Liver Injury Research Articles

Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA

BackgroundLiver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders. PurposeThe aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation. MethodsWe established liver fibrosis models in mice using carbon tetrachloride (CCl4) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms. ResultsCK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response. ConclusionCK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.

Lactobacillus plantarum LP104 improved intestinal and brain inflammation by modulating TLR4 pathway and gut flora in alcohol liver injury mice

Lactobacillus plantarum LP104 improved intestinal and brain inflammation by modulating TLR4 pathway and gut flora in alcohol liver injury mice

Efficacy and safety of higher dose rifampicin in adults with presumed drug-susceptible tuberculosis: an updated systematic review and meta-analysis

Tuberculosis (TB) remains a significant cause of mortality globally, yet first-line treatment has hardly changed for fifty years. The dose of rifampicin, the most important drug in this regimen, has been historically based on pragmatic cost- and risk-benefit considerations. Evidence suggests the current recommended dose (8-12mg/kg) may not maximise the potential benefits of this drug. We sought to evaluate the efficacy and safety of higher doses of rifampicin in adults with presumed drug-susceptible TB. In this systematic review we searched MEDLINE, EMBASE, CENTRAL and Global Health databases for randomised controlled trials up to 31 July 2024 of adults with presumed drug-susceptible TB receiving first-line treatment with an intervention of rifampicin doses higher than currently recommended. Meta-analyses were performed using random effects models where background regimens were the same. Risk ratio was used as the measure for treatment effect. Outcomes of interest related to efficacy and safety. Of the 5441 total records identified by our searches, nineteen studies (6332 patients, 31.0% female) were eligible for the systematic review and twelve (3763 patients, 31.0% female) for meta-analysis. Rifampicin doses varied from 8 to 35mg/kg and implementation of the intervention varied between trials. There was no evidence for increased efficacy with higher doses of rifampicin, however the majority of trials investigated minimally increased doses (up to 20mg/kg). At higher doses (>20mg/kg), there may be evidence of increased risk of drug-induced liver injury, albeit with no consistent dose-response relationship. Evidence on the efficacy of higher doses of rifampicin in the first-line regimen for TB remains incomplete. While higher doses appear generally safe, the risk of drug-induced liver injury may be increased above doses of 20mg/kg. Larger clinical trials reporting definitive outcomes are needed to determine whether dosing up to 40mg/kg could safely improve treatment outcomes or reduce duration of first-line therapy. WHO, Wellcome Trust.

Risk factors associated with post-tuberculosis sequelae: a systematic review and meta-analysis

