Liver Injury Research Articles

Swertia cincta and its main active ingredients regulate the PPAR-α pathway in anti-cholestatic liver injury

Ethnopharmacological relevanceSwertia cincta is a traditional remedy for cholestasis commonly utilised in Yunnan, China. Despite its widespread use, the specific active components and underlying mechanisms of action remain poorly understood. Aim of this studyThis study aimed to investigate the therapeutic properties, mechanisms, and active compounds of Swertia cincta in an animal model of cholestasis induced by alpha-naphthylisothiocyanate (ANIT). Materials and methodsUHPLC/Q-TOF-MS and high-performance liquid chromatography (HPLC) were utilised to analyse the blood components of Swertia cincta. An ANIT-induced cholestatic liver injury animal model was established, and metabolomics was employed to explore the potential mechanisms of Swertia cincta in treating cholestatic liver injury. Hepatocellular injury induced by taurochenodeoxycholic acid was evaluated in vitro, and key bioactive components of Swertia cincta for cholestatic liver injury treatment were identified and confirmed using the ANIT-induced mouse model. ResultsThe established HPLC method demonstrates good specificity and reproducibility, enabling the simultaneous determination of six components in Swertia cincta. Results from serum biochemical indicators and liver pathology analysis indicated that Swertia cincta exhibits promising anti-cholestasis liver injury effects. Specifically, gentiopicroside, loganic acid, and isoorientin were identified as key active ingredients in treating cholestatic liver injury. Their mechanism of action primarily involves regulating PPAR-α, FXR, CYP3A4, NTCP, CAR, and CPT2. By modulating PPAR-α and bile acid metabolism-related proteins, reducing pro-inflammatory factors, enhancing bile acid transport, and promoting fatty acid oxidation to reduce lipid accumulation, Swertia cincta exerts protective and therapeutic effects against cholestatic liver injury. Notably, gentian bitter glycosides appear to be the most critical components for this effect. ConclusionSwertia cincta may improve cholestatic liver injury by activating the peroxisome proliferator-activated receptor alpha pathway, and the key active compounds were gentiopicroside, loganic acid, and isoorientin.

Insufficient S-sulfhydration of Serum and Glucocorticoid-regulated Kinase 1 Participates in Hyperhomocysteinemia-induced Liver Injury.

Previous studies have established that hyperhomocysteinemia (HHcy) significantly contributes to the development of non-alcoholic steatohepatitis (NASH). Conversely, hydrogen sulfide (H2S) has shown potential in mitigating NASH. Despite these findings, it remains uncertain whether H2S can serve as a therapeutic agent against HHcy-induced liver damage. Mice were fed a high-methionine diet to induce HHcy and HepG2 cells were exposed to homocysteine (Hcy). In both models, we assessed liver injury, H2S concentration, and autophagy levels. For rescue, sodium hydrosulfide (NaHS), an H2S donor, was used to test its potential in reversing hepatic pathological features induced by HHcy. 1) Hcy accumulation led to liver damage and increased autophagy. This was linked to insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 (SGK1) at Cys244 and Cys282, a crucial autophagy regulator. The deficiency in S-sulfhydration was resulted from downregulation of cystathionine-γ-lyase (CSE) and subsequent H2S decrease, leading to SGK1 inactivation. 2) Administration of NaHS reduced the liver damage caused by high Hcy levels and restored H2S levels, promoting the S-sulfhydration and activation of SGK1. 3) Pharmacological inhibition of SGK1 induced autosis, a specific type of cell death caused by overactivation of autophagy. Conversely, a constitutively active mutant of SGK1 (SGK1S422D) significantly decreased autophagy and improved cell viability. NaHS supplementation mitigates HHcy-induced liver injury by downregulating hepatic autophagy through the S-sulfhydration and activation of SGK1. This post-translational modification by H2S holds promise as a therapeutic approach for HHcy-induced liver injury.

Alterations of Hepatic Lipidome Occur in a Gouty Model: A Shotgun Lipidomics Study.

