Serum Alanine Aminotransferase Levels Research Articles

A new model of portal vein thrombosis in rats with cirrhosis induced by partial portal vein ligation plus carbon tetrachloride and intervened with rivaroxaban

Background and aimsPortal vein thrombosis (PVT) is a common complication of liver cirrhosis that can aggravate portal hypertension. However, there are features of both PVT and cirrhosis that are not recapitulated in most current animal models. In this study, we aimed to establish a stable animal model of PVT and cirrhosis, intervene with anticoagulant, and explore the related mechanism.MethodsFirst, 49 male SD rats received partial portal vein ligation (PPVL), and 44 survival rats were divided into 6 groups: PPVL control group; 4-week, 6 -week, 8-week, and 10-week model group; and the rivaroxaban (RIVA)-treated group. The rats were intoxicated with or without carbon tetrachloride (CCl4) for 4–10 weeks. Seven normal rats were used as the normal controls. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and parameters for blood coagulation were all assayed with kits. Liver inflammation, collagen deposition and hydroxyproline (Hyp) levels were also measured. The extrahepatic macro-PVT was observed via portal vein HE staining, etc. The intrahepatic microthrombi was stained via fibrin immunohistochemistry. The portal blood flow velocity (PBFV) and diameter were detected via color Doppler ultrasound. Vascular endothelial injury was evaluated by von Willebrand Factor (vWF) immunofluorescence. Fibrinolytic activity was estimated by western blot analysis of fibrin and plasminogen activator inhibitor-1 (PAI-1).ResultsAfter PPVL surgery and 10 weeks of CCl4 intoxication, a rat model that exhibited characteristics of both cirrhosis and extra and intrahepatic thrombi was established. In cirrhotic rats with PVT, the PBFV decreased, both factors of pro- and anti-coagulation decreased, but with relative hypercoagulable state, vascular endothelial injured, and fibrinolytic activity decreased. RIVA-treated rats had improved coagulation function, increased PBFV and attenuated thrombi. This effect was related to the improvements in endothelial injury and fibrinolytic activity.ConclusionsA new rat model of PVT with cirrhosis was established through partial portal vein ligation plus CCl4 intoxication, with the characteristics of macrothrombi at portal veins and microthrombi in hepatic sinusoids, as well as liver cirrhosis. Rivaroxaban could attenuate PVT in cirrhosis in the model rats. The underlying mechanisms of PVT formation in the rat model and pharmacological action of rivaroxaban are related to the regulation of portal blood flow, coagulant factors, and vascular endothelial cell function.

Effect of grape-derived products on the serum levels of enzymes mainly produced by the liver: A systematic review and meta-analysis of parallel randomized controlled trials.

In recent years, an increase in the incidence of liver diseases has been reported all over the world. This study aims to comprehensively summarize and quantitatively analyze the existing evidence concerning the effectiveness of grape-derived products on liver enzymes through a systematic review and meta-analytic approach. PubMed, Scopus, Cochrane Library, and ISI Web of Science were comprehensively searched until January 2024. Articles that reported the effect of grape-derived products on serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels were included. Weighted mean differences (WMDs) were pooled using a random-effects model. Nine studies were included in the meta-analysis. The results revealed that grape-derived products did not significantly change the concentrations of ALT (WMD: -2.70 IU/L, 95% CI: -6.14 to 0.75, p = 0.12), and AST (WMD: -1.42 IU/L, 95% CI: -3.54 to 0.70, p = 0.18). However, a significant reduction was observed in serum ALP levels (WMD: -5.49 IU/L, 95% CI: -9.57 to -1.4, p = 0.008). The present findings suggest that grape-derived products positively influence serum ALP levels among adults. However, a more comprehensive decision necessitates additional studies.

Therapeutic Potential of Silymarin in Mitigating Paclitaxel-Induced Hepatotoxicity and Nephrotoxicity: Insights into Oxidative Stress, Inflammation, and Apoptosis in Rats.