Post-tuberculosis (TB) sequelae present a significant challenge in the management of TB survivors, often leading to persistent health issues even after successful treatment. Identifying risk factors associated with post-TB sequelae is important for improving outcomes and quality of life of TB survivors. This systematic review and meta-analysis aims to identify risk factors associated with long-term physical sequelae among TB survivors. We systematically searched Medline, Embase, PROQUEST, and Scopus for studies on long-term physical sequelae among TB survivors up to December 12, 2023. The primary outcome of interest was to quantify risk factors of long-term physical sequelae (i.e., respiratory, hepatic, hearing, neurological, visual, renal, and musculoskeletal sequelae). We included all forms of TB patients who experienced long-term physical sequelae. We used narrative synthesis for risk factors reported once and random-effect meta-analysis for primary outcomes with two or more studies. Findings were presented with odds ratios (OR) and 95% confidence intervals (CI). Publication bias was assessed using funnel plots and Egger regression, and heterogeneity was examined with a Galbraith radial plot. The protocol was registered on Prospero (CRD42021250909). A total of 73 articles from 28 countries representing 31,553TB-treated patients were included in the narrative synthesis, with 64 of these studies included in the meta-analysis. Risk factors associated with post-TB lung sequelae include older age (OR=1.62, 95% CI: 1.07-2.47), previous TB treatment history (OR=3.43, 95% CI: 2.37-4.97), smoking (OR=1.41, 95% CI: 1.09-1.83), alcohol consumption (OR=1.84, 95% CI: 1.04-3.25), smear-positive pulmonary TB diagnosis (OR=3.11, 95% CI: 1.77-6.44), and the presence of radiographic evidence of pulmonary lesions at the commencement of treatment (OR=2.04, 95% CI: 1.07-3.87). Risk factors associated with post-TB liver injury included pre-existing hepatitis (OR=2.41, 95% CI: 1.16-6.08), previous TB treatment (OR=2.64, 95% CI: 1.22-6.67), hypo-albuminemia (OR=2.10, 95% CI: 1.53-2.88), HIV co-infection (OR=2.72, 95% CI: 1.66-4.46), and CD4 count <200mm3 in HIV-infected individuals (OR=2.03, 95%CI: 1.26-3.27). Risk factors associated with post-TB hearing loss include baseline hearing problems (OR=1.72, 95% CI: 1.30-2.26), and HIV co-infection (OR=3.02, 95% CI: 1.96-4.64). This systematic review and meta-analysis found that long-term physical post-TB sequelae including respiratory, hepatic, and hearing impairment were associated with a range of socio-demographic, behavioral, and clinical factors. Identification of these risk factors will help to identify patients who will benefit from interventions to reduce the burden of suffering from post-TB treatment. Healy Medical Research Raine Foundation, the Australian National Health and Medical Research Council, and Curtin University Higher Degree Research Scholarship fund the study.

Paracetamol is both a friend and a foe: What should a pediatrician know? A clinical case

One of the most common drug-related side effects is hepatotoxicity. The most common cause of severe drug-induced liver injury is acetaminophen (paracetamol), as it is an over-the-counter drug. Paracetamol is safe and effective in children and adolescents at therapeutic doses; however, it is the leading cause of acute liver failure in children (21% of cases) and adults (40%) with overdose. The clinical presentation of toxic liver damage depends on the time elapsed after taking paracetamol and its dose. Symptoms of liver damage are not always obvious but can develop rapidly from day 2 to day 5 after poisoning. The article presents a clinical case of an unintentional overdose of paracetamol in a teenage girl due to non-compliance with the dose and regimen.

Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease. The addition of eltrombopag to immunosuppressive therapy (IST) improves the response rate and response quality of SAAs, but its hepatotoxicity is concerning. Avatrombopag (AVA), another small-molecule thrombopoietin receptor agonist without hepatotoxicity, has unknown efficacy in SAA treatment. This retrospective study aimed to assess the efficacy and safety of AVA, a small-molecule thrombopoietin receptor agonist, when added to IST in SAA patients. A total of 42 patients treated with IST and AVA were compared to a historical cohort of 84 patients receiving IST alone, utilizing propensity score matching. The median age was 31.5 (6.0-67.0) years old in Group A and 26 (16.0-45.0) years old in Group B. At 3 months, Group A showed higher complete response (CR) and overall response (OR) rates than Group B (CR: 19.0% vs. 4.8%, P = 0.024; OR: 54.8% vs. 39.3%, P=0.145). Higher CR and OR rates were also found at 6 months in Group A than in Group B (CR 31.0% vs. 14.3%, P=0.145; OR 71.4% vs. 51.2%, P=0.048). In multivariate analysis of Group A, a shorter interval from disease onset to anti-thymocyte globulin (ATG) treatment (≤6 months) (P=0.005) predicted better responses rate at 6 months. Event free survival was also improved in Group A (60.7% vs. 49.6%). AVA was well-tolerated, with no hepatic injury observed during treatment, even in those with pre-existing hepatic impairment. The addition of AVA to IST improves both the response rate and response quality in SAA patients while ensuring safety.

