoorchioides in albino rats

Background: Liver, the largest organ invertebrate body, it the major site of intense metabolic activities. Being the largest chemical factory of the body, the liver performs innumerable functions. The functional units of liver are called either hepatic or classic lobules or acini. The hepatic lobules consist largely of parenchymal or epithelial glandular cells called hepatocytes, which are arranged as interconnected plates or laminae.Methods: All the animal experiments were conducted according to the ethical norms approved by Ministry of Social Justices and Empowerment, Government of India, and Institutional Animal Ethical Committee guidelines. Fifteen rats were selected for this study and randomly divided into three groups of five each. Group I include control rats that received isocarolic quantity of sucrose in the same volume as experimental rats that received ethanol. Group II includes ethanol treated rats. Ethanol was administered daily at regular intervals by gastric intubation at a dose of as 20% aqueous solution 1 ml for 60 days. Group III includes ethanol (1ml of 25%) + Curculigoorchioides rhizome (80mg/kg b.wt) treated rats for 60 days, daily at regular intervals by gastric intubation.Results: The effect of ethanol alone and ethanol+curculigoorchioides rhizome extract (combined) on adult male rat liver metabolism were assessed in the present study and compared with the control rate. The mean body weight of ethanol treated rats was lesser than control and ethanol+curculigoorchioides rhizome extract treated rats. (Table 1, Figure 1) Data on liver weight from control, ethanol alone and ethanol+curculigoorchioides extract (combined) treated rats did not show much variation (Table 1, Figure 2).Conclusions: The effect of curculigo orchioides rizhomes extract+ethanol (combined) on adult male rat liver metabolism was assessed in the present study and compared with control and ethanol alone treated rats. The administration of ethanol accelerates the glycogenolysis and drastically reduced the hepatic glycogen content. The hepatic transaminase activity was swayed by ethanol treatment and reverted to normalcy by combined treatment. Elevated levels of serum enzyme are indicative of cellular leakage and loss of functional integrity of cell membrane in liver. The reversal of altered transaminase activities to normal by plant extract supplementation suggest its hepatoprotective action.

Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.

Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.

MONITORING OF THE EFFICACY AND SAFETY OF HIGH-DOSE ATORVASTATIN IN ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

Aim. To study the effectiveness of achievement of lipid profile target levels and safety of therapy with atorvastatin in different doses in patients with acute ST-segment elevation myocardial infarction (STEMI). Material and methods. The open prospective controlled single-center study included 90 patients with STEMI aged 32 to 65 years. In the first 24-96 hours from the disease onset the patients were randomized into two groups: the first group included 43 patients who received high-dose statin therapy – atorvastatin 80 mg/day (Group 1), the second group (Group 2) – 47 patients receiving atorvastatin 20 mg/day. Examination of patients with STEMI included the assessment of plasma lipid profile, blood levels of hepatic transaminases, creatine phosphokinase (CPK), C-reactive protein (CRP), brain natriuretic peptide (BNP), creatinine, glucose and glomerular filtration rate calculation. Results. A decrease in the level of low density cholesterol (LDC) by 52.4% (p 50% from the baseline – in another 26%. LDC decreased by 33% in Group 2 (p 50% – in 15% of patients. After 24 weeks, a statistically significant decrease in hepatic transaminase activity was found in the both groups in comparison with the baseline level. The level of CRP decreased 9.1 times (p<0.001) in Group 1, and 7.8 times (p<0.001) – in Group 2. Reduction in the level of BNP was also found in Group 1 by 60% (p=0.005), and in Group 2 – by 33.8% (p<0.001). The levels of CPK, creatinine and GFR in the both groups did not change. A comparable decrease in fasting glycemia was found after 24 weeks in the both groups. Conclusion. The revealed lipid-lowering and pleiotropic effects confirm the necessity of using atorvastatin 80 mg. The absence of changes in the level of transaminases, CPK, serious adverse effects indicates the safety of the use of high-dose statin therapy in STEMI patients for the secondary prevention of cardiovascular events.