Paclitaxel (PAX) is a widely used chemotherapy drug for various cancer types but often induces significant toxicity in multiple organ systems. Silymarin (SIL), a natural flavonoid, has shown therapeutic potential due to its multiple benefits. To evaluate the therapeutic efficacy of SIL in mitigating liver and kidney damage induced by PAX in rats, focusing on oxidative stress, inflammation, and apoptosis pathways. Experimental animal model. The study included 28 male Wistar rats aged 12-14 weeks weighing 270-300 g. The rats were divided into four groups: control, SIL, PAX, and PAX + SIL, with seven in each group. The rats received intraperitoneal (i.p.) injections at a dose of 2 mg per kilogram of body weight of PAX for 5 successive days, followed by oral gavage with 200 mg/kg body mass of SIL for 10 uninterrupted days. We examined the effect of SIL on specific serum biochemical parameters using an autoanalyzer and rat-specific kits. The spectrophotometric methods was used to investigate oxidative stress indicators in kidney and liver tissues. Aquaporin-2 (AQP-2), B-cell lymphoma-2 (Bcl-2), cysteine aspartate-specific protease-3 (caspase-3), interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), and streptavidin-biotin staining were used to assess immunoreactivity in PAX-induced liver and kidney injury models. SIL treatment significantly reduced serum levels of alanine aminotransferase, aspartate aminotransferase, creatinine, urea, and C-reactive protein, indicating its effectiveness in treating PAX-induced liver and kidney injury. SIL treatment significantly reduced oxidative stress by increasing essential antioxidant parameters, such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione. It also reduced malondialdehyde levels in liver and kidney tissues of SIL-PAX groups (p < 0.05). SIL administration reduced NF-κB, caspase-3, and IL-6 expression while increasing Bcl-2 and AQP2 levels in liver and kidney tissues of rats treated with SIL and PAX (p < 0.05). Our findings indicate the potential of SIL to alleviate PAX-induced liver and kidney damage in rats by reducing oxidative stress, inflammation, and apoptotic processes.

A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids.

Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.

Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis.

Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. l-carnitine (2g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.

Presence of eimerias in weaned alpacas and control alternative without causing liver damage

Considering eimeriosisin alpacasitis a fatal disease, raising the aim of providing an alternative to prophylactic control in alpacas. 30 weaned alpacas from CICAS “La Raya” of Cusco in August 2022were evaluated. These have been distributed in 3 groups of 10 alpacas. Toltrazuril was administered: group1(G1) 15 mg/kpv, group2 (G2) 22.5 mg/kpv and group3 (G3) control. Qualitative coproparasitological analysis of concentration by flotation. And quantitative analysis has been carried out using the modified McMaster method pre and post treatment. Possible liver damage was evidenced by serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). As results, 93.33% of weaned alpacas have presented eimeriosis. It has been shown a higher prevalence of E. macusaniensis(63.33%). In addition, 22.5 mg/kpv Toltrazuril partially controled E. macusaniensis. While 15 and 22.5 mg/kpv effectively control E. lamae. Furthermore, serum AST and ALT levels were 5.7 IU/L and 195.8 IU/L,respectively, post treatment with 22.5 mg/kpv Toltrazuril. In conclusion, Toltrazuril manages to control pathogenic eimeriae in alpacas, partially E. macusaniensis; buteffectively small eimeriae such as E. lamae. These doses do not alter liver function in weaned alpacas.

Ameliorative effect of bofutsushosan (Fangfengtongshengsan) extract on the progression of aging-induced obesity.

This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid-albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.