The novel lipid emulsion Vegaven is well tolerated and elicits distinct biological actions compared with a mixed-oil lipid emulsion containing fish oil:a parenteral nutrition trial in piglets

BackgroundVegaven is a novel lipid emulsion for parenteral nutrition (PN) based on 18-carbon n-3 fatty acids, which elicits liver protection via interleukin-10 (IL10) in the murine model of PN. ObjectiveIn a preclinical model of PN in neonatal piglets, Vegaven was tested for efficacy and safety and compared with a mixed-oil lipid emulsion containing fish-oil (SMOFlipid). Methods4-5-day-old male piglets were randomly allocated to isocaloric isonitrogenous PN for 14 days that varied only by the type of lipid emulsion (Vegaven, N=8; SMOFlipid, N=8). Hepatic IL10 tissue concentration served as primary outcome. Secondary outcomes were organ weights, bile flow, blood analyses, plasma insulin and glucagon concentrations, insulin signaling, proinflammatory cytokines, tissue lipopolysaccharide concentrations, and fatty acid composition of phospholipid fractions in plasma, liver, and brain. ResultsTotal weight gain on trial, organ weights, and bile flow were similar between the Vegaven and the SMOFlipid group. Vegaven elicited higher hepatic IL10 (Δ=148 pg/mg protein, p<0.001) and insulin receptor substrate-2 levels (Δ=0.08 O.D., p=0.012). Plasma insulin concentrations (Δ=1.46 mU/L, p=0.003) and fructosamine (glycated albumin, Δ=12.4 μmol/g protein, p=0.003) were increased in SMOFlipid as compared with Vegaven group, indicating insulin resistance. Higher hepatic injury markers were observed more frequently in the SMOFlipid group compared with the Vegaven group. Lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-6 were increased in pancreatic and brain tissues of SMOFlipid- vs Vegaven-treated piglets. Insulin signaling was reduced in the brains of SMOFlipid-treated piglets. Vegaven and SMOFlipid elicited distinct fatty acid profiles in the phospholipid fractions of the rapidly growing brains, but showed similar accretion of docosahexaenoic acid and arachidonic acid after two weeks of PN. ConclusionsVegaven was well tolerated in this piglet model of PN and demonstrated distinct biological actions compared with SMOFlipid, namely lower liver, pancreas, and brain inflammation, enhanced insulin signaling, and improved whole-body glucose control.

Microplastics exacerbate tissue damage and promote carcinogenesis following liver infection in mice

Cancer is a leading cause of death worldwide, posing a substantial threat to human well-being. Microplastics (MPs) exposure can harm human health and the carcinogenicity of MP remains uncertain. In this study, we investigated carcinogenesis by MPs exposure. We observed MP significantly exacerbated hepatic injury in infectious conditions. In addition, cancer-related p53 and p21 signals are activated by MPs. Analysis of the liver transcriptomic landscape uncovered a noteworthy intensification of the carcinogenesis pathway by MPs compared with pre-infection. The transcription factor SALL2 could act as an oncogenic promoter in the promotion of cancer regulated by MPs. Further, big data analysis presents the correlation between MPs pollution and human hepatocellular carcinoma. This work revealed a toxic amplification effect of the non-bioactive MPs on the bioactive pathogens. This finding provides new insight into understanding the potential toxicity of the MPs.

Assessing the hepatoprotective efficacy of Vitis gracilis Wall. against doxorubicin-induced hepatic injury in rats

Context: Doxorubicin is an anticancer drug that can adversely affect the liver. Therefore, seeking medical attention to manage pain and minimize side effects is crucial. Aims: To evaluate the hepatoprotective potential of Vitis gracilis Wall. nanoherbs against doxorubicin-induced hepatotoxicity. Methods: The study included five treatment groups: T0 (negative control), T+ (positive control with doxorubicin alone), TC (doxorubicin + vitamin C at 0.2 mg/kg body weight/day), T125 (doxorubicin + V. gracilis at 125 mg/kg body weight/day), and T150 (doxorubicin + V. gracilis at 150 mg/kg body weight/day). Doxorubicin, administered intraperitoneally at 0.0019 mg/kg body weight once a week for three weeks, induced hepatotoxicity in the T+ group. Results: Serum transaminases were significantly reduced in the T125 and T150 groups, indicative of the hepatoprotective effects of V. gracilis. Immunohistochemical analysis demonstrated the modulation of key markers, with decreased levels of pro-inflammatory tumor necrosis factor-α and increased levels of anti-inflammatory interleukin 10 in the T125 and T150 groups. The activities of oxidative stress markers, including superoxide dismutase and caspase 3, were favorably influenced by V. gracilis nanoherb treatment. Conclusions: These findings suggest that V. gracilis nanoherbs may effectively attenuate doxorubicin-induced hepatotoxicity, evidenced by biochemical and immunohistochemical changes. This study provides a foundation for further exploration of V. gracilis nanoherbs as a potential adjunctive therapy in preventing chemotherapy-associated liver damage.

