Sensing of Liver-Derived Nicotinamide by Intestinal Group 2 Innate Lymphoid Cells Links Liver Cirrhosis and Ulcerative Colitis Susceptibility.

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Low-dose hexavalent chromium induces mitophagy in rat liver via the AMPK-related PINK1/Parkin signaling pathway.

Hexavalent chromium (Cr(VI)) is a hazardous metallic compound commonly used in industrial processes. The liver, responsible for metabolism and detoxification, is the main target organ of Cr(VI). Toxicity experiments were performed to investigate the impacts of low-dose exposure to Cr(VI) on rat livers. It was revealed that exposure of 0.05 mg/kg potassium dichromate (K2Cr2O7) and 0.25 mg/kg K2Cr2O7 notably increased malondialdehyde (MDA) levels and the expressions of P-AMPK, P-ULK, PINK1, P-Parkin, and LC3II/LC3I, and significantly reduced SOD activity and P-mTOR and P62 expression levels in liver. Electron microscopy showed that CR(VI) exposure significantly increased mitophagy and the destruction of mitochondrial structure. This study simulates the respiratory exposure mode of CR(VI) workers through intratracheal instillation of CR(VI) in rats. It confirms that autophagy in hepatocytes is induced by low concentrations of CR(VI) and suggest that the liver damage caused by CR(VI) may be associated with the AMPK-related PINK/Parkin signaling pathway.

Cilostazol attenuates mirabegron-induced hepatic and renal toxicity in rats: regulation of metabolic, oxidative, and inflammatory pathways.

BACKGROUND: Mirabegron (MIRG) is a type of ß3 adrenoceptor agonist that is considered an alternative therapy for the treatment of overactive bladder (OAB) symptoms. Cilostazol (CITZ) is a selective inhibitor of phosphodiesterase (III) that has various pharmacological effects. OBJECTVE: The current study aimed to highlight the regulatory effects of CITZ on MIRG-induced toxicity. MATERIALS AND METHODS: Male rats were divided into six groups. Blood samples were collected to determine different hepatic and kidney function levels along with serum protein electrophoresis and inflammatory factor levels. Histopathological studies and oxidative stress (OS) were also assessed. Kidney and hepatic damage were detected following the administration of MIRG, especially at high doses, due to elevated OS, inflammation, and apoptotic marker levels. RESULTS: Rats receiving CITZ exhibited significant improvements in both hepatic and kidney functions, with decreased inflammation and OS. CONCLUSION: CITZ administration plays a beneficial role in alleviating hepatic and nephrotoxicity induced by MIRG by inhibiting OS and inflammation.

Rituximab-Associated Liver Toxicity Without Known Viral Reactivation.

Rituximab is a targeted immunotherapeutic agent that has demonstrated efficacy in treating CD20+ B-cell neoplasms as well as other lymphoproliferative and autoimmune disorders. A major adverse effect of rituximab is hepatocellular injury attributed to hepatitis B viral reactivation, necessitating viral titers before treatment. In this case report, we illustrate the rare presentation of a patient with marginal zone B-cell lymphoma who experienced symptomatic liver injury with a peak 15-fold aminotransferase elevation following his first dose of rituximab, without evidence of viral reactivation.

Generation of Multicellular 3D Liver Organoids From Induced Pluripotent Stem Cells as a Tool for Modelling Liver Diseases.

The liver is an essential organ that is involved in the metabolism, synthesis, and secretion of serum proteins and detoxification of xenobiotic compounds and alcohol. Studies on liver diseases have largely relied on cancer-derived cell lines that have proven to be inferior due to the lack of drug-metabolising enzymes. Primary human hepatocytes are considered the gold-standard for evaluating drug metabolism. However, several factors such as lack of donors, high cost of cells, and loss of polarity of the cells have limited their widescale adoption and utility. Stem cells have emerged as an alternative source for liver cells that could be utilised for studying liver diseases, developmental biology, toxicology testing, and regenerative medicine. In this article, we describe in detail an optimised protocol for the generation of multicellular 3D liver organoids composed of hepatocytes, stellate cells, and Kupffer cells as a tractable robust model of the liver. Key features • Optimising a protocol for generating multicellular 3D liver organoids from induced pluripotent stem cells. Graphical overview.

