Objective To investigate the effects of YAP on the occurrence and progression of acute liver failure by regulating the ferroptosis pathway and its underlying mechanism. Methods A total of 20 8-week-old C57BL/6 mice were randomly divided into four groups: a control group, an acute liver failure model group, a YAP agonist XMU-MP-1 treatment group and a YAP inhibitor verteporfin treatment group, five mice for each group. HE staining was used to observe the pathological changes of hepatic inflammation and necrosis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by liver biochemistry. Iron (Fe), malondialdehyde (MDA), glutathione (GSH) determination kits were used to measure their levels in liver tissues of each group. The changes of hepatocyte mitochondrial in each group were observed by electron microscopy. Real time PCR and Western blot analysis were used to detect the mRNA and protein expressions of YAP, glutathione peroxidase 4 (GPX4) and 5-lipoxygenase (5-LOX). Results Compared with the control group, mice in the acute liver failure model group and the YAP inhibitor verteporfin treatment group showed severe liver tissue congestion with inflammatory cell infiltration and structural damage to hepatic lobules. Liver injury was alleviated in the XMU-MP-1 treatment group. With the occurrence of liver failure, plasma ALT and AST levels significantly increased, and liver function was improved in XMU-MP-1 treatment group. Electron microscopy showed that mitochondria in hepatocytes of mice with liver failure became smaller and bilayer membrane density increased, while mitochondria changes in the XMU-MP-1 group were alleviated. In addition, the acute liver failure model group showed an increase in Fe and MDA contents, decreased protein expressions of GPX4, and enhanced expression of 5-LOX, suggesting that ferroptosis was involved in acute liver failure in C57BL/6 mice. Ferroptosis was inhibited by activation of YAP. Conclusion Activation of YAP may ameliorate liver injury by inhibiting ferroptosis.
Animals ; Mice ; Ferroptosis ; Glutathione ; Liver Failure ; Liver Failure, Acute/drug therapy* ; Mice, Inbred C57BL ; Verteporfin ; YAP-Signaling Proteins/metabolism*

OBJECTIVE: The maintenance of the correction of kyphotic deformity is one of the difficult problem in tuberculous spondylitis after anterior debriment and fusion with tricortical bone graft. The goal of this study is to find out the efficacy of titanium mesh cage impacted with autogenous bone chip in tuberculous spondylitis treated with anterior intervertebral fusion. MATERIALS AND METHODS: Twelve patients were treated with anterior intervertebral fusion using titanium mesh cage for tuberculous spondylitis from January 1996 to June 1999. We analized the changes in the correction of kyphotic deformity, changes of ESR and CRP, fusion state and recurrence after anterior intervertebral fusion with titanium mesh cage. RESULTS: Clinical symptoms were improved in all twelve patients without any neurologic complications. The mean kyphotic angle corrected was 7.3 degrees immediately after operation, but the loss of correction of kyphotic angle was 2.2 degrees after 3 months and 2.6 degrees after 6 months. We found that the loss of correction of kyphotic deformity occurred mainly within the first 3 months after surgery. Only one patient, suffered from acute hepatic failure after first operation and had an insufficient anti-tuberculous medication therapy, showed recurrence of tuberculous spondylitis after 6 months. The patient underwent a second operation with posterior fixation procedure with good outcome. The changes of ESR and CRP were not specifically important factor to reveal recurrence of tuberculosis of the spine in our series. CONCLUSION: The surgical procedure of tuberculous spondylitis using titanium mesh cage with bone chip seems to be an effective procedure to minimize loss of the correction of kyphotic deformity without any aggravating inflammatory change and recurrence with titanium mesh cage, when sufficient debridement and anti-tuberculous chemotherapy are achieved.
Congenital Abnormalities ; Debridement ; Drug Therapy ; Humans ; Liver Failure, Acute ; Recurrence ; Spine ; Spondylitis* ; Titanium* ; Transplants ; Tuberculosis

Differential gene expression profiles in Balb/cJ mouse model of acute hepatic failure infected with MHV-3 virus intervened by anti-hepatic failure compound (AHFC) and the changes of cytokines regulated by genes were investigated. The Balb/cj mice were divided into AHFC-intervened group and control group randomly. Acute hepatic failure model of Balb/cJ mice infected with MHV-3 virus was established. The survival rate in the two groups was observed. It was found that the survival rate in the AHFC-intervened group and control group was 90% and 50% respectively 48 h after intraperitoneal injection of MHV-3 (P<0.05). Before and after the experiment, the cytokines in peripheral blood of the survival mice were determined, and RNA was extracted from survival mouse liver tissue for the analysis of the differential gene expression by a 36 kb mouse oligonucleotide DNA array. In all the genes of microarray there were 332 genes expressed differently in the two groups, in which 234 genes were up-regulated and 78 genes down-regulated. Through clustering analysis, the differential expression of immune related genes, including TNF receptor superfamily, Kctd9, Bcl-2, Fgl2, IL-8, IL-6, IFN-gamma, TNF-alpha etc. might be related with the curative effectiveness of AHFC. It was suggested that AHFC can balance the immune state of mouse model of acute hepatic failure infected with MHV-3 virus mainly through regulating the expression of immune related genes, decrease the immune damage and inhibit liver cell apoptosis of mouse acute hepatic failure model obviously so as to increase the survival rate of mouse models of acute hepatic failure.
Coronavirus Infections/*complications ; Drugs, Chinese Herbal/therapeutic use ; Gene Expression Profiling ; Hepatitis, Viral, Animal/complications ; Liver Failure, Acute/*drug therapy ; Liver Failure, Acute/etiology ; Liver Failure, Acute/genetics ; Mice, Inbred BALB C ; Murine hepatitis virus ; Phytotherapy ; Random Allocation