Risk factors for adverse pregnancy outcomes in women with intrahepatic cholestasis of pregnant women

Intrahepatic cholestasis of pregnant women (ICPW) is associated with an increased risk of complications of pregnancy. Objective prognostic markers of adverse pregnancy outcomes except for a high level of bile acids (BA) in the mother's blood serum, exceeding 40 μmol/l, do not currently exist. However, the determination of the BA levels is not available in all laboratories, which indicates the need to search for other informative prognostic markers of complications of pregnancy in patients with ICPW. Objective: to determine the risk factors for adverse pregnancy outcomes in ICPW. Materials and methods. A prospective study included 97 pregnant women diagnosed with ICPW. The diagnosis was established with an increase in the serum level of the BA in excess of 10 μmol/l. Patients underwent clinical and laboratory examinations with assessment of biochemical markers of liver damage, antioxidant status (determination of superoxide dismutase, glutathione peroxidase, selenium, zinc level). Biochemical indices and severity of pruritus were assessed at the time of diagnosis of ICPW, after 1 and 2 weeks of treatment with ursodeoxycholic acid (UDCA) at a dose of 500 mg to 2 g per day. In the study of perinatal outcomes, the term of delivery, the method of delivery, the presence of signs of intrauterine fetal hypoxia, the state of the fetus at the time of birth were taken into account. Results of the study. In the observed group of patients, the incidence of preterm birth was 31.9%, intrauterine fetal hypoxia 29.9%, pre-eclampsia 23.7%, the need for a cesarean section due to the development of pregnancy complications arose in 40 (41.2%) cases. The risk factors for complications of pregnancy in patients with ICPW were: early onset and longer duration of ICPW, reactivation of cholestasis after its regression against the background of UDCA treatment and less effective treatment of skin itching in patients with manifest forms of ICPW. The laboratory markers of adverse pregnancy outcomes were a high level of maternal total serum BA and a low efficiency of its reduction against the background of treatment, a slow rate of decrease in hepatic transaminase activity against the background of treatment, a low level of antioxidant protection enzymes. The use of sex hormones during pregnancy promoted more frequent development of preeclampsia and increased the frequency of indications for cesarean delivery. The conclusion. Patients with early manifestation of ICPW and reactivation of cholestasis after its regression on the background of treatment, low effectiveness of treatment of pruritus, and also taking drugs of sex hormones require special attention and active management in connection with an increased risk of complications of pregnancy. It is advisable to carry out dynamic monitoring of the level of BA, hepatic transaminases and antioxidant enzymes in dynamics against the backdrop of treatment with ICPW to assess the effectiveness of treatment and timely prediction of possible complications of pregnancy.

In situ evaluation of the toxicological impact of a wastewater effluent on the fish Prochilodus lineatus: biochemical and histological assessment

Sewage effluents are the most important source of emergent pollutants in the aquatic environment. In the present study the toxicological impact of an untreated sewage effluent on the Prochilodus lineatus fish was assessed under field conditions using a caging experiment. The biomarkers which were measured here involved oxidative stress markers, hepatic function parameters, neurotoxicity indicators, energy reserves, histological alterations and brain cell proliferation. In addition, water quality parameters including the occurrence of some human pharmaceuticals were measured. Juveniles of P. lineatus were caged for 15days at three sites: the effluent site, and 2km upstream and downstream from the effluent discharge. Caffeine, atenolol, carbamazepine, enalapril and sildenafil were detected in water river samples. The increased activation of caspase-3 and the decreased cell proliferation in the diencephalon showed that the brain of fish caged at the effluent was affected. These fish also displayed a rise in hepatic transaminase activity, and oxidative stress in liver and gills which was evidenced by an increased lipid peroxidation and activation of antioxidant enzymes. At tissue level, increased glycogen and decreased lipid contents in liver as well as the highest indexes of hepatic lesions were also observed in the fish caged at the effluent. Both biochemical and histopathological findings demonstrated that effects were more severe on the liver of such fish than on their gills. The in situ exposure method carried out in our study makes it possible to observe the real effects of the sewage effluent on fish. Furthermore, our results also provide a better understanding of the harmful effects of wastewater effluents on the aquatic wildlife.