MiR-199-5p mediates the regulation of autophagy by targeting mTOR signaling and involvement in ammonia detoxification under ammonia stress in yellow catfish (Pelteobagrus fulvidraco)

Ammonia is a widely distributed hazardous aquatic pollutant that poses a threat to the development of aquatic organisms. A two-stage study was carried out to the response of yellow catfish to ammonia stress.At stage 1, yellow catfish were subjected to 0 mg/L total ammonia nitrogen (T-AN, CON group) and 125 mg/L T-AN (AM group) for 96 h, respectively. At stage 2, yellow catfish in AM group were transferred to water containing 0 mg/L T-AN for a 48-h recovery experiment (AMR group). Ammonia exposure significantly increases serum ammonia (SA), total cholesterol (T-CHO), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels, while decreases glucose (Glu) level. Only SA, GLU, TCHO, and AST returned to normal levels in AMR group, while extensive hepatocyte necrosis and vacuolization persisted. The results showed that the liver possesses a certain degree of ammonia-lowering capacity, yet ammonia-induced liver damage is irreversible. Ammonia stress-induced 486 down-regulated and 18 up-regulated microRNAs (miRNAs). Functional enrichment analysis of the top 10 miRNAs highlighted significant effects of ammonia on the “mTOR signaling pathway” and “autophagy-animals”. Furthermore, the significant negative correlation between the expression levels of miR-199-5p and mTOR suggests that mTOR as a potential target gene of miR-199-5p. The levels of LC3B, autophagosomes (AP), and autolysosomes (AL) in the AM group decreased significantly after 24 h of ammonia stress but returned to baseline after 96 h. Additionally, increased numbers of AP and AL were observed in the AMR group, suggesting that hepatic autophagy is initially suppressed under ammonia stress, followed by spontaneous recovery. This study also found that the expression levels of urea and glutamine synthesis-related genes (cps 1; arg; otc; ass; asl, and gs) significantly increased in the AM and AMR groups. Additionally, the contents of urea and glutamine in the liver was significantly elevated in the AM group. This indicates a simultaneous occurrence of urea and glutamine synthesis with the activation of autophagy during ammonia detoxification. The miR-199-5p/mTOR axis may regulate liver autophagy, potentially contributing to ammonia detoxification. The study has provided novel targets for enhancing ammonia tolerance in fish through nutritional regulation.

Spontaneous clearance of serum HCV-RNA after splenectomy in a patient with HCV-related liver cirrhosis and portal hypertension: a case report

BackgroundSpontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy reportedly has a beneficial effect on T cell immune function in patients with cirrhosis. To the best of our knowledge, the present report is the first to describe spontaneous clearance of serum HCV-RNA within 1 year after splenectomy in a patient with cirrhosis.Case presentationA 55-year-old man with HCV cirrhosis was transferred to our institution with advanced pancytopenia, splenomegaly, and gastric varices. He had a 1-year history of ascites, edema, and general fatigue. The patient had a Child–Pugh score of 8 and serological type 1 HCV; the HCV-RNA level was 4.7 log IU/mL. Contrast-enhanced computed tomography showed gastric varices and marked splenomegaly (estimated spleen volume of 2175 mL). Esophagogastroduodenoscopy revealed enlarged gastric varices with no red color sign, and the varices were larger than those 1 year prior. He was diagnosed with decompensated HCV-related liver cirrhosis and portal hypertension. We considered direct-acting antiviral (DAA) therapy; however, DAA therapy was not approved in Japan for patients with decompensated cirrhosis at that time. Hand-assisted laparoscopic splenectomy was performed to improve the worsening portal hypertension. Further, we planned the initiation of DAA therapy after surgery, when such therapy would become available. DAA therapy was approved 1 year after splenectomy. At that time, we measured the HCV-RNA level before the initiation of DAA therapy; unexpectedly, however, serum HCV-RNA was not detectable, and the virus continued to disappear during the following 4 years. His liver function (total bilirubin, albumin, and prothrombin time) and pancytopenia improved during the 5 years postoperatively. The serum aspartate and alanine aminotransferase levels normalized between 1 and 5 years postoperatively. Esophagogastroduodenoscopy showed no change in the gastric varices during the 5 years after surgery. The patient remained asymptomatic and continued to do well.ConclusionsWe have presented a case of spontaneous clearance of HCV-RNA after splenectomy in a patient with cirrhosis and portal hypertension. Splenectomy may be associated with disappearance of HCV-RNA based on previous reports. More cases should be accumulated and evaluated.

