Liver Injury Research Articles

Hiatal sling liver retraction technique in bariatric and upper gastrointestinal surgeries - Our 15 year experience with 1874 surgeries.

Liver retraction is an important aspect when performing minimal access surgeries, especially bariatric and upper gastrointestinal (GI) surgeries. Various liver retraction methods are available and have been tried. Here, we present our experience with our indigenous hiatal sling technique for liver retraction and compare it with Nathanson liver retractor which is a popular and commonly used liver retraction method. This is a retrospective observational study of 1874 patients who underwent bariatric and upper GI surgeries over the last 15 years since September 2009. A secondary study was conducted amongst the two groups of patients who underwent upper GI and bariatric surgeries using hiatal sling technique and Nathanson retractor system for liver retraction between January 2023 and October 2023. End points measured were time taken, conversions and complication along with liver function tests (LFTs) such as aspartate aminotransferase (AST) and alanine transaminase measured between the two groups pre- and postoperatively day 0, day 1, day 3 and day 7. In our series of 1874 patients, hiatal sling liver traction was possible without any difficulties in all except 2 patients with no associated liver injury and with adequate exposure. In the comparative study, patients in the hiatal sling group (Group B) had significantly lesser elevation in LFTs as compared to the patients in the Nathanson liver retraction group (Group A), with no adverse events in both the groups. Hiatal sling technique for liver retraction is an effective technique which provides adequate exposure of the hiatus and causes lesser liver insult compared to rigid liver retraction system like Nathanson liver retraction system. Hiatal sling does not interfere with surgeons' field causing less errors during surgery and thus making it more ergonomic friendly.

Inhibitory Effects of Alkaloids on OATP1B1 In Vitro and In Vivo: Prediction for Food/Herb-Drug Interactions and Hepatoprotective Effects Based on Structure-Activity Relationships.

Alkaloids, a class of low-molecular-weight nitrogenous compounds, attract a great deal of interest because of their biological activities and therapeutic potential. Yet, surprisingly little is known about their interactions with drug transporters, especially Organic Anion Transporting Polypeptide 1B1 (OATP1B1), a liver-specific uptake transporter, which is closely associated with drug-induced liver injury (DILI). This study aims to investigate the inhibitory effects of 160 alkaloids on OATP1B1, assess the hepatoprotective effects against bosentan-induced liver injury, and elucidate the structure-activity relationships of alkaloids with OATP1B1. Four alkaloids, including dihydroberberine, deacetyltaxol, dihydrocapsaicin, and tetrahydropalmatine, significantly inhibited OATP1B1 transport activity in OATP1B1-HEK293 cells (>50%), which reduced the OATP1B1-mediated uptake of methotrexate and microcystin-LR, and consequently decreased their cell toxicity. In bosentan-induced liver injury models, 4 alkaloids reduced serum total bile acid (TBA) levels and liver concentration of bosentan to different degrees, especially deacetyltaxol, which exhibited the most potent hepatoprotective effect against bosentan. The pharmacophore model suggested that the critical pharmacophores of alkaloid inhibitors are hydrogen bond acceptors and hydrophobic groups. Our findings pave the way for predicting the potential risks of alkaloids-containing food/herb-drug interactions in humans and optimizing the alkaloid structure for alleviating OATP1B1-related DILI.

Angel or devil: the dual roles of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside in the development of liver injury based on integrating pharmacological techniques: a systematic review

Background and purpose2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) exhibits a dualistic pharmacological profile, acting as both a hepatoprotective and hepatotoxic agent, which is intricately linked to its interaction with multiple signaling pathways and its stereoisomeric forms, namely, cis-SG and trans-SG. The purpose of this study is to evaluate both the hepatoprotective and hepatotoxic effects of TSG and give therapeutic guidance.MethodsThis study performed a systematic search of eight databases to identify preclinical literature up until March 2024. The CAMARADES system evaluated evidence quality and bias. STATA and Python were used for statistical analysis, including dose-effect maps, 3D maps and radar charts to show the dose-time-effect relationship of TSG on hepatoprotection and hepatotoxicity.ResultsAfter a rigorous screening process, a total of 24 studies encompassing 564 rodents were selected for inclusion in this study. The findings revealed that TSG exhibited bidirectional effects on the levels of ALT and AST, while also regulating the levels of ALT, AST, TNF-α, IL-6, serum TG, serum TC, SOD, MDA, IFN-γ, and apoptosis rate. The histological analysis of liver tissue confirmed the regulatory effects of TSG, and a comprehensive analysis revealed the optimal protective dosage range was 27.27–38.81 mg/kg/d and the optimal toxic dosage range was 51.93–76.07 mg/kg/d. TSG exerts the dual effects on liver injury (LI) through the network of Keap1/Nrf2/HO-1/NQO1, NF-κB, PPAR, PI3K/Akt, JAK/STAT and TGF-β pathways.ConclusionTSG could mediate the pathways of oxidation, inflammation, and metabolism to result in hepatoprotection (27.27–38.81 mg/kg/d) and hepatotoxicity (51.93–76.07 mg/kg/d).

Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress

BackgroundDonation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxidative stress effects. The aim of this study was to investigate whether Rut can alleviate hepatic IRI in liver transplantation (LT) and to explore the underlying mechanisms.MethodsRat DCD LT and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established to clarify the effect of Rut on hepatic IRI. The key molecules involved in the hepatoprotective effects of Rut were identified through joint analysis of data from LT patients and drug targets. The target was further validated by in silico, in vivo and in vitro experiments.ResultsRut significantly alleviated liver dysfunction, pathological injury, and apoptosis and improved the survival rate of the rats subjected to LT. In addition, Rut significantly inhibited inflammatory response and oxidative stress. Rut also had similar effects on OGD/R-induced hepatocyte injury. Mechanistically, bioinformatics analysis and in vivo and in vitro experiments revealed that PDE4B may be a key target by which Rut exerts its protective effect, and molecular docking and cellular thermal shift assay confirmed this result. The function of PDE4B was studied via gene intervention technology, and the results showed that PDE4B can aggravate hepatic IRI. Furthermore, PDE4B overexpression abrogated the protective effect of Rut on the liver in LT.ConclusionRut alleviates hepatic IRI by targeting PDE4B to inhibit inflammation and oxidative stress. These findings highlight the potential of Rut as a drug candidate for the treatment of patients undergoing LT.

Modeling and Simulation of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Healthy Adults Using the Quantitative Systems Toxicology Software Platform DILIsym.

Acetaminophen (APAP) has been formulated as immediate-, modified-, and extended-release tablets (APAP-IR, -MR, and -ER, respectively). However, there was concern that APAP-MR previously available in Europe could form a bezoar after a large overdose, leading to delayed absorption and atypical pharmacokinetics (PK) compared to APAP-IR, and that current treatment guidelines developed for APAP overdose to prevent severe hepatotoxicity are inappropriate for APAP-MR. In contrast, APAP-ER caplets available in the United States are designed with an IR layer and an erodible ER layer. Using modeling and simulation, predicted PK and hepatotoxicity biomarkers following various acute overdose and repeated supratherapeutic ingestion (RSTI) scenarios with APAP-IR and APAP-ER were compared to investigate the differences between these two formulations. The existing APAP-IR representation within DILIsym v8A, a quantitative systems toxicology model of drug-induced liver injury, was updated, and an APAP-ER model was developed, using newly acquired invitro (e.g., tiny-TIMsg) and clinical data. The model and simulated populations (SimPops) representing healthy adults were extensively validated, before simulating PK and three clinically useful hepatic biomarkers after various overdose scenarios. On average, APAP exposure after acute overdose and RSTI in healthy adults was predicted to be slightly lower for APAP-ER compared to APAP-IR, partially due to lower APAP absorption for APAP-ER, while not markedly impacting the expected time course of APAP plasma concentrations. Similar hepatic biomarker profiles were predicted for both APAP formulations. Based on these results, the APAP overdose consensus treatment guidelines updated in 2023 are not further impacted by this report.

Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice

InstructionAccumulating evidence has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with inflammation in the vascular system. However, the roles of PCSK9 in hepatic inflammation remain unclear. Because PCSK9 is mainly expressed in the liver and modulates lipid uptake through low-density lipoprotein receptor family members, the present study aimed to elucidate the effect of conditional knockdown of hepatic PCSK9 on hyperlipidemia-induced inflammation and the underlying mechanisms of action.MethodsPCSK9flox/flox mice were bred with ALB-Cre+ mice to obtain hepatic PCSK9(−/−), PCSK9(+/−), and PCSK9(+/+) mice. These mice were fed with a high-fat diet for 9 weeks to induce inflammation. The effects of conditional knockdown of hepatic PCSK9 on inflammation and the underlying mechanisms were investigated by molecular biological techniques. Moreover, the findings were verified in vitro using HepG2 cells.Results and DiscussionConditional knockdown of hepatic PCSK9 remarkably decreased plasma levels of total cholesterol and alleviated hyperlipidemia-induced liver injury. Mechanistically, conditional knockdown of hepatic PCSK9 significantly reduced the levels of pro-inflammatory factors by downregulating the expression of Toll-like receptors, mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase/protein kinase B, which subsequently attenuated the expression of downstream molecules, namely nuclear factor kappa-B and activator protein-1. The related mechanisms were confirmed using lipid-loaded HepG2 cells together with PCSK9 siRNA, alirocumab (anti-PCSK9 antibody), and/or a p38-MAPK inhibitor. These findings confirmed that conditional knockdown of hepatic PCSK9 attenuates liver inflammation following hyperlipidemia induction by modulating multiple signaling pathways; this suggests that targeting PCSK9 knockdown/inhibition with appropriate agents is useful not only for treating hyperlipidemia but also for ameliorating hyperlipidemia-induced liver inflammation.

Two chromatographic methods for analyzing paracetamol in spiked human plasma with its toxic metabolite, N-acetyl parabenzoquinone imine and its antidote, N-acetyl-l-cysteine

Acetaminophen, also known as paracetamol (APAP), is a highly utilized pharmaceutical agent on a global scale, particularly in the field of pediatrics. Regrettably, an overdose of APAP, resulting from the predominant oxidation, has the potential to trigger acute liver injury. The study’s goal was to find an easy, accurate, and selective way to measure APAP, N-acetyl para benzoquinone imine (NAPQI) (an APAP metabolite that is harmful), and N-acetyl-l-cysteine (NAC) (an antidote). Two different chromatographic methods were used. The HPTLC method, which used silica gel 60 F254 as a stationary phase and a developing liquid made up of methanol, ethyl acetate, and glacial acetic acid (8:2:0.2, v/v/v) and a UV detection at 254 nm. The HPLC method was developed using a mobile phase consisting of water, methanol, and formic acid in a proportion of (70:30:0.15, v/v/v). The stationary phase used in the approach was a C18 column. Analytes quantification was established utilizing a UV detector operating at a wavelength of 254 nm. The present methods make it possible to measure the amount of APAP in plasma samples. When it comes to pharmacokinetics or medication levels in children’s plasma, for example, this may be also very helpful. The current methods can quantify NAPQI, which is helpful in figuring out drug concentrations in individuals with APAP intoxication diagnoses. Additionally, the current approaches can estimate NAC as an antidote; as a result, this study is a complete study because it can analyse drug, toxic metabolite, and antidote in one analytical run. Using the innovative blue applicability grade index software, which measures the practicality of procedures, both methodologies were compared with a reported methods. Additionally, the achievement of the eco-friendliness profile of the designed procedures was assessed. Both techniques passed the ICH validation tests.

The influence of childhood trauma on social media-induced secondary traumatic stress among college students: the chain mediating effect of self-compassion and resilience

ABSTRACT Background: Studies have shown that media exposure to critical public events can lead to secondary traumatic stress (STS). Personal trauma history, self-compassion and resilience are important factors influencing STS in healthy professionals. However, whether these variables are associated with social media-induced STS in college students and the underlying mechanisms remain unclear. The purpose of this study was to explore the complex relationship linking childhood trauma to social media-induced STS in a large sample of college students. Methods: A total of 1151 Chinese college students from Chengdu, Sichuan Province of China completed a web-based cross-sectional survey, which included standard assessments of childhood trauma, self-compassion, resilience and social media-induced STS, as well as sociodemographic questionnaires. The chain mediation model was tested using the PROCESS macro programme in SPSS software. Results: There was a moderate correlation between childhood trauma and social media-induced STS (r = 0.34, p < .001). This association was significantly mediated by self-compassion (indirect effect [95% CI] = 0.14[0.11, 0.17]) and resilience (indirect effect = 0.03[0.01, 0.04]), respectively. Further, a chained mediating effect was observed with self-compassion and resilience consecutively mediated the relationship between childhood trauma and social media-induced STS (indirect effect = 0.02[0.01, 0.03]). These results persisted after sociodemographic characteristics were included as controlling variables. Conclusions: Early life trauma impacts STS induced by exposure to traumatic materials on social media through self-compassion and resilience among Chinese college students. Psychological interventions targeting self-compassion and resilience can be implemented to reduce the risk of STS, especially in vulnerable individuals.