Ketamine-Induced Sclerosing Cholangitis Associated With Early Inflammatory Bowel Disease During Chronic Topical Ketamine Use.

Ketamine-induced sclerosing cholangitis has been described with chronic intranasal and intravenous use. Our case follows chronic topical use for peripheral neuropathy. It is also uniquely associated with early inflammatory bowel disease, a known complication of primary sclerosing cholangitis.

Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway.

Triptolide (TP), known for its effectiveness in treating various rheumatoid diseases, is also associated with significant hepatotoxicity risks. This study explored Catalpol (CAT), an iridoid glycoside with antioxidative and anti-inflammatory effects, as a potential defense against TP-induced liver damage. In vivo and in vitro models of liver injury were established using TP in combination with different concentrations of CAT. Metabolomics analyses were conducted to assess energy metabolism in mouse livers. Additionally, a Seahorse XF Analyzer was employed to measure glycolysis rate, mitochondrial respiratory functionality, and real-time ATP generation rate in AML12 cells. The study also examined the expression of proteins related to glycogenolysis and gluconeogenesis. Using both in vitro SIRT1 knockout/overexpression and in vivo liver-specific SIRT1 knockout models, we confirmed SIRT1 as a mechanism of action for CAT. Our findings revealed that CAT could alleviate TP-induced liver injury by activating SIRT1, which inhibited lysine acetylation of hypoxia-inducible factor-1α (HIF-1α), thereby restoring the balance between glycolysis and oxidative phosphorylation. This action improved mitochondrial dysfunction and reduced glucose metabolism disorder and oxidative stress caused by TP. Taken together, these insights unveil a hitherto undocumented mechanism by which CAT ameliorates TP-induced liver injury, positioning it as a potential therapeutic agent for managing TP-induced hepatotoxicity.

Liver dysfunction in adults with COVID-19 infection: A longitudinal study with transient elastography evaluation.

Background and Aim: Abnormal liver biochemistry (ALB) is common among patients with COVID-19 infection due to various factors. It is uncertain if it persists after the acute infection. We aimed to investigate this. Methods: A multicenter study of adult patients hospitalized for COVID-19 infection, with at least a single abnormal liver function test, was conducted. Detailed laboratory and imaging tests, including transabdominal ultrasound and FibroScan, were performed at assessment and at 6-month follow-up after hospital discharge. Results: From an initial cohort of 1246 patients who were hospitalized, 731 (58.7%) had ALB. A total of 174/731 patients fulfilled the inclusion criteria with the following characteristics: 48.9% patients had severe COVID-19; 62.1% had chronic liver disease (CLD); and 56.9% had metabolic-associated fatty liver disease (MAFLD). ALB was predominantly of a mixed pattern (67.8%). Among those (55.2%) who had liver injury (aspartate aminotransferase/alanine aminotransferase >3 times the upper limit of normal, or alkaline phosphatase/γ-glutamyl transferase/bilirubin >2 times the upper limit of normal), a mixed pattern was similarly predominant. Approximately 52.3% had normalization of the liver lunction test in the 6-month period post discharge. Patients with persistent ALB had significantly higher mean body mass index (BMI) and serum low-density lipoprotein (LDL), higher rates of MAFLD and CLD, higher mean liver stiffness measurement and continuous attenuated parameter score on FibroScan, and higher rates of liver injury on univariate analysis. Multivariate analysis was not statistically significant. Conclusions: Approximately 47.7% of COVID-19 patients were found to have persistent ALB up to 6 months following the acute infection, and it was associated with raised BMI, elevated serum LDL, increased rates of MAFLD and CLD, and higher rates of liver injury on univariate analysis, but not on multivariate analysis.

A preliminary study of T-2 toxin that cause liver injury in rats via the NF-kB and NLRP3-mediated pyroptosis pathway.