[Arbutin ameliorates liver fibrosis in mice by inhibiting macrophage recruitment and regulating the Akt/NF-κB and Smad signaling pathways].

To investigate the protective effect of arbutin against CCl4-induced hepatic fibrosis in mice and explore the underlying mechanisms. Twenty-four C57BL/6 mice were randomly divided into control group, model group, and low- and high-dose arbutin treatment (25 and 50 mg/kg, respectively) groups. Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4, and arbutin was administered daily via gavage for 6 weeks. After the treatments, serum biochemical parameters of the mice were tested, and liver tissues were taken for HE staining, Sirius Red staining and immunohistochemical staining. RT-qPCR was used to detect the mRNA levels of α-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a, and Western blotting was performed to detect α-SMA protein expression in the liver tissues. In the cell experiment, the effect of arbutin treatment for 24 h on THP-1 and RAW264.7 cell migration and recruitment was examined using Transwell migration assay and DAPI staining; The changes in protein levels of Akt, p65, Smad3, p-Akt, p-p65, p-Smad3 and α-SMA in arbutintreated LX-2 cells were detected with Western blotting. Arbutin treatment significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels, alleviated liver tissue damage and collagen deposition, and reduced macrophage infiltration and α-SMA protein expression in the liver of the mouse models (P < 0.05 or 0.001). Arbutin treatment also significantly reduced CCl4-induced elevation of a-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a mRNA levels in mice (P < 0.05). In the cell experiment, arbutin treatment obviously inhibited migration and recruitment of THP-1 and RAW264.7 cells and lowered the phosphorylation levels of Akt, p65 and Smad3 and the protein expression level of α-SMA in LX-2 cells. Arbutin ameliorates liver inflammation and fibrosis in mice by inhibiting hepatic stellate cell activation via reducing macrophage recruitment and infiltration and suppressing activation of the Akt/NF-κB and Smad signaling pathways.

Salvia miltiorrhiza polysaccharide mitigates AFB1-induced liver injury in rabbits

Aflatoxin B1 (AFB1) is one of the common dietary contaminants worldwide, which can harm the liver of humans and animals. Salvia miltiorrhiza polysaccharide (SMP) is a natural plant-derived polysaccharide with numerous pharmacological activities, including hepatoprotective properties. The purpose of this study is to explore the intervention effect of SMP on AFB1-induced liver injury and its underlying mechanisms in rabbits. The rabbits were administered AFB1 (25 μg/kg/feed) and or treatment with SMP (300, 600, 900 mg/kg/feed) for 42 days. The results showed that SMP effectively alleviated the negative impact of AFB1 on rabbits' productivity by increasing average daily weight gain (ADG) and feed conversion rate (FCR). SMP reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in serum, ameliorating AFB1-induced hepatic pathological changes. Additionally, SMP enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) activity, and inhibited reactive oxygen species (ROS), malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression, thus mitigating AFB1-induced oxidative stress and inflammatory responses. Moreover, SMP upregulated the expression of nuclear factor E2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NADPH quinone oxidoreductase 1 (NQO1) and B-cell lymphoma 2 (Bcl2) while downregulating kelch like ECH associated protein 1 (Keap1), cytochrome c (cyt.c), caspase9, caspase3, and Bcl-2-associated X protein (Bax) expression, thereby inhibiting AFB1-induced hepatocyte apoptosis. Consequently, our findings conclude that SMP can mitigate AFB1-induced liver damage by activating the Nrf2/HO-1 pathway and inhibiting mitochondria-dependent apoptotic pathway in rabbits.