Exposure of pregnant and lactating parental mice to aflatoxin B1 promotes hepatotoxicity in offspring mice.

Aflatoxin B1 (AFB1) taints feeds stuffs, endangering livestock's health and resulting in the liver and breast damage. At the same time, while breastfeeding, AFB1 crosses the mammary glands and enters the milk, harming the offspring. This study investigated the liver damaging effects of maternal AFB1 exposure during pregnancy and lactation in offspring mice. The livers of 8-day-old offspring mice were obtained from female mice who were administered AFB1 (2mg/kg) 1week prior to and 1week following birth. The results showed that AFB1 increased the levels of malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), pro-inflammatory-related proteins (iNOS, COX-2, IL-6), and apoptosis-related proteins (Caspase-3, Caspase-9, Bax) by AFB1-induced in liver of offspring mice. Furthermore, the use of F40/80, HE, and TUNEL staining further demonstrated the existence of inflammation and apoptosis in the liver. Intriguingly, in the liver of offspring mice, AFB1 increased antioxidant protein and inhibit ferroptosis-related protein activity (FTH, GPX4), mitochondrial function-associated proteins (UQCRC2, COX IV, Cyt C), lipid metabolism-associated proteins (HMGCR, SPEBE1, FAS), and autophagy-related proteins (Atg7, Beclin-1, LC3I/II) in the liver of mice. In conclusion, AFB1 enters the liver of offspring mice through milk, which in turn causes liver injury. This outcome explains how AFB1 exposure affects female animals and their progeny and lays the strategy for livestock prevention.

Unraveling Human Hepatocellular Responses to PFAS and Aqueous Film-Forming Foams (AFFFs) for Molecular Hazard Prioritization and In Vivo Translation.

Aqueous film-forming foams (AFFFs) are complex product mixtures that often contain per- and polyfluorinated alkyl substances (PFAS) to enhance fire suppression and protect firefighters. However, PFAS have been associated with a range of adverse health effects (e.g., liver and thyroid disease and cancer), and innovative approach methods to better understand their toxicity potential and identify safer alternatives are needed. In this study, we investigated a set of 30 substances (e.g., AFFF, PFAS, and clinical drugs) using differentiated cultures of human hepatocytes (HepaRG, 2D), high-throughput transcriptomics, deep learning of cell morphology images, and liver enzyme leakage assays with benchmark dose analysis to (1) predict the potency ranges for human liver injury, (2) delineate gene- and pathway-level transcriptomic points-of-departure for molecular hazard characterization and prioritization, (3) characterize human hepatocellular response similarities to inform regulatory read-across efforts, and (4) introduce an innovative approach to translate mechanistic hepatocellular response data to predict the potency ranges for PFAS-induced hepatomegaly in vivo. Collectively, these data fill important mechanistic knowledge gaps with PFAS/AFFF and represent a scalable platform to address the thousands of PFAS in commerce for greener chemistries and next-generation risk assessments.

Oral Cornstarch and Glycyrrhizin Improve Severe Liver Injury Caused by Glycogen Storage Disease Type IXa

Oral Cornstarch and Glycyrrhizin Improve Severe Liver Injury Caused by Glycogen Storage Disease Type IXa

Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury.

Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) regulate critical cell functions, including actomyosin contractility, apoptosis, and proliferation. Some studies suggest that ROCK inhibition may serve as a treatment for liver fibrosis. More investigation is needed to understand the role of hepatocyte ROCK signaling in vivo, especially in the context of profibrotic liver injury. Rock1fl/fl, Rock2fl/fl, and Rock1fl/fl; Rock2fl/fl mice were given adeno-associated virus serotype 8 (AAV8)-thyroid hormone-binding globulin (TBG)-Cre to produce targeted gene deletion in hepatocytes, or given AAV8-TBG-Null to generate littermate controls (WT). Mice were then placed on a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce liver injury. Upon DDC-induced liver injury, mice with hepatocyte-specific deletion of ROCK1 alone (R1 KO) or ROCK2 alone (R2 KO) demonstrated minimal differences compared to WT. In contrast, mice with hepatocyte-specific deletion of both ROCK1 and ROCK2 (DKO) showed pervasive early mortality, increased hepatocellular injury, and decreased hepatic function. DDC-injured DKO mice demonstrated markedly distorted liver histology characterized by large cavities in the parenchyma. RNA-seq analysis showed upregulation of cell death, inflammatory, and profibrotic pathways in DDC-injured DKO liver as compared to DDC-injured WT liver. Cdkn1a (gene encoding p21) was one of the most highly upregulated genes in the DKO liver in response to DDC-induced injury. Correspondingly, there was increased hepatocyte nuclear localization of p21 and expression of cleaved caspase-3 in DDC-injured DKO liver, consistent with the activation of p21-mediated caspase-3-dependent apoptotic cell death pathways. ROCK1/ROCK2-deficient primary hepatocytes demonstrated increased susceptibility to both caspase-3-mediated apoptosis and caspase-3-independent forms of cell death in a cell intrinsic manner. ROCK signaling plays a critical role in mediating hepatocyte cell survival pathways in response to liver injury.

Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure.

Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N3-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N3-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.

Novel bioactive peptides alleviate Western diet-induced MAFLD in C57BL/6J mice by inhibiting NLRP3 inflammasome activation and pyroptosis via TLR4/NF-κB and Keap1/Nrf2/HO-1 signaling pathways.

Metabolic-associated fatty liver disease (MAFLD) has emerged as a leading chronic liver disease. This condition is characterized by an abnormal accumulation of fat within liver and can progress from simple steatosis to more severe stages involving chronic inflammation and oxidative stress. In this study, we investigated the potential therapeutic effects and underlying mechanism of novel bioactive peptides (EWYF and EWFY) on Western diet-induced MAFLD in C57BL/6J mice. Mice fed a normal chow diet (ND group) and Western diet (WD and treatment groups) for 8weeks. Treatment groups received EWYF and EWFY peptides in low (10mg/kg/day) and high (50mg/kg/day) doses were divided into four groups: EWYF10, EWYF50, EWFY10, and EWFY50. Western diet-induced body weight gain and increased liver weight along with visceral adiposity, which were markedly reversed by bioactive peptides in a dose-dependent manner. Additionally, bioactive peptides significantly reduced hepatic steatosis, liver injury and proinflammatory response. Western diet-induced glucose tolerance and insulin resistance, whereas bioactive peptides significantly improved glucose tolerance and insulin sensitivity. Persistent intake of Western diet triggered chronic inflammation and severe oxidative stress, which were significantly alleviated by bioactive peptides treatment via inhibiting NOD-like receptor protein 3 (NLRP3) inflammasome activation and mitigated pyroptosis by modulating TLR4/NF-κB and Keap1/Nrf2/HO-1 signaling pathways. Furthermore, molecular docking studies suggest that EWYF and EWFY act as fructokinase antagonists and TLR4 inhibitors, which potentially alleviates Western diet-induced MAFLD. Collectively, these findings highlight EWYF and EWFY as promising candidates for MAFLD treatment due to their potent antioxidant and anti-inflammatory properties via specific molecular inhibition.

Role of liver-resident NK cells in liver immunity.

The tolerogenic immune microenvironment of the liver (the immune system avoids attacking harmless antigens, such as antigens derived from food and gut microbiota) has garnered significant attention in recent years. Inherent immune cells in the liver play a unique role in regulating this microenvironment. Liver-resident natural killer (LrNK) cells, also known as livertype 1 innate lymphoid cells (ILC1s), are a recently discovered subset of immune cells that possess properties distinct from those of conventional NK (cNK) cells. Accumulating evidence suggests that there are significant differences between LrNK and cNK cells, with LrNK cells potentially exhibiting immunosuppressive functions in the liver. This review summarizes the latest findings on LrNK cells, focusing on their phenotype, heterogeneity, plasticity, origin, development, and the required transcription factors. In addition, immune functions of LrNK cells in various liver diseases, including liver cancer, viral infections, liver injury, and cirrhosis, were analyzed. By elucidating the role of LrNK cells in liver immunity, this review aims to enhance our understanding of the mechanisms underlying liver immunity and contribute to the improvement of liver disease treatment.

