Globular adiponectin protects hepatocytes from tunicamycin-induced cell death via modulation of the inflammasome and heme oxygenase-1 induction

Khakurel, Amrita; Park, Pil-Hoon

doi:10.1016/j.phrs.2017.10.010

Cited by 25 publications

(15 citation statements)

References 56 publications

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“…Excessive oxidative stress directly triggers the occurrence of ER stress, which subsequently increases the expression of HO-1 in cells. The increase in HO-1 expression is a compensative auto-regulatory mechanism or a negative-feedback mechanism that is supposed to scavenge ROS and attenuate cell death caused by ER stress [42]. In the present study, we found that the amount of Nrf-2 in the nucleus of HT-22 neuronal cells was increased following OGD, while FCPR03 further increased the level of Nrf-2 in the nucleus.…”

Section: Discussionsupporting

confidence: 53%

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Qin

et al. 2020

Redox Biology

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Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation of endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative stress is an inducer of ER stress. The present study aimed to determine whether suppression of ER stress is involved in the protective effects of PDE4 inhibition against cerebral ischemia. We found that exposing HT-22 cells to oxygen-glucose deprivation (OGD) significantly activated ER stress, as evidenced by increased expression of the 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), and C/EBP-homologous protein (CHOP). Overexpression of PDE4B increased ER stress, while knocking down PDE4B or treatment with the PDE4 inhibitor, FCPR03, prevented OGD-induced ER stress in HT-22 cells. Furthermore, FCPR03 promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus. Importantly, the Nrf-2 inhibitor, ML385, blocked the inhibitory role of FCPR03 on OGD-induced ER stress. ML385 also abolished the protective role of FCPR03 in HT-22 cells subjected to OGD. Knocking down heme oxygenase-1 (HO-1), which is a target of Nrf-2, also blocked the protective role of FCPR03, enhanced the level of reactive oxygen species (ROS), and increased ER stress and cell death. We then found that FCPR03 or the antioxidant, N-Acetyl-l-cysteine, reduced oxidative stress in cells exposed to OGD. This effect was accompanied by increased cell viability and decreased ER stress. In primary cultured neurons, we found that FCPR03 reduced OGD-induced production of ROS and phosphorylation of eIF2α. The neuroprotective effect of FCPR03 against OGD in neurons was blocked by ML385. These results demonstrate that inhibition of PDE4 activates Nrf-2/HO-1, attenuates the production of ROS, and thereby attenuates ER stress in neurons exposed to OGD. Additionally, we conclude that FCPR03 may represent a promising therapeutic agent for the treatment of ER stress-related disorders.

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Section: Discussionsupporting

confidence: 53%

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Qin

et al. 2020

Redox Biology

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“…It replicates inflammatory cascade 39 . All the possible factors that induce liver damage can cause pyroptosis, including hepatotoxic compounds such as benzopyrene (Bap) 40 , CdSe/ZnS quantum dots (QDs) 41 , tunicamycin 42 , LPS 43 , hepatitis C virus (HCV) 44 ; surgical injury, such as cecal ligation and puncture (CLP) 45 ; physical injury, such as thermal shock 46 . Therefore, pyroptosis may be a good indicator of organ failure and systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 2 regulates ULK1 mediated pyroptosis during acute liver failure by the K68 acetylation site

et al. 2021

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Pyroptosis is a new necrosis pattern of hepatocyte during liver inflammation in acute liver failure (ALF). Histone deacetylase 2 (HDAC2) is associated with several pathological conditions in the liver system. The aim of this study is to investigate whether knockdown or pharmacological inhibition of HDAC2 could reduce the level of pyroptosis in ALF through ULK1-NLRP3-pyroptosis pathway. The role of HDAC2 on ULK1-NLRP3-pyroptosis pathway during ALF was detected in clinical samples. The mechanism was investigated in transfected cells or in ALF mouse model. The RNA-sequencing results revealed that ULK1 was a negative target regulatory molecule by HDAC2. During the process of pyroptosis, the HDAC2 exerted the antagonistic effect with ULK1 by the K68 acetylation site in L02 cells. Then the role of HDAC2 on ULK1-NLRP3-pyroptosis pathway in ALF mouse model was also detected. Moreover, the related molecules to ULK1-NLRP3-pyroptosis pathway were verified different expression in normal health donors and clinical ALF patients. HDAC2 in hepatocytes plays a pivotal role in an ULK1-NLRP3 pathway driven auto-amplification of pyroptosis in ALF. One of the important mechanisms is that inhibition HDAC2 to reduce pyroptosis may be by modulating the K68 lysine site of ULK1.

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“…Inflammasome activation is held responsible for the tissue damage caused by TM. 23 Tunicamycin-dependent hepatic ROS formation has also been reported. The increase in NADPH oxidase activity is held responsible for oxidant formation.…”

Section: Discussionmentioning

confidence: 96%

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

et al. 2020

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Disorders of the endoplasmic reticulum (ER) lead to cellular damage but can cause cell death if ER dysfunction is prolonged. We aimed to examine liver/kidney functions, neutral sphingomyelinase (N-SMase) activity, sphingolipid levels, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) protein expression in rats under ER stress. ER stress was induced by tunicamycin (TM) and the ER stress inhibitor taurodeoxycholic acid (TUDCA) was injected before induction of ER stress. ER stress was confirmed by increased tissue levels of GRP78. Hematological and biochemical profiles were measured by autoanalyzers while hepatic and renal injury was evaluated via microscopy and histopathological scoring. Tissue levels of C16-C24 sphingomyelins (SM), C16-C24 ceramides (CERs) and sphingosine-1-phosphate (S1P) were determined by LC-MS/MS. Tissue cPLA2 and COX-2 were measured by western blot and activity assays. Tunicamycin treatment caused kidney and liver function test abnormalities, increased hematocrit and hemoglobin levels but decreased white blood cell counts. Histopathological findings showed hepatic necroinflammation and renal tubular damage in rats treated with TM. TUDCA administration attenuated WBC abnormalities and TM- induced hepatic/renal functional impairment in ER stress, as evident by significantly restored serum ALT, AST, creatinine, and total bilirubin levels. A significant increase was observed in N-SMase activity, tissue levels of C16-C24 CERs, cPLA2 and COX-2 expression in liver and kidney tissue under ER stress. TUDCA administration decreased tissue CER levels, cPLA2 and COX-2 expression as well as prostaglandin E2 (PGE2) formation. These results signify that ER stress causes hepatic and renal toxicity as well as CER-induced PGE2 formation in liver and kidney.

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Globular adiponectin protects hepatocytes from tunicamycin-induced cell death via modulation of the inflammasome and heme oxygenase-1 induction

Cited by 25 publications

References 56 publications

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Histone deacetylase 2 regulates ULK1 mediated pyroptosis during acute liver failure by the K68 acetylation site

Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

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