HIV Outcomes Among Women Living With HIV Who Experienced Early Sexual Violence Across Four Sub-Saharan African Countries.

Early experiences of sexual violence may influence HIV care and treatment outcomes among women living with HIV (WLHIV). We examined whether self-report by WLHIV of being forced into their first sexual experience was associated with awareness of HIV-positive status, being on antiretroviral therapy (ART) and being virologically suppressed. We conducted a secondary analysis using nationally representative, cross-sectional Population-based HIV Impact Assessment surveys from Lesotho, Malawi, Zambia, and Zimbabwe conducted from 2015 through 2017. Adjusted logistic regression models with survey weights and Taylor series linearization were used to measure the association between forced first sex and 3 HIV outcomes: (1) knowledge of HIV status among all WLHIV, (2) being on ART among WLHIV with known status, and (3) virological suppression among WLHIV on ART. Among WLHIV, 13.9% reported forced first sex. Odds of knowledge of HIV status were not different for WLHIV with forced first sex compared with those without (adjusted odds ratio [aOR], 1.17; 95% CI: 0.95 to 1.45). Women living with HIV with forced first sex had significantly lower odds of being on ART (aOR 0.74, 95% CI: 0.57 to 0.96) but did not have lower odds of virological suppression (aOR 1.06, 95% CI: 0.80 to 1.42) compared with WLHIV without forced first sex. While high proportions of WLHIV were on ART, report of nonconsensual first sex was associated with a lower likelihood of being on ART which may suggest that early life trauma could influence long-term health outcomes.

Posthepatectomy Liver Failure in Patients with Splenomegaly Induced by Induction Chemotherapy for Colorectal Liver Metastases.

With advances in chemotherapy, conversion surgery is often performed for initially unresectable colorectal cancer liver metastasis (CLM). However, unexpected posthepatectomy liver failure (PHLF) is sometimes associated with chemotherapy-associated liver injuries following long-term chemotherapy. We aimed to identify predictive factors for PHLF after conversion surgery for initially unresectable CLM. We retrospectively identified 774 consecutive patients who underwent initial liver resections for histologically confirmed CLMs between 2010 and 2019 at our institute. We enrolled 107 patients with initially unresectable CLMs. Clinicopathological characteristics were evaluated to determine their association with PHLF. Logistic regression analysis was performed to analyze the predictors of PHLF. Among the 107 patients, PHLF occurred in 15 cases (14%). Multivariate analysis revealed that splenomegaly during preoperative chemotherapy (> 135%) was an independent risk factor for PHLF (P = 0.002; odds ratio 14.30; 95% confidence interval 2.69-76.08). In the analysis limited to the splenomegaly group, lower platelet counts, increased blood loss and operative times, and large liver resection areas (> 100 cm2) were significant risk factors for PHLF (P = 0.018, 0.043, 0.020, and 0.024, respectively). Among them, a liver resection area > 100 cm2 can be calculated preoperatively and correlate with a complex hepatectomy. These findings could help predict PHLF after conversion surgery and induction chemotherapy for initially unresectable CLMs. Careful decisions, including detailed procedures and timing of hepatectomy, should be made before conversion hepatectomy in patients who develop splenomegaly after induction chemotherapy and require complex hepatectomies with a large liver resection area.