Liver injury, such as nonalcoholic fatty liver disease, is a common symptom observed in patients with gout/hyperuricaemia. However, the exact mechanisms are still unclear. There is ongoing controversy about whether representative agents like colchicine and febuxostat, commonly used to manage gout, could also help prevent the liver injury. Liver plays a crucial role in uric acid (UA) production and lipid metabolism. Thus, the study aimed to investigate the aberrant lipid metabolism in the liver during injury and the effects of these drugs. An advanced multi-dimensional mass spectrometry-based shotgun lipidomics technology was employed for class-targeted lipid analysis of cellular lipidomes in hepatic tissue of a gouty model induced by a combination of monosodium urate crystals and high-fat diet with or without treatment with colchicine and febuxostat. Serum UA, blood urea nitrogen, creatinine, proinflammatory cytokines, expression of AMP-activated protein kinase protein, footpad histopathology, and footpad swelling and pain threshold of these mice were assessed to evaluate the progression of gout. Lipidomics analysis clearly demonstrated that the ectopic fat accumulation as well as changes in fatty acyls composition in TAG pool, impaired mitochondrial function resulted by decreased tetra 18:2 cardiolipin, and reduced 4-hydroxyalkenal bioavailability in liver tissue could contribute to liver damage to the gouty model. Treatment with colchicine or febuxostat not only ameliorated gouty symptoms but also corrected these abnormal hepatic lipid metabolism patterns. This study shed light on underlying mechanism(s) for liver injury in gout/hyperuricaemia and suggested that administration of drugs like colchicine and febuxostat could prevent liver injury.

Drug Acute Liver Failure in Children Caused by Anthelmintic Agents (Albendazole): Treatment Strategy.

Drug-induced liver injury accounts for numerous clinically significant events each year and can cause severe injury, resulting in a need for liver transplant or fatality. Liver injury triggered by albendazole is relatively common, resulting in mild to moderate changes in liver enzymes and affecting ~16% of patients who use this medication. Albendazole-induced liver injury and jaundice have been previously documented, but a case of fulminant hepatic failure requiring liver transplant has not yet been described. Acute liver failure is a clinical syndrome that is potentially reversible. About 2% of liver transplants are performed because of acute liver failure. We reviewed drug-induced fulminant and subfulminant hepatic failures among pediatric patients transferred to the Batumi Center for Liver Diseases and Transplantation in Georgia. The 6 cases were children aged 2 to 14 years who were diagnosed in Georgia between 2018 and 2023. Of 6 children, patients N1 and N2 had reversible acute liver failure and treatment ended with recovery, patients N3 and N4 had successful transplant procedures performed at the peak of disease development, and patients N5 and N6 did not receive transplant procedures because of presence of irreversible brain damage. Although the Model for End-Stage Liver Disease Score (the model score for patients with end-stage liver disease) is useful for patients with chronic hepatocytic failure, the score does not apply for patients with acute liver failure. On the basis of our study, at the first signs of disease development, patients should be referred to the transplant center and the preparation of a living donor should be started immediately, so that organ transplant can be performed without a long elapse of time.

The chemokine receptor type 5 inhibitor maraviroc alleviates sepsis-associated liver injury by regulating MAPK/NF-κB signaling.

Sepsis-related organ damage, as the most intractable problem in intensive care units (ICUs), receives a great deal of attention from healthcare professionals. Sepsis-associated liver injury (SALI) often leads to poor clinical outcomes due to its complex physiological mechanism. In previous studies, chemokine receptor 5 (CCR5) inhibitors were shown to exert unique anti-inflammatory effects. As the therapeutic effect of maraviroc (MVC) on SALI is still unclear, we aimed to explore whether MVC is effective in treating SALI. We established a model of SALI by cecal ligation and puncture (CLP) and intraperitoneally injected 20mg/kg MVC 2h after CLP. The results showed that MVC could significantly ameliorate liver injury after CLP. Furthermore, we demonstrated that MVC reduced inflammatory infiltration and apoptosis after SALI. In addition, we found that the function of MVC in reducing inflammation was obtained through the inhibition of the two inflammatory signaling pathways mentioned above. Finally, the JNK agonist AN was chosen for reverse research. As shown by the results, the therapeutic effects of MVC disappeared after AN treatment, indicating that MVC exerted anti-inflammatory and antiapoptotic effects through JNK. Our study revealed that MVC could reduce liver injury after SALI by inhibiting liver inflammation and hepatocyte apoptosis induced by CLP and that MVC exerted diminish inflammatory effects by inhibiting the NF-κB and MAPK signaling pathways.

Severe acute liver disease in adults: Contemporary role of histopathology.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).