ОСОБЛИВОСТІ КЛІНІЧНОГО ПЕРЕБІГУ АРТЕРІАЛЬНОЇ ГІПЕРТЕНЗІЇ НА ТЛІ ОЖИРІННЯ ТА НЕАЛКОГОЛЬНОЇ ЖИРОВОЇ ХВОРОБИ ПЕЧІНКИ ЗАЛЕЖНО ВІД ГЕНДЕРНИХ ОСОБЛИВОСТЕЙ

В Україні у структурі загальної смертності на частку серцево-судинних захворювань (ССЗ) припадає 62,5–63,4 %. Зокрема, не менш ніж 75–80 % випадків смерті від ССЗ пов’язані з атеросклеротичним ураження кровоносних судин, а саме: з артеріальною гіпертензією (АГ), інфарктом міокарда, інсультом.Мета дослідження – провести порівняльну оцінку антропометричних, інструментальних та лабораторних показників у пацієнтів з артеріальною гіпертензією, поєднаною із ожирінням та неалкогольним стеатогепатитом залежно від гендерних особливостей.Матеріали і методи. Обстежено 110 хворих, яких поділили на групи за гендерною ознакою. Чоловіків було 42 (38,2 %), жінок – 68 (61,8 %). Пацієнтам проведено антропометричні та низку інструментальних і лабораторних досліджень.Результати досліджень та їх обговорення. Порівнюючи антропометричні показники, виявлено, що за зростом, масою та окружністю талії достовірно переважали чоловіки. Однак за середнім значенням ІМТ не встановлено достовірної різниці між чоловіками та жінками, відповідно (32,94±0,54) кг/м2 у чоловіків проти (34,32±0,41) кг/м2 у жінок. За даними ехокардіографії відзначено гіпертрофію лівого шлуночка і лівого передсердя однаково у чоловіків і жінок, що корелює зі зростанням індексу маси тіла однаково у них. Середні рівні загального холестерину, ліпопротеїдів високої щільності, ліпопротеїдів середньої щільності та тригліцеридів, як і рівень загального білірубіну, серед чоловіків і жінок вірогідно не відрізнялися. Відзначено певні відмінності рівнів печінкових трансаміназ. Середнє значення АЛТ у чоловіків становило (1,97±0,82) ммоль/(год·л), у жінок – (0,64±0,05) ммоль/(год·л). Рівень АСТ теж був вищий у чоловіків ((1,74±0,81) ммоль/(год·л) проти (0,53±0,02) ммоль/ (год·л), що вказувало на частіше виникнення стеатогепатиту саме у них. У жінок середня концентрація лептину становила (45,63±9,06) нг/мл і була вищою, ніж у чоловіків (35,94±8,12) нг/мл. Показники рівня інтерлейкіну-6 серед жінок і чоловіків достовірно не відрізнялися і становили (8,46±1,02) пг/мл і (7,98±0,86) пг/мл відповідно. За результатами 13С-метацетинового дихального тесту швидкість метаболізму серед жінок і чоловіків достовірно не відрізнялася.Висновки. У пацієнтів з артеріальною гіпертензією, поєднаною з ожирінням та неалкогольним стеатогепатитом, не відзначено гендерних відмінностей при антропометричних обстеженнях, при ультрасонографії серця і печінки, а також у ліпідограмі. Діагностовано достовірне підвищення середніх значень рівнів печінкових трансаміназ у чоловіків, що вказувало на частіше виникнення в них стеатогепатиту. В жінок відзначено достовірне підвищення рівня лептину.

Magnesium isoglycyrrhizinate shows hepatoprotective effects in a cyclophosphamide-induced model of hepatic injury.

The purpose of the current study was to investigate the effect of Magnesium Isoglycyrrhizinate (GM) on cyclophosphamide (CP)-induced hepatic injury in vivo and in vitro. The results demonstrated that GM exerted a protective effect on CP-induced acute liver injury, as evidenced by the alleviations of hepatic pathological damage and serum transaminase activities. Meantime, GM attenuated serum and HepG2 cell supernatant levels of TNF-α, IL-6, IL-1β, SOD and MDA. Western blot results presented that GM down-regulated the expressions of the microtubule associated protein 1A/1B-light chain 3 (LC3), Lysosome associated membrane protein-1 (LAMP-1), p-phosphatidylinositol 3-kinase (PI3K), p-protein Kinase B(Akt), p-mechanistic target of rapamycin(mTOR), p-ribosomal protein S6 kinase 70 kDa (p70S6K), p-4E binding protein 1(4EBP1), p- inhibitor of NF-κB(IκB)α and p-nuclear factor kappa B(NF-κB)p65 in CP-stimulated hepatic tissue and HepG2 cells. Taken together, our results suggested that GM showed beneficial effect on CP-induced liver injury through NF-κB-mediated inflammation and PI3K/Akt/mTOR/p70S6K/4EBP1 axis-mediated autophagy in vivo and in vitro.