T-2 toxin is recognized as the most potent and prevalent secondary metabolite among monotrichous mycotoxins produced by Fusarium species. Multiple studies have substantiated the hepatotoxic effects of T-2 toxin. This study aimed to investigate whether NF-κB and NLRP3-mediated pyroptosis is involved in the underlying mechanism of T-2 toxin hepatotoxicity. We designed three groups of rat models, blank control; solvent control and T-2 toxin (0.2 mg/kg body weight/day), which were euthanized at week 8 after gavage staining of the toxin. Through HE staining and biochemical indicators associated with liver injury, we observed that T-2 toxin induced liver damage in rats. By Western blot analysis and qRT-PCR, we found that the expression levels of pyroptosis-related genes and proteins were significantly higher in the T-2 toxin group. In addition, we also found a significant increase in the expression of p-NF-κB protein, an upstream regulator of NLRP3. In conclusion, NF-κB and NLRP3-mediated pyroptosis may be involved in the mechanism of hepatotoxic action of T-2 toxin, which provides a new perspective.

Liver-Targeted Nanoparticles Loaded with Cannabidiol Based on Redox Response for Effective Alleviation of Acute Liver Injury.

The purpose of this work was to construct liver-targeted nanoparticles based on the redox response to effectively deliver cannabidiol (CBD) for the prevention of acute liver injury (ALI). CBD-loaded nanoparticles (CBD NPs) with a particle size of 126.5 ± 1.56 nm were prepared using the polymer DA-PP-LA obtained by grafting pullulan polysaccharide with deoxycholic acid (DA) and α-lipoic acid (α-LA). CBD NPs showed typical redox-response release behavior. Interestingly, CBD NPs exhibited admirable liver targeting ability, significantly accumulated in the liver, and effectively promoted the internalization of CBD in liver cells, thus effectively reducing the H2O2-induced oxidative damage of HepG2 cells and avoiding apoptosis. More importantly, CBD NPs effectively prevented CCl4-induced ALI by protecting liver function, ameliorating oxidative stress levels, inhibiting the production of inflammatory factors, and protecting the liver from histological damage. This study provides a promising strategy for achieving targeted delivery of CBD NPs in the liver, thereby effectively preventing ALI.

Challenges in herbal-induced liver injury identification and prevention.

Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS-induced liver injury, also known as HDS-induced liver injury (HILI), has increased significantly over the past three decades in the Drug-Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug-induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi-ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at-risk genetic phenotypes, the use of chemical analysis on multi-ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS.

Does drug-induced liver injury still occur after sevoflurane anesthesia? -A case report.

BACKGROUND: Several factors contribute to post-anesthetic hepatic dysfunction, including a decrease in oxygen supply to the liver, direct physical compression of the liver, viral hepatitis, blood transfusions, preexisting hepatic dysfunction, and the use of hepatotoxic drugs. Diagnosing volatile anesthetic drug-induced liver injury (VA-DILI) involves excluding these causes. CASE: The patient underwent total mastectomy under anesthesia using sevoflurane. He had diabetes, and no abnormal results were found on preoperative laboratory examinations, and surgery was uneventful. Abnormal laboratory findings were observed after surgery, including an aspartate aminotransferase level of 1,417 IU/L, an alanine aminotransferase level of 2,176 IU/L, and a total bilirubin level of 3.8 mg/dl. He presented with symptoms of mild icteric sclera, fatigue, and pruritus. After ruling out other causes of liver injury, we concluded that these results indicated VA-DILI. CONCLUSIONS: VA-DILI, though rare, we should be aware of the association between the disease and the use of halogenated anesthetics.

Enhanced In Vitro Recapitulation of In Vivo Liver Regeneration by Co-Culturing Hepatocyte Organoids with Adipose-Derived Mesenchymal Stem Cells, Alleviating Steatosis and Apoptosis in Acute Alcoholic Liver Injury.

Hepatocyte organoids (HOs) have superior hepatic functions to cholangiocyte-derived organoids but suffer from shorter lifespans. To counteract this, we co-cultured pig HOs with adipose-derived mesenchymal stem cells (A-MSCs) and performed transcriptome analysis. The results revealed that A-MSCs enhanced the collagen synthesis pathways, which are crucial for maintaining the three-dimensional structure and extracellular matrix synthesis of the organoids. A-MSCs also increased the expression of liver progenitor cell markers (KRT7, SPP1, LGR5+, and TERT). To explore HOs as a liver disease model, we exposed them to alcohol to create an alcoholic liver injury (ALI) model. The co-culture of HOs with A-MSCs inhibited the apoptosis of hepatocytes and reduced lipid accumulation of HOs. Furthermore, varying ethanol concentrations (0-400 mM) and single-versus-daily exposure to HOs showed that daily exposure significantly increased the level of PLIN2, a lipid storage marker, while decreasing CYP2E1 and increasing CYP1A2 levels, suggesting that CYP1A2 may play a critical role in alcohol detoxification during short-term exposure. Moreover, daily alcohol exposure led to excessive lipid accumulation and nuclear fragmentation in HOs cultured alone. These findings indicate that HOs mimic in vivo liver regeneration, establishing them as a valuable model for studying liver diseases, such as ALI.