Aqueous Extract of Rhubarb Promotes Hepatotoxicity via Facilitating PKM2-Mediated Aerobic Glycolysis in a Rat Model of Diethylnitrosamine-Induced Liver Cancer.

To identify the polar parts in Rhubarb that cause hepatotoxicity and explore the underlying mechanisms. The rat model of liver cancer was established by gavage of diethylnitrosamine (DEN; 0.002 g/rat) for 14weeks. Starting from the 11th week, Rhubarb granule (4 g/kg), aqueous, ethyl acetate and n-butanol extract of Rhubarb or Rhein equivalent to a dose of 4 g/kg Rhubarb granule were administered intragastrically for 4 consecutive weeks. Liver tissues from rats treated with DEN and Rhubarb granules were used for non-targeted metabolomics analysis. The correlation between pyruvate kinase isozyme type M2 (PKM2) expression level and the progress and prognosis of hepatocellular carcinoma (HCC) was evaluated through bioinformatics analysis based on TCGA database. Liver tissues and blood samples from rats treated with DEN and aqueous, ethyl acetate and n-butanol extract of Rhubarb were used for the screening of hepatotoxic polar parts of Rhubarb. The liver injuries were evaluated by the changes in pathology, liver function, and the expression levels of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta1 (TGF-β1). The mechanism studies focus on PKM2 expression, and the metabolic reprogramming via detecting the activities of lactate dehydrogenase A (LDHA) and isocitrate dehydrogenase (ICDH). Furthermore, molecular docking analysis was performed to validate the target interaction between Rhein and PKM2, and the hepatotoxicity of Rhein was evaluated by testing liver function in the DEN-induced liver cancer model. The non-targeted metabolomics analysis revealed that Rhubarb promoted aerobic glycolysis in the rat model of DEN-induced liver cancer. And bioinformatics analysis revealed that high PKM2 expression was closely related to the progression and poor prognosis of HCC. In vivo studies indicated that the aqueous extract of Rhubarb, but not ethyl acetate and n-butanol extract, promoted the liver injuries induced by DEN. The mechanism study showed that the aqueous extract of Rhubarb increased the expression of PKM2 and promoted aerobic glycolysis. Moreover, Rhein had a strong binding affinity for PKM2 and aggravated liver injury in the DEN-induced liver cancer model. Aqueous extract of Rhubarb promoted hepatotoxicity via facilitating PKM2-mediated aerobic glycolysis in the rat model of DEN-induced liver cancer.

Integrated multi-omics approach and pathological analyses provide new insights into the hepatic injury and metabolic alterations in Saanen goats after dietary exposure to aflatoxin B1

Exploring the toxicity and metabolic mechanisms of Aflatoxin B1 (AFB1) in ruminants can help to develop strategies to prevent or reduce the transfer of the toxin and its metabolites to milk and meat. This study aimed to explore the effects of 3 concentrations of dietary AFB1 (0, 50, and 500 μg/kg) on hepatic injury and metabolism in Saanen goats via histological examination, Western blot analysis, as well as integrated multi-omics techniques. Eighteen Saanen goats were assigned to 1 of 3 treatments and the AFB1 challenge lasted for 14 d. Results showed that the liver tissue was enlarged and the relative organ index of the liver was linearly increased with elevated AFB1 levels. The hepatocyte apoptosis rate was significantly increased after AFB1 exposure and the Western blotting results revealed that both the external apoptotic pathway and mitochondrial-mediated intrinsic apoptotic pathway might be involved in AFB1-induced hepatocyte apoptosis. There were 251, 269, 154 significant differentially expressed genes (DEGs) and 340, 596, 127 significant differential metabolites for the control (C; 0 μg/kg) and low-dose (L; 50 μg/kg), C and high-dose (H; 500 μg/kg), L and H comparisons. The DEGs annotated were mainly involved in the cell part, cell, single-organism process, cellular process, binding, and other functional categories. The identified metabolites primarily belonged to glycerophospholipids, prenol lipids, carboxylic acids and derivatives. Integrative analysis of transcriptomics and metabolomics revealed that glycerophospholipids metabolism and choline metabolism in cancer were the most affected pathways related to AFB1 exposure. The identified differential metabolites, DEGs, and pathways might have played a crucial role in the hepatic injury induced by AFB1 in goats.

Neoastilbin ameliorates sepsis-induced liver and kidney injury by blocking the TLR4/NF-κB pathway.