Transcriptome sequencing reveals prenatal PFOS exposure on liver disorders

Perfluorooctane sulfonate (PFOS), a hepatic toxicant and a potential hepatocarcinogen, is commonly used in industrial products. The widespread contamination of PFOS in human maternal and cord blood has raised concerns about its potential risks to the fetus. It is believed that adverse environmental exposure during the critical period of embryo development can have long-lasting consequences in later life. In this report, we used transcriptome sequencing, followed by bioinformatics analysis, to elucidate the potential hepatotoxic and hepatocarcinogenic effects of prenatal PFOS exposure in the fetus. Our results demonstrated that prenatal PFOS exposure could activate the synthesis and metabolism of fatty acids and lipids, leading to liver damage and interference with liver development in the fetus. In addition, a number of cancer-promoting signaling pathways, including Wnt/β-catenin, Rac, and TGF-β, were found to be activated in the fetal liver. More importantly, hepatic transaminase activity, including aspartate aminotransferase and alanine transaminase activity, was induced in the liver of mice offspring after prenatal PFOS exposure. For the first time, our results demonstrate that the hepatotoxic effects of prenatal exposure to PFOS may predispose to a long-term liver disorder in the offspring.

COMBINATION THERAPY OF HIGH-RISK PATIENTS IN REAL CLINICAL PRACTICE. RESULTS OF SYNERGY STUDY. PART 1. ANTIHYPERTENSIVE BRANCH

Aim. To study the efficacy and safety of the use of combined antihypertensive therapy with perindopril (as monotherapy or as a fixed combination with amlodipine or indapamide) together with lipid-lowering therapy with rosuvastatin, and to assess the level of satisfaction of doctors with the efficacy and safety of these combinations. Material and methods. 24 008 patients with arterial hypertension (HT) and dyslipidemia were included into the multicentre observational study. Researchers were free to choose a group of drugs and a prescription schedule. Inclusion criteria: age ≥18 years; the confirmed HT; combined therapy, including perindopril (monotherapy or fixed combination with indapamide or amlodipine) and rosuvastatin. The total duration of the study was 8 months (2 visits). At each visit, all patients underwent an office blood pressure (BP) and heart rate (HR) measurement, electrocardiogram registration, and assessment of lipids, electrolytes, creatinine, uric acid blood concentrations, and hepatic transaminase activity. Results. 10 330 men (43%) and 13 678 women (57%) were included into the study. The mean age of the patients was 61.83Ѓ}11.20 years. Ischemic heart disease was found in 9 792 (41%) patients, the history of myocardial infarction – in 12%, the history of stroke – in 6%, atrial fibrillation – in 2 428 (10%), chronic heart failure – in 15 449 (64%), diabetes mellitus – in 6 037 (25%) patients. Previous antihypertensive therapy was not available in 2 504 patients. A significant decrease in systolic and diastolic BP, HR was detected at visit 2 in patients using perindopril containing drugs (monodrug, fixed combinations with indapamide or amlodipine). Target systolic BP levels were achieved in 95% of patients with perindopril monotherapy, in 91% – with a fixed combination of perindjpril/indapamide, and in 88.6% – with perindopril/amlodipine. Doctors noted high satisfaction with the therapy. According to safety assessment the average score for perindopril monotherapy was 9.64, for a fixed combination of perindopril/indapamide – 9.61, for a fixed combination of perindopril/amlodipine – 9.64. Conclusion. Some aspects of the efficacy and safety of antihypertensive therapy in the SYNERGY study are discussed in this article. The use of combination therapy is associated with high efficacy, greater patient adherence to treatment and a lower incidence of discontinuation. All these provisions were confirmed in the SYNERGY study.