A comparative study on the clinical efficacy and pregnancy outcomes of methimazole and propylthiouracil in managing pregnancy complicated with hyperthyroidism

The objective of the study was to compare the clinical efficacy and pregnancy outcomes of methimazole and propylthiouracil in managing hyperthyroidism during pregnancy. This retrospective analysis included 100 pregnant women with hyperthyroidism, who were divided into two groups: the methimazole group (Group A) and the propylthiouracil group (Group B). Indicators such as thyroid function, liver function, pregnancy outcomes, and newborn health were closely monitored. The results revealed that both groups experienced a reduction in thyroid function indicators, with Group B showing a more modest decrease. Group B exhibited a higher incidence of liver injury but also achieved more full-term pregnancies. There were no significant differences in adverse reactions, miscarriage rates, or cesarean rates between the two groups. Apgar scores were higher in Group B, while neonatal weights were comparable. We conclude that propylthiouracil improved thyroid function more substantially than methimazole although it was associated with a higher risk of liver injury.

MiR-103–3p attenuates liver injury with severe acute pancreatitis by inhibiting pyroptosis through miR-103–3p/NLRP1 axis

BackgroundSevere acute pancreatitis (SAP) is a common digestive system disorder in clinical practice, and it is often associated with liver damage in patients with severe acute pancreatitis. Several studies have indicated that pyroptosis plays a role in liver damage following severe acute pancreatitis (SAP). However, the precise mechanisms remain unclear. This study aims to elucidate the association and specific mechanisms between liver injury following SAP and pyroptosis, providing theoretical support for research on SAP-induced liver injury. MethodsA rat model of SAP with concomitant liver injury was successfully established. The expression levels of miR-103–3p across different liver tissue groups were quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Bioinformatic analyses and dual-luciferase reporter assays confirmed that NLRP1 is a direct target of miR-103–3p. In vivo assessments of miR-103–3p levels were performed, and the extent of cell pyroptosis during liver injury post-SAP was evaluated through western blotting, qRT-PCR, scanning electron microscopy, histopathology, immunofluorescence, and immunohistochemistry. The role of miR-103–3p in regulating NLRP1-mediated pyroptosis and its impact on SAP-induced liver injury were validated. ResultsThis study reports that following SAP-induced liver injury, the expression of miR-103–3p in liver tissue was significantly decreased, and cell pyroptosis was involved in the process of liver injury. Experimental validation indicated that NLRP1 was a downstream target of miR-103–3p. Overexpression of miR-103–3p in vitro significantly alleviated the severity of liver injury following SAP, while simultaneously inhibiting cell pyroptosis. ConclusionThese findings indicate that pyroptosis may be linked to SAP-induced liver injury and that miR-103–3p mitigates hepatocyte pyroptosis by reducing liver injury through the suppression of NLRP1 expression.

Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles in Liver Injury

Liver injury caused by various factors significantly impacts human health. Stem cell transplantation has potential for enhancing liver functionality, but safety concerns such as immune rejection, tumorigenesis, and the formation of emboli in the lungs remain. Recent studies have shown that stem cells primarily exert their effects through the secretion of extracellular vesicles (EVs). EVs have been shown to play crucial roles in reducing inflammation, preventing cell death, and promoting liver cell proliferation. Additionally, they can function as carriers to deliver targeted drugs to the liver, thereby exerting specific physiological effects. EVs possess several advantages, including structural stability, low immunogenicity, minimal tumorigenicity targeting capabilities, and convenient collection. Consequently, EVs have garnered significant attention from researchers and are expected to become alternative therapeutic agents to stem cell therapy. This article provides a comprehensive review of the current research progress in the use of stem cell-derived EVs in the treatment of liver injury.