Sepsis frequently causes systemic inflammatory response syndrome and multiple organ failure in patients. Neoastilbin (NAS) is a flavonoid that plays vital functions in inflammation. This work aims to investigate the protective effects of NAS against sepsis-induced liver and kidney injury and elucidate its underlying mechanisms. The mouse model was established using cecal ligation puncture (CLP) induction. NAS was given to mice by gavage for 7 consecutive days before surgery. Liver and kidney function, oxidative stress, and inflammatory factors in serum or tissues were examined by ELISA or related kits. The expression of relevant proteins was assessed by Western blot. Hematoxylin and eosin and/or periodic acid-Schiff staining revealed that NAS ameliorated the pathological damage in liver and kidney tissues of CLP-induced mice. NAS improved liver and kidney functions, as evidenced by elevated levels of blood urea nitrogen, Creatinine, ALT, and AST in the serum of septic mice. TUNEL assay and the expression of Bcl-2 and Bax showed that NAS dramatically reduced apoptosis in liver and renal tissues. NAS treatment lowered the levels of myeloperoxidase and malondialdehyde, while elevated the superoxide dismutase content in liver and kidney tissues of CLP-induced mice. The levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β) in the serum and both tissues of CLP-injured mice were markedly decreased by NAS. Mechanically, NAS downregulated TLR4 expression and inhibited NF-κB activation, and overexpression of TLR4 reversed the protective effects of NAS against liver and kidney injury. Collectively, NAS attenuated CLP-induced apoptosis, oxidative stress, inflammation, and dysfunction in the liver and kidney by restraining the TLR4/NF-κB pathway.

Relevance of intra-abdominal pressure monitoring in non-operative management of patients with blunt liver and splenic injuries

PurposeNon-operative management (NOM) has been validated for blunt liver and splenic injuries. Literature on continuous intra-abdominal pressure (IAP) monitoring as a part of NOM remains to be equivocal. The study aimed to find any correlation between clinical parameters and IAP, and their effect on the NOM of patients with blunt liver and splenic injury. MethodA prospective cross-sectional study conducted at a level I trauma center from October 2018 to January 2020 including 174 patients who underwent NOM following blunt liver and splenic injuries. Hemodynamically unstable patients or those on ventilators were excluded, as well as patients who suffered significant head, spinal cord, and/or bladder injuries. The study predominantly included males (83.9%) with a mean age of 32.5 years. IAP was monitored continuously and the relation of IAP with various parameters, interventions, and outcomes were measured. Data were summarized as frequency (percentage) or mean ± SD or median (Q1, Q3) as indicated. χ2 or Fisher's exact test was used for categorical variables, while for continuous variables parametric (independent t-test) or nonparametric tests (Wilcoxon rank sum test) were used as appropriate. Clinical and laboratory correlates of IAP < 12 with p < 0.200 in the univariable logistic regression analysis were included in the multivariable analysis. A p < 0.05 was used to indicate statistical significance. ResultsIntra-abdominal hypertension (IAH) was seen in 19.0% of the study population. IAH was strongly associated with a high injury severity score (p < 0.001), and other physiological parameters like respiratory rate (p < 0.001), change in abdominal girth (AG) (p < 0.001), and serum creatinine (p < 0.001). IAH along with the number of solid organs involved, respiratory rate, change in AG, and serum creatinine was associated with the intervention, either operative or non-operative (p = 0.001, p = 0.002, p < 0.001, p < 0.001, p = 0.013, respectively). On multivariable analysis, IAP (p = 0.006) and the mean change of AG (p = 0.004) were significantly associated with the need for intervention. ConclusionAs a part of NOM, IAP should be monitored as a continuous vital. However, the decision for any intervention, either operative or non-operative cannot be guided by IAP values alone.

Identifying specific functional roles for senescence across cell types.

Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an invivo genetic toolbox consisting of three p16Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.

Loss of Cdkn1a protects against MASLD alone or with alcohol intake by preserving lipid homeostasis

Background & AimExpression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. MethodsCDKN1A expression levels were evaluated in different patients‘ cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH binges, or a DuAL diet. Primary hepatocytes were isolated and functional assays performed. ResultsA significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAS and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in – fatty acid oxidation (FAO) and reduction in free fatty acid (FFA) uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. ConclusionsCdkn1a deletion protected against preclinical SLD by promoting FAO and preventing FFA uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAS and fibrosis in SLD patients. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in SLD patients, with and without alcohol consumption.