Concanavalin-A-Induced Acute Liver Injury in Mice.

Acute liver injury is a life-threatening disease. Although immune responses are involved in the development and exacerbation of acute liver injury, the cellular and molecular mechanisms are not fully understood. Intravenous administration of the plant lectin concanavalin A (ConA) is widely used as a model of acute liver injury. ConA triggers T cell activation and cytokine production by crosslinking glycoproteins, including the T cell receptor, leading to the infiltration of myeloid cells into the liver and the subsequent amplification of inflammation in the liver. Thus, the pathogenesis of ConA-induced acute liver injury is considered a model of immune-mediated acute liver injury or autoimmune hepatitis in humans. However, the severity of the liver injury and the analyses of immune cells and non-hematopoietic cells in the liver following ConA injection are significantly influenced by the experimental conditions. This article outlines protocols for ConA-induced acute liver injury in mice and evaluation methods for liver injury, immune cells, and non-hematopoietic cells in the liver. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Induction of acute liver injury by ConA injection Basic Protocol 2: Evaluation of inflammatory cytokines in mouse plasma Basic Protocol 3: Preparation of liver sections and histological analysis of liver injury Basic Protocol 4: Preparation of liver immune cells Basic Protocol 5: Preparation of hepatocytes, endothelial cells, and hepatic stellate cells Basic Protocol 6: Flow cytometry of immune and non-hematopoietic liver cells Basic Protocol 7: Flow cytometric sorting of endothelial cells and hepatic stellate cells Basic Protocol 8: Quantitative reverse transcription polymerase chain reaction.

Specialized educational program for high-grade liver injury management: a three-dimensional printed model approach.

PURPOSE: The study aims to present a specialized educational program using a 3D printed model for managing Grade IV and V liver injuries. Hepatic packing, a common technique, may not always achieve sufficient hemostasis in these cases, warranting alternative solutions such as mesh liver wrapping. However, mastering this procedure is challenging due to limited teaching resources and the need for repeated practice. METHODS: A computer-based model was created from an abdominal CT scan to produce a real-sized injured liver model using thermoplastic elastomer TPU-95. Trainees received systematic instruction from an instructor, allowing them to perform the procedure under supervision and independently. RESULTS: Eight surgical residents at Hillel Yaffe Medical Center participated in the program, with the majority successfully completing the procedure under supervision. Furthermore, trainees demonstrated reduced procedure times when performing independently, indicating improved proficiency. CONCLUSION: This educational approach offers a simple and repeatable method for continuous training in managing high-grade liver injuries, holding potential for enhanced patient outcomes.

Recent advances in COVID-19-induced liver injury: causes, diagnosis, and management.

Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups. Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cirrhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy, and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition, we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2, liver health, and broader health management strategies, providing valuable insights for both current clinical practice and future research directions.

Triterpenoid saponins from the roots of Panax notoginseng with protective effects against APAP-induced liver injury.

Five previously undescribed protopanaxatriol type saponins, notoginsenoside Ta-Te (1-5), together with eighteen known triterpenoid saponins (6-23) were isolated from the roots of Panax notoginseng. The structures of new compounds were determined by HRESIMS and NMR spectroscopic analyses and chemical methods. Compounds 1 and 2 were the first examples of ginsenosides featuring a 6-deoxy-ß-d-glucose moiety from Panax species. Compounds 1-4, 7, 10, 12, 21-22 showed protective effects on L02 cells against the injury of acetaminophen (APAP). Among them, notoginsenoside R1 (12), ginsenoside Rg1 (21), and ginsenoside Re (22) were the most potent ones, with cell viabilities >80%. Moreover, compounds 12 and 22 remarkably alleviated APAP-induced liver injury in mice. These saponins are potential hepatoprotective agents.

