Possible Pathways of Hepatotoxicity Caused by Chemical Agents

Mohi-ud-din, Roohi; Mir, Reyaz Hassan; Sawhney, Gifty; Dar, Mohd Arif; Bhat, Zulfiqar Ali

doi:10.2174/1389200220666191105121653

Cited by 54 publications

(26 citation statements)

References 126 publications

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“…When ingested accidentally, CCl 4 injures livers and kidneys within a short time. Also, CCl 4 is often used as a model agent in ALI models often used to study liver toxicity mechanisms [12].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: LP-cs Ameliorated CCl 4 -Induced Acute Liver Injury by Suppression of Cellular Stress

Xu¹,

et al. 2021

Preprint

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Background: Acute liver injury (ALI) involves excessive oxidative stress(OS) and inflammatory responses, leading to a high mortality rate due to lack of effective therapy. Carbon tetrachloride (CCl4) is widely used to induce ALI by induction of reactive oxygen species. Probiotics, including Lactobacillus plantarum ST-III, have been shown to produce antibacterial and antioxidant substances such as organic acids or bacteriocins that reduce liver damage. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (L-P-cs) on CCl4-induced liver injury remains unclear.Methods: Mice were pretreated with L-P-cs or medium for 14days before one dose of 0.2% CCl4 at 10ml/kg body weight delivered by intraperitoneal injection. CCl4-induced liver injury was examined by measuring serum levels of liver transaminases and high mobility-group box 1 protein (HMGB1) and liver histological staining. Inflammation and apoptosis in liver were evaluated by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and TUNEL staining. Apoptosis in NCTC 1469 cells was detected using CCK8 and western blotting (WB). In liver, OS and endoplasmic reticulum stress(ERS)-related proteins were measured using kits and WB.Results: L-P-cs significantly ameliorated CCl4-induced liver injury and reduced CCl4- induced inflammatory response and apoptosis, consistent with NCTC 1469 cells' results. L-P-cs also restored CCl4-induced increases in cell OS and ERS to normalize liver function. Specifically, L-P-cs pretreatment decreased CCl4-induced increases in nuclear factor (erythroid-2 related) factor 2, HO-1, superoxide dismutase, glucose regulatory protein, and activating transcription factor 6.Conclusion: L-P-cs synergistically improves liver lobule necrosis, hepatocyte inflammation, and apoptosis by reducing liver OS and ERS.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: LP-cs Ameliorated CCl 4 -Induced Acute Liver Injury by Suppression of Cellular Stress

Xu¹,

et al. 2021

Preprint

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“…CCl4 can cause hepatic damage by increasing oxidative stress and the inflammatory response ( Mohi-Ud-Din et al, 2019 ). Many chemicals showed a hepatic protective effect in the CCl4-induced mice model by activating the anti-oxidative pathway and increasing antioxidant synthesis ( Ji et al, 2019 ; Yi R. et al, 2020 ; Lyu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Yang

Yin

et al. 2021

Front. Pharmacol.

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The liver is an important metabolic organ, and acute liver injury (ALI) is potentially lethal. Itaconate, a metabolic intermediate from the tricarboxylic acid cycle, showed emerging anti-oxidative and anti-inflammation properties, and an accumulating protective effect in multiple diseases, but its role in ALI still needs to be further explored. Here we established an ALI model induced by carbon tetrachloride in mice. Our results showed that 4-Octyl itaconate (OI), a derivate of itaconate, mitigated hepatic damage by improving liver function, reducing histopathological damage, and decreasing the death of hepatocytes. Additionally, OI decreased myeloperoxidase and thiobarbituric acid reactive substances (TBARS) levels in the ALI model. OI also inhibited the inflammatory response by reducing pro-inflammatory cytokine secretion (IL-6, TNF-α, IL-1β, and MCP-1) and infiltration of macrophages and neutrophils in the ALI model. However, administration of ML385, a specified Nrf2 inhibitor, eliminated the protective properties of OI in the CCl4-induced liver injury model by increasing hepatic damage and oxidative stress. Furthermore, OI increased the expression and nuclear translocation of Nrf2 and elevated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1, while knockdown of Nrf2 eliminated these effects in murine hepatocyte NCTC 1469 under CCl4 treatment. Moreover, we found that OI reduced serum High-mobility group box 1 (HMGB1) levels in CCl4-treated mice. Finally, OI inhibited nuclear translocation of factor-kappa B (NF-𝜅B) and inflammatory cytokine production in murine macrophages. In conclusion, these results indicated that OI ameliorated CCl4-induced ALI by mitigating oxidative stress and the inflammatory response. The possible mechanism was associated with the elevation of Nrf2 nuclear translocation and inhibition of HMGB1 mediated the nuclear translocation of NF-𝜅B.