S4661 A Case of Herbs and Dietary Supplements-Drug-Induced Liver Injury From Unripe Ackee Fruit!

S4661 A Case of Herbs and Dietary Supplements-Drug-Induced Liver Injury From Unripe Ackee Fruit!

Investigation of the Role of Chemical Analysis in Causality Assessment of Herbal and Dietary Supplement-Induced Liver Injury.

The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (DILIN) determines the attribution of injury to an agent through its structured expert opinion causality assessment process, but without the use of chemical analysis data of HDS. We aimed to determine the impact of chemical analysis of HDS products on prior causality assessment scores. Obtained samples of HDS consumed by DILIN-enrolled patients were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Chemical analysis data were compared to label accuracy and detect whether the product contained botanical and non-botanical compounds. A comparison of the causality scores reassessed with chemical analysis was compared with the original scores. A total of 54 previously adjudicated cases with chemical analysis available were reassessed for causality with chemical analysis data; reviewers were blinded to original causality scores. Using the chemical analysis data, 37% (n = 20) of the 54 cases were scored with a higher likelihood of DILI compared with the original causality scores; 14 of the 20 (70%) moved from probable to highly likely; 52% had no change in causality score; and 11% of cases were scored as a lower likelihood of DILI. Our study demonstrates that there is value in using HDS chemical analysis data in the causality assessment process for DILI. In more than a third of cases, chemical analysis of products led to an increased confidence in DILI attribution to HDS. These findings suggest that chemical analysis is an important tool in causality assessment for HDS agents, specifically in challenging situations, and further studies are needed to confirm its applicability in clinical practice.

Caveolin-1 ameliorates hepatic injury in non-alcoholic fatty liver disease by inhibiting ferroptosis via the NOX4/ROS/GPX4 pathway

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology

Role of viral hepatitis in pregnancy and its triggering mechanism.

Hepatitis viral infection can cause severe complications, even mortality in pregnant women and their offspring. Multiple studies have shown that vertical transmission can cause viral hepatitis infections in newborns, especially in hepatitis B, C, and E. Screening for hepatitis viral infection in pregnant women is essential. Once infected, pregnant women should be given timely antiviral treatments, which could effectively alleviate the disease progression and reduce adverse outcomes. Besides, the mechanism of viral hepatitis mediating adverse pregnancy outcomes has been a hot topic. Hepatitis B virus has been found to mediate both mother- to-child and parent-child transmission. Liver injury in hepatitis C virus infection is associated with immune-mediated mechanisms, which can be regulated by hormonal factors as well. The mediating mechanism of adverse maternal and infant outcomes caused by hepatitis E virus infection is mainly related to viral replication in the placenta and changes in cytokine and estrogen. Nevertheless, the specific mechanisms related to hepatitis A virus and hepatitis D virus remain unclear, and more research is needed. This review shows that the existence of viral hepatitis during pregnancy can pose certain risks for pregnant women and infants, and different interventions have been used to treat pregnant women infected with viral hepatitis. It may provide deep insight into adverse pregnancy outcomes caused by viral hepatitis and give guidance on treatment.

Three consecutive cases of acute liver failure in young women due to acetaminophen overdose: insights into Japanese social issues and transplantation landscape.

Acetaminophen (APAP) is an over-the-counter (OTC) drug known worldwide for its safety and efficacy. However, in Japan, OTC drug overdose has become a prominent social problem in recent years due to stricter regulations for other drugs, especially among young people, and APAP is an increasing cause of acute liver injury due to overdose. This report describes three consecutive cases of acute liver failure in young women (22, 22 and 19years old) due to APAP overdose in December 2023. Despite severe liver injury, indicated by high ALT levels and coagulopathy, these cases recovered without requiring liver transplantation. This report discusses three cases of acute liver failure in young Japanese women following APAP overdose, reflecting a national increase in such cases due to increased misuse of OTC drugs and societal factors. Key findings include the need for early treatment with N-acetylcysteine (NAC) and the importance of mental health assessment in the management of overdose patients. The cases underscore the need for prompt team-based care to prevent serious outcomes and highlight the complexity of liver transplantation decisions in Japan, highlighting the need for comprehensive strategies to address the escalating problem of APAP overdose.

