A mouse monoclonal antibody against influenza C virus attenuates acetaminophen-induced liver injury in mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Sasaki Y
PROVIDER: S-EPMC8175586 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both in vitro and in vivo biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5β loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI in vivo. Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.
| S-EPMC9847341 | biostudies-literature
Project description:Acetaminophen (APAP) is a widely used over-the-counter antipyretic and analgesic drug. Overdose of APAP is the leading cause of hospital admission for acute liver failure. Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (Cysltr1), which protects from inflammation and oxidative stress. However, the function of montelukast in APAP-induced hepatotoxicity remains unknown. In this study, we examined whether pharmacological inhibition of Cystlr1 could protect mice against APAP-induced hepatic damage. We found that APAP treatment upregulated messenger RNA and protein levels of Cysltr1 both in vitro and in vivo. Pharmacological inhibition of Cysltr1 by montelukast ameliorated APAP-induced acute liver failure. The hepatoprotective effect of montelukast was associated with upregulation of hepatic glutathione/glutathione disulfide level, reduction in c-Jun-NH2-terminal kinase activation and oxidative stress. In mouse primary hepatocytes, inhibition of Cysltr1 by montelukast ameliorated the expression of inflammatory-related genes and APAP-induced cytotoxicity. We conclude that montelukast may be used to treat APAP-induced acute hepatic injury.
| S-EPMC6759817 | biostudies-literature
Project description:Acetaminophen-induced liver injury (AILI) is a significant health problem and represents the most frequent cause of drug-induced liver failure in the United States. The development and implementation of successful therapeutic intervention strategies have been demanding, due to significant limitations associated with the current treatment for AILI. Lactoferrin (Lac), a glycoprotein present in milk, has been demonstrated to possess a multitude of biological functions. Our study demonstrated a profound protective effect of Lac in a murine model of AILI, which was not dependent on its iron-binding ability, inhibition of acetaminophen (APAP) metabolism, or a direct cytoprotective effect on hepatocytes. Instead, Lac treatment significantly attenuated APAP-induced liver sinusoidal endothelial cell dysfunction and ameliorated hepatic microcirculation disorder. This protective effect of Lac appeared to be dependent on hepatic resident macrophages (Kupffer cells [KCs]).Collectively, our data indicate that Lac, through activation of KCs, inhibited APAP-induced liver sinusoidal endothelial cell damage and improved hepatic congestion, thereby protecting against AILI. These findings reveal the significant therapeutic potential of Lac during AILI and other types of liver diseases.
| S-EPMC2908515 | biostudies-literature
Project description:Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy.
| S-EPMC10136285 | biostudies-literature
Project description:Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies show that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the gut microbiota and their metabolic pathway, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury compared with the mice receiving feces from the APAP group. ATAB therapy also improved the gut barrier functions in mice and reduced the expression of protein zonulin. Our results revealed that gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found the monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through the change of the gut microbiota, metabolic pathways, and gut barrier function. This work suggested the gut microbiota can be the therapeutic target of the APAP-induced acute liver injury, and we performed the fundamental research for further research.
| S-EPMC9241835 | biostudies-literature
Project description:BackgroundIL-17 has been shown to be involved in liver inflammatory disorders in both mice and humans. Baicalin (BA), a major compound extracted from traditional herb medicine (Scutellariae radix), has potent hepatoprotective properties. Previous study showed that BA inhibits IL-17-mediated lymphocyte adhesion and downregulates joint inflammation. The aim of this study is to investigate the role of IL-17 in the hepatoprotective effects of BA in an acetaminophen (APAP)-induced liver injury mouse model.MethodsEight weeks male C57BL/6 (B6) mice were used for this study. Mice received intraperitoneal hepatotoxic injection of APAP (300 mg/kg) and after 30 min of injection, the mice were treated with BA at a concentration of 30 mg/kg. After 16 h of treatment, mice were killed. Blood samples and liver tissues were harvested for analysis of liver injury parameters.ResultsAPAP overdose significantly increased the serum alanine transferase (ALT) levels, hepatic activities of myeloperoxidase (MPO), expression of cytokines (TNF-α, IL-6, and IL-17), and malondialdehyde (MDA) activity when compared with the control animals. BA treatment after APAP administration significantly attenuated the elevation of these parameters in APAP-induced liver injury mice. Furthermore, BA treatment could also decrease hepatic IL-17-producing γδT cells recruitment, which was induced after APAP overdose.ConclusionOur data suggested that baicalin treatment could effectively decrease APAP-induced liver injury in part through attenuation of hepatic IL-17 expression. These results indicate that baicalin is a potential hepatoprotective agent.
| S-EPMC5113979 | biostudies-literature
Project description:BACKGROUND & AIMS:Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in the US and many other countries. Metabolism of APAP results in formation of APAP protein adducts (APAP-AD) in hepatocytes and triggers mitochondrial dysfunction and necrosis. However, the mechanisms for how APAP-AD are removed from hepatocytes remain unknown. METHODS:Mice or primary hepatocytes were treated with APAP. APAP-AD were determined by immunoblot, immunostaining and high pressure liquid chomatography with electrochemical detection analysis. RESULTS:We found that APAP-AD were detected at 1h, peaked at approximately 2h, declined at 6h and almost full removed at 24h post treatment with APAP in mouse livers and in primary mouse hepatocytes. APAP-AD displayed a punctate pattern and were colocalized with GFP-LC3 positive autophagosomes and Lamp1 positive lysosomes in APAP-treated primary hepatocytes. Moreover, isolated autophagosomes and autolysosomes from APAP-treated mouse livers contained APAP-AD, suggesting autophagy may selectively remove APAP-AD. APAP-AD were detected in both detergent soluble and insoluble pools in APAP-treated mouse livers and hepatocytes. More importantly, pharmacological inhibition of autophagy by leupeptin or chloroquine increased whereas induction of autophagy by Torin 1 decreased serum APAP-AD levels in APAP-treated mice, which correlated with alanine aminotransferase levels and liver necrosis. Furthermore, SQSTM1/p62, an autophagy receptor protein, was recruited to APAP-AD. Adenovirus-mediated shRNA knockdown of SQSTM1/p62 led to increased APAP-AD and necrosis in primary hepatocytes. CONCLUSIONS:Our data indicate that APAP-AD are removed though selective autophagy. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury. LAY SUMMARY:Acetaminophen overdose can form acetaminophen protein adducts and mitochondria damage in hepatocytes resulting in liver injury. Activation of autophagy-lysosomal degradation pathway can help to remove acetaminophen protein adducts. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury.
| S-EPMC4955750 | biostudies-literature
Project description:BackgroundDrug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury.MethodsDifferent doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection.ResultsThe results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP.ConclusionOur findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.
| S-EPMC9739375 | biostudies-literature
Project description:Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies have shown that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that the gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the members of the gut microbiota and their metabolic pathways, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury than mice that received feces from the APAP group. ATAB therapy also improved gut barrier functions in mice and reduced the expression of the protein zonulin. Our results revealed that the gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found that a monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through changes in the gut microbiota, metabolic pathways, and gut barrier function. This work suggested that the gut microbiota can be a therapeutic target of APAP-induced acute liver injury, and we performed foundation for further research.
| S-EPMC10186863 | biostudies-literature
Project description: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.
| S-EPMC9253030 | biostudies-literature