Caspase inhibitor z-VAD-FMK increases the survival of hair cells after Actinomycin-D-induced damage in vitro

Chang, Hui-Min; Sun, Fei; Tian, Keyong; Wang, Weilong; Zhou, Ke; Zha, Dingjun; Qiu, Jianhua

doi:10.1016/j.neulet.2020.135089

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…Recently, there have been some new inhibitors against caspase, such as Z-VAD-FMK [ 37 ], VX-765 [ 38 ] and wedelolactone [ 39 ], but they are all expensive. Functional exploration of old drugs means reduced costs for the research and development of new pharmaceuticals.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway

Cai

Sun

et al. 2022

Renal Failure

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Acute kidney injury (AKI) is a serious condition with high mortality. The most common cause is kidney ischemia/reperfusion (IR) injury, which is thought to be closely related to pyroptosis. Disulfiram is a well-known alcohol abuse drug, and recent studies have shown its ability to mitigate pyroptosis in mouse macrophages. This study investigated whether disulfiram could improve IR-induced AKI and elucidated the possible molecular mechanism. We generated an IR model in mouse kidneys and a hypoxia/reoxygenation (HR) injury model with murine tubular epithelial cells (MTECs). The results showed that IR caused renal dysfunction in mice and triggered pyroptosis in renal tubular epithelial cells, and disulfiram improved renal impairment after IR. The expression of proteins associated with the classical pyroptosis pathway (Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-related specific protein (ASC), caspase-1, N-GSDMD) and nonclassical pyroptosis pathway (caspase-11, N-GSDMD) were upregulated after IR. Disulfiram blocked the upregulation of nonclassical but not all classical pyroptosis pathway proteins (NLRP3 and ASC), suggesting that disulfiram might reduce pyroptosis by inhibiting the caspase-11-GSDMD pathway. In vitro , HR increased intracellular ROS levels, the positive rate of PI staining and LDH levels in MTECs, all of which were reversed by disulfiram pretreatment. Furthermore, we performed a computer simulation of the TIR domain of TLR4 using homology modeling and identified a small molecular binding energy between disulfiram and the TIR domain. We concluded that disulfiram might inhibit pyroptosis by antagonizing TLR4 and inhibiting the caspase-11-GSDMD pathway.

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Section: Discussionmentioning

confidence: 99%

Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway

Cai

Sun

et al. 2022

Renal Failure

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“…Next, we tested whether suppression of apoptosis or necroptosis in the hippocampus can alleviate the behavioral changes induced by sepsis. Necrostatin-1 (Nec-1) [a specific inhibitor of necroptosis ( Cao and Mu, 2021 )] and benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) [a specific inhibitor of apoptosis ( Chang et al, 2020 )] were administered intracerebroventricularly to mice immediately after CLP surgery. Then, their behaviors were observed 14 days after CLP ( Supplementary Figure S3A, B ).…”

Section: Resultsmentioning

confidence: 99%

Neuronal MD2 induces long-term mental impairments in septic mice by facilitating necroptosis and apoptosis

Fan

et al. 2022

Front. Pharmacol.

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Sepsis-associated encephalopathy (SAE) is a complication of sepsis with high morbidity rates. Long-lasting mental health issues in patients with SAE result in a substantial decrease in quality of life. However, its underlying mechanism is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to mental dysfunction in sepsis. In a mouse model of sepsis constructed by cecal ligation and puncture (CLP), altered behavior was detected by the open field, elevated-plus maze and forced swimming tests on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of septic mice. Long-lasting depression-like behaviors were detected in the CLP mice, as well as significant increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting myeloid differentiation factor 2 (MD2), the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treating mental health issues in sepsis by inhibiting necroptosis and apoptosis.

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“…Apoptosis and necroptosis were related according to Ramsay's rule in the brains of the septic mice Next, we tested whether suppression of apoptosis or necroptosis in the hippocampus can alleviate the mental dysfunction induced by sepsis. Necrostatin-1 (Nec-1) (a speci c inhibitor of necroptosis [14]) and benzyloxycarbonyl-Val-Ala-Asp-uoromethyl ketone (Z-VAD-FMK) (a speci c inhibitor of apoptosis [15]) were administered intracerebroventricularly to mice immediately after CLP surgery. Then, we observed their behaviors at 14 days after CLP (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Fan¹,

et al. 2021

Preprint

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Sepsis-associated encephalopathy (SAE) is a complication of sepsis that has high morbidity rates. Long-lasting depression is a major mental health disorder in patients with SAE that results in a substantial decrease in quality of life and economic burden. However, the underlying mechanism of SAE is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to depression in sepsis. In a mouse model of cecal ligation and puncture (CLP), we detected mental impairments by the open field test, elevated-plus maze and forced swimming test on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of the septic mice. These mice showed depression-like behaviors at 14 days after CLP, with substantial increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting the function of MD2, the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treatment of mental health issues in sepsis by inhibiting necroptosis and apoptosis.

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Caspase inhibitor z-VAD-FMK increases the survival of hair cells after Actinomycin-D-induced damage in vitro

Cited by 4 publications

References 21 publications

Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway

Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway

Neuronal MD2 induces long-term mental impairments in septic mice by facilitating necroptosis and apoptosis

Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

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