BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies.
OBJECTIVE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms.
METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques.
RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury.
CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Many etiologies of acute liver injury (ALI) include drug-induced liver injury (DILI), viral illness, and autoimmune disease. Acute pancreatitis is an uncommon though significant etiology of ALI caused by inflammation, fluid shifts, and ischemia secondary to microthrombi formation that can progress to liver failure if left untreated. We present a case of hypertriglyceridemia-induced pancreatitis resulting in liver injury-associated acute pancreatitis (LIAAP) and a concurrent consumptive coagulopathy consistent with an ischemic hepatopathy. Through treatment of her pancreatitis with intravenous insulin and plasmapheresis and subsequent transition to an oral regimen for her hypertriglyceridemia upon hospital discharge, the patient demonstrated full resolution of her ALI and coagulopathy. Through this case, we hope to highlight the importance of recognizing LIAAP and its underlying pathogenesis.

Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD-including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD.

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.

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.

UNASSIGNED: Drug-induced liver injury (DILI), a type of acute inflammation, has sparked significant concern owing to its unpredictability and severity. Psoraleae Fructus (PF), an edible Chinese herb widely used in traditional Chinese medicine (TCM), causes liver injury. Therefore, the elucidation of the mechanism underlying PF-induced liver injury and the search for more effective means of detoxification using herbal compatibility has become an urgent issue. This study evaluated the hepatoprotective effects of Paeoniae Radix Alba (PRA), a hepatoprotective Chinese medicine, on PF-induced liver injury and explored the underlying mechanisms.
UNASSIGNED: A rat model of lipopolysaccharide (LPS)-induced immune stress was established to evaluate the hepatotoxicity of PF and the detoxifying effect of PRA. Subsequently, inflammatory pathways were identified using network pharmacology. Finally, the molecular mechanism by which PRA alleviates PF-induced liver injury was validated using an inflammasome activation model in bone marrow-derived macrophages (BMDMs).
UNASSIGNED: In vivo, hepatocytes in rats treated with LPS + PF exhibited massive inflammatory infiltration and apoptosis, and the expression of liver injury indicators and inflammatory factors was significantly upregulated, which was reversed by PRA pretreatment. Network pharmacology showed that PRA alleviated PF-induced liver injury and was associated with the NOD-like receptor signaling pathway. Moreover, PF directly induced inflammasome activation in LPS-primed BMDMs which in turn induced caspase-1 activation and the secretion of downstream effector cytokines such as IL-1β. PRA pretreatment inhibited PF-induced activation of the NLRP3 inflammasome by mitigating the accumulation of mitochondrial reactive oxygen species (mtROS).
UNASSIGNED: The present study demonstrates that PRA alleviated PF induced-liver injury by inhibiting NLRP3 inflammasome activation. The results of this study are expected to inform the prevention and control of PF-induced hepatotoxicity in clinical practice.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Herbal and complementary medicine are frequently integrated with conventional medicine. We aim to report a case of severe herbal-induced liver injury (HILI) due to chronic use of green tea and protein shake. We present both clinical and laboratory evidence implicating mitochondrial toxicity and an immune response leading to a hypersensitivity reaction to the products. We have recently treated a 39-year-old man with hepatotoxicity resulting from a combination of a green tea-containing powder and a branched-chain amino acid supplement that was commenced 2 months previously. The hepatotoxicity resolved by stopping the consumption of these products and no other cause was detected. We decided to perform a lymphocyte toxicity assay (LTA) to determine if there was laboratory support for this diagnosis. LTA (% toxicity) represents the response of the mitochondria to toxic injury. To determine the role of the proinflammatory and anti-inflammatory cytokines and chemokines in the patient\'s reaction, we measured the level of cytokines and chemokine in the media of growing cells, exposed to each product or to a combination of products. The increased cytokines and chemokines are presented as the x-fold elevations from the upper limit of normal (ULN) for matrix metalloproteinase (MMP) (pg/mL × 1.5 ULN) and interleukin (IL)-1β (pg/mL × 1.8 ULN). Higher elevations were found for interferon (IFN)-β, IFN-γ, IL-8, IL 13, IL-15 (pg/mL × 2 ULN), regulated upon activation, normal T cell expressed and presumably secreted (RANTES) (pg/mL × 2 ULN), and nuclear factor (NFκB) (pg/mL × 3 ULN). The highest increases were for vascular endothelial factor (VEGF) (pg/mL × 10 ULN), tumor necrosis factor (TNF)-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL × 13 ULN). An examination of cellular markers showed the difference between programmed cell death (apoptosis) and cell death due to necrosis. In our case, cytokeratin-ccK18 (M-30) U/L was within the normal limits, suggesting that apoptosis was normal, while ccK8(M65) U/L was elevated at 1.5 × ULN. This result implies that upon the treatment of the patient\'s lymphocytes with the products, the mechanism of toxicity is necrosis. In susceptible individuals, the combination of protein and herbal tea produces mitochondrial toxicity and a strong T-lymphocyte-1 response, leading to HILI. There is a need of international reporting of adverse drug reactions by clinicians, laboratories, and pharmaceutical manufacturers to drug regulatory authorities. This requires internationally accepted standard definitions of reactions, as well as criteria for assessment.

BACKGROUND: Acetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein-coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI).
METHODS: GPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116△HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI.
RESULTS: Intrahepatic GPR116 was upregulated in human and mice with AILI. GPR116△HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116△HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with β-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model.
CONCLUSIONS: Upregulation of GPR116 on hepatocytes inhibits ER stress by binding to β-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.