Liver Safety of Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: interim Data from a Post-authorization Safety Study

Abstract Background After risk of drug-induced liver injury was detected during tolvaptan clinical development for the treatment of autosomal dominant polycystic kidney disease (ADPKD), a post-marketing pharmacovigilance study was required for EU regulatory approval. Methods This is an interim analysis from a prospective, observational study enrolling patients prescribed tolvaptan for ADPKD in routine clinical practice. Data were obtained through physician records collected during regular care. Per the prescribing label, liver transaminases were to be monitored monthly for the first 18 months of treatment and once every 3 months thereafter. Patients and physicians were required to report adverse events suggestive of serious and potentially fatal liver injury. Data collection was from October 2016–April 2022. Results Of 2074 patients (median follow-up, 528 days), in 75 (3.6%) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 3 x upper limit of normal (ULN) were reported. At data cutoff, the enzyme elevations were confirmed for 65 patients. Among the 65 confirmed patients, in addition to the transaminase elevations, there were 69 adverse events suggestive of liver injury. Tolvaptan was interrupted or withdrawn in 59/65 (90.8%) participants with confirmed ALT or AST ≥ 3 x ULN, with most transaminase elevations and adverse events resolved or resolving at data cutoff. No liver enzyme elevations met laboratory criteria for Hy's Law cases. Conclusions Transaminase elevations occurred post-marketing in a similar proportion of patients as reported in clinical trials (4.4–5.6%). Regular monitoring per label facilitates prompt detection of liver adverse events and intervention to mitigate risk of severe injury.

Mitochondria-Targetable Cyclometalated Iridium(III) Complex-Based Luminescence Probe for Monitoring and Assessing Treatment Response of Ferroptosis-Mediated Hepatic Ischemia-Reperfusion Injury.

Ferroptosis plays an essential role in the pathological progression of hepatic ischemia-reperfusion injury (HIRI), which is closely related to iron-dependent lipid peroxidation. Since mitochondria are thought to be the major site of reactive oxygen species (ROS) production and iron storage, monitoring the variations of mitochondrial hypochlorous acid (HClO) (an important member of ROS) has important implications for the assessment of ferroptosis status, as well as the formulation of treatment strategies for HIRI. However, reliable imaging tools for the visualization of mitochondrial HClO and monitoring its dynamic changes in ferroptosis-mediated HIRI are still lacking. Herein, in this work, an HClO-activated near-infrared (NIR) cyclometalated iridium(III) complex-based probe, named NIR-Ir-HClO, was developed for the visual monitoring of the mitochondrial HClO fluxes in ferroptosis-mediated HIRI. The newly prepared probe showed fast response (<30 s), good sensitivity, excellent selectivity, good cell biocompatibility, and satisfactory mitochondrial-targeting performance, making it suitable for accurate monitoring of mitochondrial HClO in living cells. Moreover, visualization of the variations of mitochondrial HClO in ferroptosis-mediated HIRI and monitoring of the treatment response of ferroptosis-mediated HIRI to the ferroptosis inhibitors were achieved for the first time. All these show that probe NIR-Ir-HClO can be utilized as a reliable imaging tool for revealing the pathological mechanism of mitochondrial HClO in ferroptosis-mediated HIRI, as well as for the formulation of new treatment strategies for HIRI.

Alleviation of alcoholic liver injury through composite postbiotics regulation of intestinal flora and promotion of bile acid metabolism

Alcoholic liver disease (ALD) arises from chronic alcohol consumption, leading to liver damage and gut microbiota disruption. Current clinical treatments, including pharmacological interventions, are often inadequate for early-stage ALD, highlighting the urgent need for novel therapeutic approaches. In this study, we explored the therapeutic potential of composite postbiotics, combined with ursodeoxycholic acid (UDCA) as a farnesoid X receptor (FXR) agonist, to alleviate ALD by modulating gut microbiota and bile acid metabolism. Using a murine model of ALD, composite postbiotics were found to restore intestinal barrier integrity, promote bile acid metabolism, and reduce liver inflammation. The treatment increased beneficial gut microbes such as Firmicutes and Bacteroidetes, while reducing pathogenic Proteobacteria, which enhanced bile acid metabolism and activated the FXR pathway. This activation led to a reduction in pro-inflammatory cytokines, restoration of lipid metabolism, and overall alleviation of liver injury. The addition of UDCA further enhanced the activation of the FXR pathway, providing additional protection against liver damage. Our findings suggest that composite postbiotics, particularly when combined with FXR agonists like UDCA, represent a promising therapeutic strategy for ALD by targeting the gut-liver axis and optimizing bile acid metabolism. Future research should investigate the clinical application of these treatments to offer a non-invasive and effective approach for early ALD intervention.