Polyoxometalates Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease by Activating the AMPK Signaling Pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disorder, has garnered increasing attention globally owing to its associated health complications. However, the lack of available therapeutic medications and inadequate management of complications in metabolic dysfunction-associated steatohepatitis (MASH) present significant challenges. There are little studies evaluating the effectiveness of POM in treating MASLD. In this study, we synthesized polyoxometalates (POM) for potential treatment of MASLD. We induced liver disease in mice using two approaches: feeding a high-fat diet (HFD) to establish MASLD or feeding a methionine-choline deficient (MCD) diet to induce hepatic lipotoxicity and MASH. Various metabolic parameters were detected, and biochemical and histological evaluations were conducted on MASLD. Western blotting, qRT-PCR and immunofluorescence assays were used to elucidate the molecular mechanism of POM in the treatment of MASLD. POM therapy resulted in significant improvements in weight gain, dyslipidemia, liver injury, and hepatic steatosis in mice fed a HFD. Notably, in a more severe dietary-induced MASH model with MCD diet, POM significantly attenuated hepatic lipid accumulation, inflammation, and fibrosis. POM treatment effectively attenuated palmitic acid and oleic acid-induced lipid accumulation in HepG2 and Huh7 cells by targeting the AMPK pathway to regulate lipid metabolism, which was confirmed by AMPK inhibitor. Additionally, the activation of AMPK signaling by POM suppressed the expression of lipid synthesis genes, including sterol regulatory element-binding protein 1c (SREBP1c) and SREBP2, while concurrently upregulating the expression of sirtuin 1 (SIRT1) to promote fatty acid oxidation. These findings suggest that POM is a promising therapeutic strategy with high efficacy in multiple MASLD models.

Structural elucidation of an active arabinoglucan from Gomphrena globosa and its protection effect and mechanism against metabolic dysfunction-associated steatohepatitis

The flower of Gomphrena globosa (G. globosa.) is used as Chinese traditional medicine and functional food. Extractions from G. globosa. have been reported to exert hepatoprotective effects. We further hypothesized that the polysaccharide components, as a bioactive ingredient, might have anti-fatty and hepatitis function. Here, a novel homogeneous arabinoglucan GGL0.05S1 (Mw = 83.9 kDa) from this flower, was characterized by monosaccharide composition analysis, methylation analysis, and NMR. Structural analysis showed that the backbone of GGL0.05S1 consists of →4)-α-Glcp-(1→ and →4,6)-α-Glcp-(1→ residues, and the branched chain linked to the main chain via C-6 of →4,6)-α-Glcp-(1→ in the form α-Araf-(1 → [4)-α-Glcp-(1]b → (b > 2). In vitro experiments demonstrated that GGL0.05S1 could inhibit lipid deposition and ROS overload in free fatty acid-induced hepatocytes, meanwhile in vivo tests showed that GGL0.05S1 effectively protected against liver injury, steatohepatitis, and fibrosis in a CDA-HFD-fed MASH model. Mechanism study further uncovered that GGL0.05S1 augmented the expression and antioxidant ability of thioredoxin protein that ameliorated oxidative stress, promoted fatty acid β-oxidation and mitophagy, up to reducing lipotoxicity and alleviating inflammation via inhibiting NLRP3 signaling pathway. Overall, GGL0.05S1 might be a potential novel active compound with liver-protective effect from G. globosa., and which is informative for anti-MASH new drug development.

Lactobacillus helveticus attenuates alcoholic liver injury via regulation of gut microecology in mice.

Previous reports have demonstrated that alcohol consumption significantly reduces the abundance of Lactobacillus in the gut. In this study, we selected five species of the genus Lactobacillus, commonly found in fermented foods, and acknowledged them as safe, edible, and effective in preventing or treating certain diseases, to evaluate their effects on alcoholic liver disease (ALD). By comparing the liver damage indices in each group, we found that the type strain of Lactobacillus helveticus (LH, ATCC 15009) had the most marked alleviating effect on ALD-induced liver injury. Furthermore, experiments combining microbiomics and metabolomics were conducted to explore the mechanisms underlying the hepatoprotective effects of LH. Finally, we discovered that LH mitigated ethanol-induced liver steatosis and inflammation in ALD mice by altering the structure and function of the gut microbiome, increasing intestinal levels of short-chain fatty acids (SCFAs), and enhancing gut barrier integrity. These findings suggest a potential strategy for the clinical management of patients with ALD.