Drugs, Chinese Herbal ; therapeutic use ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Liver Failure, Acute ; prevention & control ; Male ; Phytotherapy

Animals ; Disease Models, Animal ; Ephedra ; chemistry ; Galactosamine ; Lipopolysaccharides ; Liver Failure, Acute ; chemically induced ; drug therapy ; Protective Agents ; pharmacology ; Rats

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe²⁺, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe²⁺, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Liver Failure, Acute/drug therapy* ; Isothiocyanates/pharmacology* ; Glutathione ; Histone Deacetylase 6

Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function results in altered mentation and coagulopathy in individuals without previously recognized liver disease. The outcomes of patients with ALF vary greatly according to etiology, and the etiology of ALF varies markedly by geographical region. In Korea, about 90% of ALF are associated with etiologies that usually result in poor outcomes, including hepatitis B virus (HBV) infection and herbal remedies. The main causes of death in patients with ALF are increased intracranial pressure, systemic infection, and multi-organ failure. Recent advances in the intensive care of patients with ALF have contributed to a marked improvement in their overall survival. Emergency adult to adult living-donor liver transplantation (LDLT) can be performed expeditiously and safely for patients with ALF, and greatly improves survival rate as well as deceased-donor transplantation. As the window during which transplantation is possible is limited, emergency adult LDLT should be considered to be one of the first-line treatment options in patients with ALF, especially in regions in which ALFs are caused by etiologies associated with poor outcome and the supply of organs is very limited.
Drug-Induced Liver Injury/complications ; Hepatitis B/complications ; Humans ; Kidney Failure, Acute/etiology ; Liver Failure, Acute/*etiology/mortality/therapy ; Liver Transplantation ; Prognosis ; Republic of Korea ; Respiration Disorders/etiology ; Survival Rate

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, anti-neoplastic drugs), and signal and assessment of DILI in clinical trials.
Humans ; Chemical and Drug Induced Liver Injury/therapy* ; Drug-Related Side Effects and Adverse Reactions ; Liver Failure, Acute ; Dietary Supplements/adverse effects* ; Risk Factors

Acute Disease ; Bacterial Infections ; prevention & control ; Brain Edema ; drug therapy ; etiology ; Critical Care ; Hepatic Encephalopathy ; etiology ; therapy ; Humans ; Intracranial Hypertension ; etiology ; therapy ; Liver Failure, Acute ; etiology ; nursing ; therapy ; Liver Transplantation ; nursing ; standards

OBJECTIVETo investigate the impact of early rapid virological response on the outcomes of hepatitis B associated acute on chronic liver failure during antiviral treatment.

METHODS106 acute on chronic liver failure patients in our hospital from January 2008 to July 2010 were enrolled in present study retrospectively. Besides internal medicine therapy, all patients received lamivudine (100 mg/d) or entecavir (0.5 mg/d) treatment. The profile of liver biochemistry, prothrombin time activity and viral load were detected at baseline and week 4, respectively. The patients were divided into HBV DNA negative group and HBV DNA positive group according to the viral load at week 4. The clinical features and treatment outcomes were compared between groups. Frequency variables were compared by x2 test or Fisher's exact test. Continuous variables were compared using independent samples T-test. The factors that impact on the treatment outcomes were determined using stepwise multivariate logistic regression analysis.

RESULTSAt the week 4, the TBil and PTA in HBV DNA positive group [(261.6+/-205.6)mumol/L and 44.7%+/-19.7%, respectively] were significantly different from those in HBV DNA negative group [(160.1+/-173.4) mumol/L and 56.8%+/-23.1%, respectively] ( t = 2.190 and -2.077, respectively, P less than 0.05). The non-effective rate of HBVDNA positive group (50%, 9/18) was significantly higher than that of HBV DNA negative group (14.8%, 13/88) (x2 = 9.235, P less than 0.01). By using stepwise multivariate logistic regression analysis, the disease stage and HBV DNA undetectable at week 4 were the independent factor. The OR values of disease stage and HBV DNA undetectable were 6.559 and 0.209, respectively, and 95% CI was 2.316~18.576 and 0.058~0.747, respectively.

CONCLUSIONThe rapid suppression of viral load by nucleotide analogue may improve the efficacy of hepatitis B associated acute on chronic liver failure treatment. The early rapid virological response within first 4 weeks may contribute to the prediction of the treatment outcomes.

Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; End Stage Liver Disease ; drug therapy ; virology ; Female ; Hepatitis B ; drug therapy ; Humans ; Liver Failure, Acute ; drug therapy ; virology ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Treatment Outcome ; Viral Load