Clinical risk factors for moderate and severe antituberculosis drug-induced liver injury.

Objective: To analyze the clinical and laboratory characteristics and to identify predictors of moderate to severe anti-tuberculosis drug-induced liver injury (ATB-DILI) in patients with tuberculosis. Methods: This prospective study enrolled Tuberculosis (TB) patients treated with first-line anti-tuberculosis drugs at the Affiliated Hospital of Zunyi Medical University between May 2022 and June 2023. The occurrence of ATB-DILI was monitored, and demographic and clinical data were gathered. We analyzed risk factors for the development of moderate to severe ATB-DILI. Results: ATB-DILI was detected in 120 (10.7%) of the patients, with moderate to severe ATB-DILI occurring in 23 (2.0%) of the 1,124 patients treated with anti-tuberculosis treatment. Multivariate cox regression analysis identified malnutrition (HR = 4.564, 95% CI: 1.029-20.251, p = 0.046) and hemoglobin levels <120 g/L (HR = 2.825, 95% CI: 1.268-11.540, p = 0.017) as independent risk factors for moderate to severe ATB-DILI. Conclusion: The incidence of moderate to severe ATB-DILI was found to be 2.0%. Malnutrition and hemoglobin levels below 120 g/L emerged as significant independent risk factors for the occurrence of moderate to severe ATB-DILI in this patient population.

Activation of pregnane X receptor protects against cholestatic liver injury by inhibiting hepatocyte pyroptosis.

Our previous study shows that activation of pregnane X receptor (PXR) exerts hepatoprotection against lithocholic acid (LCA)-induced cholestatic liver injury. In this study we investigated whether PXR activation could inhibit hepatocyte pyroptosis, as well as the underlying mechanisms. Male mice were treated with mouse PXR agonist pregnenolone 16α-carbonitrile (PCN, 50 mg·kg-1·d-1, i.p.) for 7 days, and received LCA (125 mg/kg, i.p., bid) from D4, then sacrificed 12 h after the last LCA injection. We showed that LCA injection resulted in severe cholestatic liver injury characterized by significant increases in gallbladder size, hepatocellular necrosis, and neutrophil infiltration with a mortality rate of 68%; PCN treatment significantly inhibited hepatocyte pyroptosis during LCA-induced cholestatic liver injury, as evidenced by reduced serum lactic dehydrogenase (LDH) levels, TUNEL-positive cells and hepatocyte membrane damage. Furthermore, PXR activation suppressed both the NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and the apoptosis protease activating factor-1 (APAF-1) pyroptosome-induced non-canonical pyroptosis. Inhibition of the nuclear factor kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways was also observed following PXR activation. Notably, dual luciferase reporter assay showed that PXR activation inhibited the transcriptional effects of NF-κB on NLRP3, as well as FOXO1 on APAF-1. Our results demonstrate that PXR activation protects against cholestatic liver injury by inhibiting the canonical pyroptosis through the NF-κB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis, providing new evidence for PXR as a prospective anti-cholestatic target.

Inhibition of Macrophage Pyroptosis─A New Therapeutic Strategy to Alleviate T-2 Toxin-Induced Subacute Liver Injury by Directly Competing with the Key Target.

Multiple compounds are related to the development of liver injury, such as toxins, drugs, and environmental pollutants. Although there are reports that the T-2 toxin can cause liver injury, its toxic mechanism remains unclear, which further impedes the development of effective antidotes. In this study, CRISPR-Cas9 genome-wide screening technology was used to identify transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) as a toxic target of the T-2 toxin. Mechanism studies have shown that the T-2 toxin induced pyroptosis of macrophages (J774A.1 cells) by activating the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, leading to a subacute liver injury. Also, the new drug berberine (BER) identified through virtual screening significantly alleviated the subacute liver injury by competitively binding trp53inp1 via His224; the effect was better than those of the positive control drugs N-acetylcysteine (NAC) and disulfiram (DSF). In summary, the above results indicate that trp53inp1 is a key target for T-2 toxin to induce subacute liver injury and that inhibiting macrophage pyroptosis is a new method for treating liver injury. In addition, this study provides a new method and strategy for the discovery of key disease targets and the search for effective drugs.