Tarragon (Artemisia dracunculus) Essential Oil at Optimized Dietary Levels Prompted Growth, Immunity, and Resistance to Enteric Red-Mouth Disease in the Rainbow Trout (Oncorhynchus mykiss)

Fingerlings of the rainbow trout, Oncorhynchus mykiss (n = 300, 10.63 ± 0.6 g), were fed tarragon (Artemisia dracunculus) essential oil (TGO) for 2 months to examine its effects on growth properties, immunity, and resistance to Yersinia ruckeri infection. The treatments were control or TG1, TG2 (fed 0.5% TGO), TG3 (1% TGO), and TG4 (2% TGO). According to the results, an improvement was observed in growth parameters in all TGO-treated groups compared to the control (P&lt;0.05). The digestive enzyme activities (protease and lipase) were significantly elevated in response to dietary TGO (P&lt;0.05). The immune system of the fish was enhanced by TGO, as it stimulated the immune parameters in serum (lysozyme, myeloperoxidase (MPO), alternative complement (ACH50), Ig) and mucus (lysozyme, protease, ACH50, Ig) (P&lt;0.05). The treatments, TG3 and TG4, showed more immune performance in response to TGO (P&lt;0.05). The fish in TG2 treatment had a higher levels of serum total protein than other groups (P&lt;0.05). The concentration of triglycerides (TRIG) and cholesterol (CHOL) in serum significantly decreased (P&lt;0.05) in response to TGO, as the lowest levels were observed in the treatment, TG3. The antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)) of serum elevated in TGO-treated fish, with the maximum values for the TG4 group (P&lt;0.05). TGO reduced (P&lt;0.05) alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in serum. After bacterial challenge, the TGO-treated fish showed lower mortality compared to the control, where the lowest mortality was observed in TG4 (P&lt;0.05). In conclusion, TGO improved growth, immunity, and survival after bacterial challenge in the rainbow trout, with more performance in fish fed 1%–2% TGO.

The interplay between diabetes and non-alcoholic fatty liver disease: a cross-sectional study from Pakistan.

Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic deposition of fat in the liver, in the absence of other secondary causes of fat buildup. The relationship between NAFLD, including alanine aminotransferase (ALT), and glycated haemoglobin (HbA1c), is important for predicting the severity of disease and prognosis. This study aims to investigate the association of HbA1c in type 2 diabetes mellitus (T2DM) patients with NAFLD via measuring the ALT levels. This retrospective cross-sectional study enroled 130 patients with T2DM and NAFLD. The association between levels of HbA1c and ALT in patients of NAFLD with controlled and uncontrolled T2DM, respectively, was investigated. Stratification was done based on gender and diabetic control, using HbA1c levels as a marker of glycemic control. Serum ALT levels were also compared in both groups. The mean age of the participants was 50.2±5.7 years. The total participants were 130, of which 77 (59.3%) were females and 53 (40.7%) were males. The numbers of patients having uncontrolled T2DM (HbA1c>7%), and controlled T2DM (HbA1c <7%) were 78 (60%) and 52 (40%), respectively. Moreover, 46 (35.3%) females and 32 (24.7%) males had uncontrolled T2DM, and 31 (23.8%) females and 21 (16.2%) males had controlled T2DM. The mean ALT level for uncontrolled and controlled T2DM in female patients was found to be 24.6±3.4 and 13.5±2.4, respectively, (P <0.05). For male patients, it was found to be 54.0±4.9 and 29.1±5.4, respectively (P=0.008). There is a positive association between elevated HbA1c and ALT levels in T2DM patients with NAFLD.

PIM1 inhibitor SMI-4a attenuated concanavalin A-induced acute hepatitis through suppressing inflammatory responses.

Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis. C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB. Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3. In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.

Clinical Efficacy and Safety of Low-Dose Pemafibrate in Patients With Severe Renal Impairment: A Retrospective Study.

