Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice.

BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen (APAP). However, the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear. AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation. METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury. C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment. We detected the effects of C2-FH on liver function, inflammatory response and complement activation. Additionally, RNA-sequencing (RNA-Seq) analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury. RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity, aspartate aminotransferase activity and lactate dehydrogenase, and reduced liver tissue necrosis caused by APAP. Moreover, it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury. RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury. CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.

Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice

Fibrin(ogen)-Independent Role of Plasminogen Activators in Acetaminophen-Induced Liver Injury

Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice

High Fischer ratio oligopeptides from hard-shelled mussel: Preparation and hepatoprotective effect against acetaminophen-induced liver injury in mice

Excess acetaminophen(APAP) can be converted by the cytochrome P450 system to the toxic metabolite N-acetyl-p-benzoquinoneimine(NAPQI), which consumes glutathione(GSH). When GSH is depleted, NAPQI covalently binds with proteins, inducing mitochondrial dysfunction and oxidative stress and thereby leading to hepatotoxicity. Schisandrin C(SinC) is a dibenzocyclooctadiene derivative isolated from Schisandra chinensis. Although there is some evidence showing that SinC has hepatoprotective activity, its protective effect and mechanism on APAP-induced liver injury remain unclear. In this paper, an acute liver injury mouse model was established by intraperitoneal injection of APAP at a dose of 400 mg·kg~(-1) to evaluate the effect of SinC administration on the APAP-induced liver injury and its mechanism through an animal experiment. At the same time, a potential candidate drug was provi-ded for traditional Chinese medicine(TCM) prevention and treatment of overdose APAP-induced liver injury. In the APAP-induced liver injury mouse model, we found that SinC can relieve hepatic histopathological lesions and significantly reduce the activities of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP). It was also capable of increasing the content of GSH and superoxide dismutase(SOD) and decreasing the levels of total bilirubin(TBIL), direct bilirubin(DBIL), malondialdehyde(MDA), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). Further analysis showed that SinC decreased the content of CYP2 E1 in liver tissues at protein and mRNA levels and increased nuclear factor erythroid 2-related factor 2(Nrf2) and the expression of its downstream targets(including HO-1, NQO1 and GCLC). Taken together, the above results indicate that SinC can alleviate APAP-induced liver injury by reducing the expression of CYP2 E1, suppressing apoptosis, improving inflammatory response and activating the Nrf2 signaling pathway to inhibit oxidative stress.

Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.

SW033291 promotes liver regeneration after acetaminophen-induced liver injury in mice.

Objective：Gagam-Gongjin-dan (GGD) is an oriental medicinal prescription composited with Cervi parvum Cornu, Corni Fructus, Angelica Gigantis Radix, Lycii Fructus, Dioscoreae Rhizoma, Citri Pericarpium, Gastrodiae Rihzoma, Agastachis Herba, Cassiae cortex, Scutellariae Radix and Schisandrae Fructus. The purpose of this study was to investigate the effects of GGD extract against acetaminophen (APAP)-induced liver injury in mice. Methods：GGD extract was prepared by extracting with methanol for 7 days. The extract was freeze-dried following filtration through vacuum distillation system. The first, we investigated the antioxidant effects of GGD extract on electronic donating ability (DPPH), nitrite (NO) scavenging and superoxide dismutase (SOD)-like activity. The next, we investigated the possible hepatoprotective effect of GGD extract administration against acetaminophen-induced liver injury in mice. Mice were orally administrated with or without GGD extract of different doses (25-100 mg/kg/day) one times per day for 6 days. After 3 days, APAP was orally applied with a single dose (400 mg/kg). Results：GGD extract increased DPPH, NO and SOD-like activities in dose dependant. APAP treatment significantly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in plasma. Also, APAP treatment significantly evaluated lipid peroxidation product thiobarbituric reacting substances (TBARS) and depleted some antioxidant enzymes (superoxide dismutase, catalase, d-aminolevulinate dehydratase and gluthathione peroxidase activities) in liver homogenates compared to the control group. However, the orally administration of GGD extract was able to counteract these effects. Histological studies provided supportive evidence for biochemical analysis Conclusions：These results suggest that GGD extract has a potential antioxidant and hepatoprotective effect against APAP-induced liver injury, these properties may contribute to liver disease care.

Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1.

Acute liver injury is a common consequence of taking overdose of acetaminophen (APAP). The aim of this study was to evaluate the antioxidant activity and hepatoprotective effect of a mangrove plant Sonneratia apetala fruit extract (SAFE) on APAP-induced liver injury in mice. Mice were orally pretreated with SAFE (100, 200, and 400 mg/kg) daily for one week. The control and APAP groups were intragastrically administered with distilled water, and NAC group was treated with N-Acetyl-L-cysteine (NAC) before APAP exposure. The results manifested that SAFE significantly improved survival rates, attenuated hepatic histological damage, and decreased the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum in APAP-exposed mice. SAFE treatment also increased glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity, enhanced catalase (CAT), and total antioxidant capacity (T-AOC), as well as reducing malondialdehyde (MDA) level in liver. In addition, the formation of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and elevation of myeloperoxidase (MPO) in APAP-exposed mice were inhibited after SAFE treatment. And SAFE also displayed high DPPH radical scavenging activity and reducing power in vitro. The main bioactive components of SAFE such as total phenol, flavonoid, condensed tannin, and carbohydrate were determined. The current study proved that SAFE exerted potential protective effect against APAP-induced acute liver injury, which might be associated with the antioxidant and anti-inflammatory activities of SAFE.

Application of Interleukin-22 Mediates Protection in Experimental Acetaminophen-Induced Acute Liver Injury

Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy and c-Jun N-terminal kinase activation

ADAMTS13 Plays a Critical Role in Acetaminophen-Induced Acute Liver Injury in Mice, and Can be a Novel Therapeutic Option

Magnolin ameliorates acetaminophen-induced liver injury in mice via modulating the MAPK pathway and lipid metabolism.