Impact of Traditional Chinese Medicine Antioxidants on Oxidative Stress and Drug-Induced Liver Injury: A Review

Impact of Traditional Chinese Medicine Antioxidants on Oxidative Stress and Drug-Induced Liver Injury: A Review

Pea Albumin Alleviates Oleic Acid-Induced Lipid Accumulation in LO2 Cells Through Modulating Lipid Metabolism and Fatty Acid Oxidation Pathways

Excessive lipid accumulation in the liver can cause NAFLD, leading to chronic liver injury. To relieve liver lipid accumulation by dietary proteins, this study used oleic acid (OA) induction to establish a stable in vitro LO2 cell lipid accumulation model. This model was used to explore the mechanism by which pea albumin (PA) regulates lipid levels in LO2 cells. PA has been shown to ameliorate OA-induced lipid accumulation in LO2 cells by reducing the aggregation of intracellular lipid droplets and lowering cell TG and TC levels. In addition, it can alleviate OA-induced LO2 cell damage and oxidative stress, reduce cellular ALT and AST secretion, lower cellular MDA levels, and increase GSH-Px viability. Regulation of lipid metabolism in LO2 cells involves inhibiting the cellular lipid synthesis pathway and activating the expression of proteins related to the triglyceride catabolic and fatty acid oxidation pathways. PA contributes to regulating lipid accumulation in LO2 cells. This study provides new insights into alleviating liver fat accumulation and a theoretical basis for exploring the mechanism of protein regulation of liver cell lipid metabolism.

A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex

BackgroundPhospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions. Therefore, IPMK plays critical functions in key biological events such as cell growth. However, the contribution of IPMK to the activation of PLCγ1 in TCR signaling remains mostly unelucidated. The current study aimed to elucidate the functions of IPMK in TCR signaling and to uncover the mode of IPMK-mediated signaling action in PLCγ1 activation.MethodsConcanavalin A (ConA)-induced acute hepatitis model was established in CD4+ T cell-specific IPMK knockout mice (IPMKΔCD4). Histological analysis was performed to assess hepatic injury. Primary cultures of naïve CD4+ T cells were used to uncover the role of mechanisms of IPMK in vitro. Western blot analysis, quantitative real-time PCR, and flow cytometry were performed to analyze the TCR-stimulation-induced PLCγ1 activation and the downstream signaling pathway in naïve CD4+ T cells. Yeast two-hybrid screening and co-immunoprecipitation were conducted to identify the IPMK-binding proteins and protein complexes.ResultsIPMKΔCD4 mice showed alleviated ConA-induced acute hepatitis. CD4+ helper T cells in these mice showed reduced PLCγ1 Y783 phosphorylation, which subsequently dampens calcium signaling and IL-2 production. IPMK was found to contribute to PLCγ1 activation via the direct binding of IPMK to Src-associated substrate during mitosis of 68 kDa (Sam68). Mechanistically, IPMK stabilizes the interaction between Sam68 and to PLCγ1, thereby promoting PLCγ1 phosphorylation. Interfering this IPMK-Sam68 binding interaction with IPMK dominant-negative peptides impaired PLCγ1 phosphorylation.ConclusionsOur results demonstrate that IPMK non-catalytically promotes PLCγ1 phosphorylation by stabilizing the PLCγ1–Sam68 complex. Targeting IPMK in CD4+ T cells may be a promising strategy for managing immune diseases caused by excessive stimulation of TCR.