Epimedin B Through Enhancing NLRP3 Inflammasome Activation To Induces Idiosyncratic Hepatotoxicity

Background: The NLRP3 inflammasome plays a crucial role in the pathogenesis of various human diseases, also idiosyncratic drug-induced liver injury (IDILI). Epimedii Folium (EF) is commonly used for treating bone fractures, joint diseases and some chronic illness, but the EF also could induce IDILI. Several studies have confirmed that EF may induce liver injury by upregulating the activity of the NLRP3 inflammasome. However, the major active constituents of EF have not been well-studied. Results: In the present study, we showed that epimedin B, a major active ingredient of EF, induced the development of IDILI by promoting the activation of the NLRP3 inflammasome. Synergistic induction of mitochondrial reactive oxygen species was a crucial contributor to the promoting effect of epimedin B observed on nigericin- or ATP-induced NLRP3 inflammasome activation. Importantly, epimedin B induced liver injury in the LPS-mediated susceptibility mouse model of IDILI，while specifical NLRP3 inhibitor MCC950 pretreatment completely abrogated the Caspase-1 activation and IL-1β secretion then couldn't induce liver injury. Conclusions: Epimedin B specifically facilitated nigericin- or ATP-induced NLRP3 inflammasome activation and the development of IDILI, which is responsible for EF-induced liver injury. These findings suggest that epimedin B is one of the key constituents of liver injury caused by EF，the content of epimedin B in EF may be a risk factor for IDILI, especially in patients with diseases related to nigericin- or ATP-induced NLRP3 inflammasome activation.

Hepatotoxicity Induced by Anti-Tubercular Drugs Therapy: A Case Report

Anti-tubercular therapy induced liver injury (ATTILI) is the most important risk for the past many years. Many pre-existing factors and conditions like persisting liver injury, female gender, alcohol abuse etc. are important risk factors for the ATT induce liver injury. I read many case reports and literature review for the drugs induce liver injury, and concluded the results, ATT drugs are the most responsible for the liver injury during the therapy periods. The present case was 42-year-old male patient and known case of pulmonary tuberculosis, patients were on the ATT drugs therapy in the last 14 days. After few days of therapy, he produced signs of vomiting (multiple episode), fever (high grade), abdomen pain, coughing, loss of appetite, epigastric discomforts & generalized weakness. On general examination the patient was found to produce signs of Jaundice with yellowish appearance of the sclera. Pulmonologist had firstly withdrawal the anti-tubercular drugs therapy and started the modified anti-tubercular drugs therapy. As a Clinical pharmacist we advise the patients & patients relatives, proper monitoring of liver and renal function test should also be carried out by the health care professional specialist from time to time in order to avoid critical situations. Keywords: Anti-tubercular therapy, Anti-tubercular therapy induced liver injury, Pulmonologist, Hepatotoxicity.

Intestinal Clostridioides difficile Can Cause Liver Injury through the Occurrence of Inflammation and Damage to Hepatocytes

This study investigated if intestinal Clostridioides difficile (CD) causes liver injury. Four-week-old male C3H/HeN mice were treated with phosphate-buffered solution (control), CD, diethylnitrosamine (DEN) to induce liver injury with PBS (DEN+PBS), and DEN with CD (DEN+CD) for nine weeks. After sacrifice, livers and mesenteric lymph nodes (MLNs) were removed and bacterial translocation, transcriptomes, and proteins were analysed. CD was found in 20% of MLNs from the control and DEN+PBS groups, in 30% of MLNs from the CD group, and in 75% of MLNs from the DEN+CD groups, which had injured livers. Also, CD was detected in 50% of the livers in the DEN+CD group with CD-positive MLNs. Elevated IL-1β, HB-EGF, EGFR, TGF-α, PCNA, DES, HMGB1, and CRP expressions were observed in the CD and DEN+CD groups as compared to the control and DEN+PBS groups. Protein levels of IL-6 and HMGB1 were higher in the CD and DEN+CD groups than in the control and DEN+PBS groups. These results indicate that intestinal CD can initiate and aggravate liver injury, and the mechanism of pathogenesis for liver injury should be investigated in further studies.

Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition

Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by CHST3 and CHST13. In this study, we investigated whether dual ER inhibition in the liver could alter CHST3 and CHST13 expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased CHST3 and CHST13 expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased CHST3 and CHST13 expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that CHST3- and CHST13-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury.

Role of Fn14 in acute alcoholic steatohepatitis in mice

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14+ progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.