The management of hypertriglyceridemia in patients with chronic kidney disease (CKD) is important. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator with less toxic effects on liver and kidney function than those of other fibrates, has recently been approved for the treatment of patients with an estimated glomerular filtration rate (eGFR) lower than 30mL/min/1.73 m2. However, the efficacy and safety of pemafibrate in patients with severe renal impairment have not yet been established. This single-center, retrospective observational study included 12 outpatients with CKD and hypertriglyceridemia, who were newly started on low-dose pemafibrate (0.1 mg/day) treatment between December 2021 and May 2023 and whose eGFRs were less than 30 mL/min/1.73 m2 at baseline. Blood samples were collected before and at 12 weeks after pemafibrate treatment. After 12 weeks of treatment, the serum triglyceride level was significantly decreased, whereas the high-density lipoprotein cholesterol level was significantly increased. The serum alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and uric acid levels were also significantly decreased, without worsening of the eGFR and serum creatinine levels. In the subgroup analysis, there were no significant differences in the changes in clinical parameters regardless of statin use and CKD stage at baseline. Low-dose pemafibrate administration in patients with severe renal impairment resulted in significant improvements in triglyceride, high-density lipoprotein cholesterol, and serum uric acid levels, and liver function, without adverse events.

Effect of dietary fish oil sparing with blended vegetable oils on growth, fatty acid composition and lipid-metabolism-related genes expression in juvenile rainbow trout (Oncorhynchus mykiss)

Abstract A nutritional study was conducted to evaluate the influence of dietary fish oil (FO) sparing by using a mixture of vegetal oils (VO) on rainbow trout (Oncorhynchus mykiss) juveniles (30.0 g). A basal diet was supplemented with the experimental oils at a 10% level, including FO (FO diet), a blend of VO (sunflower, soybean and rapeseed oils with a 1:1:1 ratio), and a mixture (1:1 ratio) of FO and the blends of VO (MIX). In a raceway system, 450 fish were stocked in nine rectangular concrete tanks (50 fish/ tank−1). Three experimental diets, with three replicates each, were offered to fish up to visual satiation for eight weeks. Growth performance did not change among groups (P&gt;0.05). The highest and lowest proportions of n-3 polyunsaturated fatty acids (PUFA), n-3 long chain-PUFA, especially docosahexaenoic acid, and n-3/n-6 PUFA ratio were in the whole body of FO and the VO groups, respectively (P&lt;0.05). Serum catalase and glutathione peroxidase activities in VO group were higher than others. Serum superoxide dismutase activity in fish fed FO and VO diets was higher than MIX group (P&lt;0.05). VO group had higher serum lysozyme, alternative complement pathway, and total immunoglobulin levels than other experimental groups. MIX group had highest serum triglyceride, cholesterol, and low-density lipoproteins. Serum high-density lipoproteins, aspartate aminotransferase, and alanine aminotransferase levels in VO treatment were in the lowest level compared to others (P&lt;0.05). The highest relative transcription levels of fatty acid synthase, delta-6 fatty acyl desaturase, and apolipoprotein b-100 genes were in the liver of fish fed the MIX diet. The relative transcription level of the fatty acid-binding protein1 gene did not change (P&gt;0.05). In summary, the results of this study revealed that dietary FO sparing with VO did not adversely affect the growth and health indices of rainbow trout; nevertheless, it had adverse effects on its nutritional values by reducing whole-body n-3 LC-PUFA content.

Maternal PFOS exposure in mice induces hepatic lipid accumulation and inflammation in adult female offspring: Involvement of microbiome-gut-liver axis and autophagy