Unlocking therapeutic potential of amlexanox in MASH with insights into bile acid metabolism and microbiome

Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health issue associated with obesity and diabetes. It is becoming a leading cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite its increasing prevalence, effective pharmacotherapies for MASH remain limited, underscoring the urgent need for novel interventions. Amlexanox, an inhibitor of noncanonical IκB kinases, has demonstrated potential in restoring insulin sensitivity and glucose homeostasis in obese mice and human patients, as shown in our earlier studies. Here, we aimed to assess the therapeutic potential of amlexanox in dyslipidemia-associated diseases, particularly MASH and HCC, and to elucidate the underlying mechanism. We employed GAN diet-fed Ldlr−/− mice, which simultaneously develop obesity, MASH, and atherosclerosis, to recapitulate human metabolic syndrome and associated complications. Amlexanox was administrated orally to these mice after disease onset to examine its therapeutic efficacy. Our study demonstrates that even a low dose of amlexanox significantly reversed MASH and nearly completely prevented the progression from MASH to HCC. Both phenotypic and transcriptomic studies revealed that amlexanox markedly improved MASH-related dyslipidemia, hepatic steatosis, inflammation, liver injury, and hepatic fibrosis. Furthermore, multi-omics analysis revealed that amlexanox enhances hepatic bile acid synthesis and promotes fecal bile acid excretion. Notably, amlexanox reprogrammed gut microbiota, robustly increasing the abundance of Akkermansia muciniphila, a probiotic known to improve metabolic dysfunction. These findings uncover the multifaceted therapeutic potential of amlexanox in treating MASH and atherosclerosis by targeting bile acid metabolism, gut microbiota, hepatic inflammation, and fibrosis. Our study highlights amlexanox as a promising candidate for clinical applications.

A multi-functional oxidative konjac glucomannan/ε-poly-l-lysine hydrogel with antibacterial, haemostatic, and chronic diabetic wound-treating properties.

A chronic diabetic wound, one of the most severe complications of diabetes, has a high incidence and causes great pain to patients, threatening their lives. In this paper, oxidative konjac glucomannan (OKGM) was reacted with ε-poly-l-lysine (EPL) through the dynamic Schiff's base reaction to make a multi-functional hydrogel. This hydrogel had excellent mechanical properties, injectability, self-healing ability, adhesivity and cytocompatibility. The outstanding haemostatic property was also expressed in rat liver incision, liver injury and tail truncation models. In addition, this hydrogel exhibited unique antibacterial ability against the Gram-positive Staphylococcus aureus (S. aureus), the Gram-negative Escherichia coli (E. coli) and the Gram-negative Pseudomonas aeruginosa (P. aeruginosa). It also promoted wound healing, enhanced angiogenesis and regulated macrophage polarisation in the whole-layer rat diabetic wound model. The multi-functional hydrogel is a dressing with huge potential and prospects in chronic diabetic wound healing.

Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH.

Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver. The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol-fed S1pr1MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol-fed S1pr1MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator-activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1MKO consistent with attenuated MASH in mice. Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

Engineered S. cerevisiae-pYD1-ScFv-AFB1 mitigates aflatoxin B1 toxicity via bio-binding and intestinal microenvironment repair.

The highly toxic aflatoxin B1 (AFB1) is considered one of the primary risk factors for hepatocellular carcinoma, while effective measures after AFB1 exposure remain to be optimized. This study utilized cell-surface-display technique to construct an engineered S. cerevisiae-pYD1-ScFv-AFB1 (S.C-AF) that specifically binds AFB1, and verified the potential mechanism of S.C-AF in vivo through AFB1-induced (gastric perfused with 0.3mg/kg/d AFB1 per day) liver injury mouse model. In this experiment, the C57BL/6 mouse model of AFB1-induced liver injury was treated with S.C (gastric perfused with 1×109CFU/mL S.C per day) and S.C-AF (gastric perfused with 1×109CFU/mL S.C-AF per day) for 4 weeks, respectively. With probiotic properties optimized, S.C.-AF achieved an in vitro AFB1 binding capacity 1.7 times higher than S. cerevisiae. Furthermore, S.C-AF could alleviate AFB1-induced liver injury by reducing proinflammatory cytokine secretion and apoptotic protein expression, enhancing antioxidative capacity via Nrf2 activation, and simultaneously reversing intestinal tight junction protein deficiency, increasing intestinal barrier permeability, and improving intestinal dysbiosis caused by AFB1 exposure. S.C-AF alleviates AFB1-induced liver lesions, which might be a novel intervention to mitigate aflatoxin toxicity.

447 Autoimmune hepatitis and acute liver injury secondary to drug induced liver injury in an adolescent with ADHD

447 Autoimmune hepatitis and acute liver injury secondary to drug induced liver injury in an adolescent with ADHD