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“…Oxidative stress has a crucial role in the development of paracetamol toxicity ( 16 ). The hepatotoxicity of paracetamol is characterized by the production of its metabolite; NAPQI that can be successfully scavenged by reduced glutathione ( 17 ). The paracetamol reactive metabolite; NAPQI, accumulates and results in GSH consumption, thus decreasing GSH stores.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective effect of kaempferol glycosides isolated from Cedrela odorata L. leaves in albino mice: involvement of Raf/MAPK pathway

et al. 2021

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Background and purpose: Paracetamol is the most implicated xenobiotic in inducing hepatotoxicity. Our study aimed to determine the impact of some kaempferol glycosides isolated from the leaves of Cedrela odorata L. on paracetamol hepatotoxicity. Experimental approach: The methanolic extract of dried leaves of C. odorata L . was subjected to the combination of spectroscopic methods ( 1 H and 13 CNMR). Six kaempferol glycosides were isolated: kaempferol-3- O -β-D-glycopyranoside (astragalin), kaempferol-3- O -β-L-rhamnopyranoside, kaempferol-3- O -β-D-rutinoside, kaempferide-3- O -β-D-rutinoside, kaempferide-3- O -β-Drutinosyl-7- O -β-D-rhamnopyranoside, and kaempferol-3- O -β-D- rutinosyl-7- O -a-D-arabinopyranoside. Fifty-four female Swiss Albino mice were divided randomly into 9 groups including (1) control negative (1 mL/kg saline; IP), (2) control positive (paracetamol 300 mg/kg; IP), (3) silymarin 50 mg/kg (IP). Animals of groups 4-9 were injected with 6 different samples of isolated compounds at 100 mg/kg (IP). One h later, groups 3-9 were injected with paracetamol (300 mg/kg IP). Two h later, tissue samples were taken from all animals to assess nitrotyrosine, c-Jun N-terminal protein kinase (c-JNK), Raf -1kinase, and oxidative stress biomarkers viz . reduced glutathione (GSH) and malondialdehyde (MDA). Findings/Results: Isolated glycosides had a prominent anti-apoptotic effect via inhibition of c-JNK and Raf-1 kinase. They also exerted a powerful antioxidant effect by modulating the oxidative stress induced by paracetamol via increasing GSH, reducing MDA and nitrotyrosine concentrations compared to positive control. The glycoside (1) showed a better effect than silymarin (standard) in ameliorating the formation of nitrotyrosine, Raf-1 kinase, c-JNK, and GSH. Conclusion and implication: Kaempferol glycosides isolated for the first time from C. odorata L. leaves exerted antioxidant and antiapoptotic effects via amelioration of oxidative stress and inhibition of Raf/MAPK pathway.

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Possible Pathways of Hepatotoxicity Caused by Chemical Agents

Cited by 54 publications

References 126 publications

WITHDRAWN: LP-cs Ameliorated CCl 4 -Induced Acute Liver Injury by Suppression of Cellular Stress

WITHDRAWN: LP-cs Ameliorated CCl 4 -Induced Acute Liver Injury by Suppression of Cellular Stress

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Hepatoprotective effect of kaempferol glycosides isolated from Cedrela odorata L. leaves in albino mice: involvement of Raf/MAPK pathway

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