Perfluorooctane sulfonates (PFOS) are the persistent organic pollutants. In the present study, 0, 0.3, or 3-mg/kg PFOS were administered to pregnant mice from GD 11 to GD 18. The histopathology of liver and intestine, serum and hepatic lipid levels, lipid metabolism related genes, and gut microbiota were examined in adult female offspring. The results suggested that maternal PFOS exposure increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and induced F4/80+ macrophage infiltration in adult female offspring, in addition to the elevation of TNF-α and IL-1β mRNA levels in low-dose and high-dose groups, respectively. Furthermore, maternal exposure to PFOS increased serum triglyceride (TG) and hepatic total cholesterol (TC) levels, which was associated with the alteration of the process of fatty acid transport and β-oxidation, TG synthesis and transport, cholesterol synthesis and excretion in the liver. The AMPK/mTOR/autophagy signaling was also inhibited in the liver of adult female offspring. Moreover, changes in gut microbiota were also related to lipid metabolism, especially for the Desulfovibrio, Ligilactobacillus, Enterorhabdus, HT002 and Peptococcaceae_unclassified. Additionally, maternal exposure to PFOS decreased mRNA expressions of the tight junction protein and AB+ goblet cells in the colon, while increasing the overproduction of lipopolysaccharides (LPS) and F4/80+ macrophage infiltration. Collectively, maternal PFOS exposure induced liver lipid accumulation and inflammation, which strongly correlated with the disruption of the gut-liver axis and autophagy in adult female offspring, highlighting the persistent adverse effects in offspring exposed to PFOS.

Type I/II Immune Balance Contributes to the Protective Effect of AIF-1 on Hepatic Immunopathology Induced by Schistosoma japonicum in a Transgenic Mouse Model.

Schistosomiasis is the second most debilitating neglected tropical disease in the world. Liver egg granuloma and fibrosis are the main damage of schistosomiasis. In this study, the role of allograft inflammatory factor-1 (AIF-1) in liver pathology and its regulation in immune responses were investigated in a transgenic mouse infected with Schistosoma japonicum. We found that AIF-1 overexpression reduced worm burden and decreased egg granuloma sizes and serum alanine aminotransferase levels, along with inhibited hepatic collagen deposition and serum hydroxyproline levels during S. japonicum infection. Moreover, AIF-1 overexpression resulted in an increased ratio of Th1/Th2, increased levels of IFN-γ and T-bet, and lower levels of GATA-3 in the spleen, accompanied by increased M1 percentages, decreased M2 percentages, and thus a higher ratio of M1/M2 in the peritoneal cavity and liver. AIF-1 induced CD68 and iNOS mRNA expression and protein levels of cytoplasmic p-P38 and nuclear NF-κB, along with enhanced levels of TNF-α and TGF-β in macrophages in vitro. Moreover, the hepatic pathology had a negative correlation with Th1/Th2 and M1/M2 ratios in the infected mice. The findings reveal that the beneficial role of AIF-1 in alleviating hepatic damage is related to restoring type I/II immune balance in S. japonicum infection.

Hepatitis A in Adults: Experience from a Moroccan Hospital Center

Background: In children, hepatitis A virus infection is usually symptom-free and provides long-term immunity. However, in changing socio-economic environments, certain adults encounter infection risks, exposing them to symptomatic illness and complications. This study aims to outline the profile of adult hepatitis A patients. Methods: We conducted a retrospective study from 2017 to 2023, involving all patients aged over 14 years who presented with acute hepatitis and tested positive for anti-HAV antibodies. Demographic, laboratory and clinical data were analyzed. Results: The analysis involved 109 cases (mean age 21 +/- 6 years, 57.8% males). All patients were symptomatic. Among them, 71.6% presented with a pseudo-flu-like syndrome, 89% with jaundice, 50.5% with fever and 30.2% with gastrointestinal symptoms. Thirty patients were hospitalized (26.6%), among them one subfulminant was recorded. Clinically, hepatomegaly was found in 8 patients (7.3%). One patient had presented with a skin rash. Serum alanine aminotransferases levels were more than 50 times the normal range in 47.7% of cases, with an average bilirubin level of 89 mg/l. Severe acute hepatitis was observed in 26.6% of patients. Conclusion: Our findings revealed that over 25% of adult patients experienced severe acute hepatitis, with one patient progressing to acute liver failure. These results underline the importance of raising awareness of hygiene practices and prompt a study of the overall seroprevalence of hepatitis in the adult population in order to improve viral hepatitis prevention and control strategies in the country.

Porphyromonas gingivalis Strain W83 Infection Induces Liver Injury in Experimental Alcohol-Associated Liver Disease (ALD) in Mice

The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.