<i>p53</i>‐Dependent pathway and the opening of mPTP mediate the apoptosis of co‐cultured Sertoli‐germ cells induced by microcystin‐LR

Wu, Jinxia; Liu, Haohao; Huang, Hui; Yuan, Long; Liu, Chuanrui; Wang, Yueqin; Cheng, Xuemin; Zhuang, Donggang; Xu, Min; Chen, Xinghai; Losiewicz, Michael D.; Zhang, Huizhen

doi:10.1002/tox.22808

Cited by 13 publications

(3 citation statements)

References 61 publications

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“…In the early stages of mitochondria-dependent apoptosis, the MMP decreases, while the mitochondrial outer membrane permeability increases, along with high expression levels of cyto-C [51]. These two major changes facilitate the release of soluble membrane proteins from the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Damage Bovine Endometrial Epithelial Cells via the Cytochrome C-mPTP Pathway

Song,

Sun,

Liu

et al. 2023

Antioxidants

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After parturition, bovine endometrial epithelial cells (BEECs) undergo serious inflammation and imbalance between oxidation and antioxidation, which is widely acknowledged as a primary contributor to the development of endometritis in dairy cows. Nevertheless, the mechanism of oxidative stress-mediated inflammation and damage in bovine endometrial epithelial cells remains inadequately defined, particularly the molecular pathways associated with mitochondria-dependent apoptosis. Hence, the present study was designed to explore the mechanism responsible for mitochondrial dysfunction-induced BEEC damage. In vivo, the expressions of proapoptotic protein caspase 3 and cytochrome C were increased significantly in dairy uteri with endometritis. Similarly, the levels of proapoptotic protein caspase 3, BAX, and cytochrome C were markedly increased in H2O2-treated BEECs. Our findings revealed pronounced BEEC damage in dairy cows with endometritis, accompanied by heightened expression of cyto-C and caspase-3 both in vivo and in vitro. The reduction in apoptosis-related protein of BEECs due to oxidant injury was notably mitigated following N-acetyl-L-cysteine (NAC) treatment. Furthermore, mitochondrial vacuolation was significantly alleviated, and mitochondrial membrane potential returned to normal levels after the removal of ROS. Excessive ROS may be the main cause of mitochondrial dysfunction. Mitochondrial permeability transition pore (mPTP) blockade by cyclophilin D (CypD) knockdown with CSA significantly blocked the flow of cytochrome C (cyto-C) and Ca2+ to the cytoplasm from the mitochondria. Our results indicate that elevated ROS and persistent opening of the mPTP are the main causes of oxidative damage in BEECs. Collectively our results reveal a new mechanism involving ROS-mPTP signaling in oxidative damage to BEECs, which may be a potential avenue for the clinical treatment of bovine endometritis.

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Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Damage Bovine Endometrial Epithelial Cells via the Cytochrome C-mPTP Pathway

Song,

Sun,

Liu

et al. 2023

Antioxidants

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“…To damage the mitochondria, cyanotoxins, including MCs, CYN, and MC-produced cyanobacterial strains, cause an increase in intracellular ROS in fish that definitely has to act on the mitochondria’s outer membrane [ 54 , 100 , 102 , 105 , 106 ]. Based on the results from mammals, the abovementioned ROS induction may lead to a mitochondrial membrane potential drop and the opening of the mitochondrial permeability transition pore [ 168 ]. Following these events, cytochrome c is released through the mitochondrial permeability transition pore, which stimulates the activation of the downstream caspase family proteins [ 169 ].…”

Section: Cyanotoxin Exposure Triggers Mitochondrial Damage and Endopl...mentioning

confidence: 99%

A Review of Common Cyanotoxins and Their Effects on Fish

Falfushynska

Kasianchuk

Siemens

et al. 2023

Toxics

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Global warming and human-induced eutrophication drive the occurrence of various cyanotoxins in aquatic environments. These metabolites reveal diversified mechanisms of action, encompassing cyto-, neuro-, hepato-, nephro-, and neurotoxicity, and pose a threat to aquatic biota and human health. In the present paper, we review data on the occurrence of the most studied cyanotoxins, microcystins, nodularins, cylindrospermopsin, anatoxins, and saxitoxins, in the aquatic environment, as well as their potential bioaccumulation and toxicity in fish. Microcystins are the most studied among all known cyanotoxins, although other toxic cyanobacterial metabolites are also commonly identified in aquatic environments and can reveal high toxicity in fish. Except for primary toxicity signs, cyanotoxins adversely affect the antioxidant system and anti-/pro-oxidant balance. Cyanotoxins also negatively impact the mitochondrial and endoplasmic reticulum by increasing intracellular reactive oxygen species. Furthermore, fish exposed to microcystins and cylindrospermopsin exhibit various immunomodulatory, inflammatory, and endocrine responses. Even though cyanotoxins exert a complex pressure on fish, numerous aspects are yet to be the subject of in-depth investigation. Metabolites other than microcystins should be studied more thoroughly to understand the long-term effects in fish and provide a robust background for monitoring and management actions.

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“…Our study showed HFE could alleviate the decrease of Bcl2 and increase of Bax induced by MC-LR at the protein and gene levels.Abnormal expression of the Bcl2 family leads to mitochondrial damage. Meanwhile, Mitochondria are the main organelles that produce ROS, which could promote the occurrence of cell apoptosis 44,48,49. Under normal circumstances, proper mitochondrial function requires periodic opening of the mitochondrial membrane permeability transition pore (MPTP) while excessive ROS would keep the MPTP hole open, which in turn causes the reduction of mitochondrial membrane potential and the release of apoptosis related factors, activates the caspase cascade, and ultimately regulated hepatocyte apoptosis and liver damage 24,50.…”

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confidence: 99%

Hawthorn fruit extract protect against MC‐LR‐induced hepatotoxicity by attenuating oxidative stress and apoptosis

Wang

Guo

Liu

et al. 2023

Environmental Toxicology

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Microcystins (MCs) is a class of cyclic heptapeptide compounds with biological activity. There is no effective treatment for liver injury caused by MCs. Hawthorn is a medicinal and edible plant traditional Chinese medicine with hypolipidemic, reducing inflammation and oxidative stress in the liver. This study discussed the protective effect of hawthorn fruit extract (HFE) on liver damage caused by MC‐LR and the underlying molecular mechanism. After MC‐LR exposure, pathological changes were observed and hepatic activity of ALT, AST and ALP were increased obviously, but they were remarkably restored with HFE administration. In addition, MC‐LR could significantly reduce SOD activity and increase MDA content. Importantly, MC‐LR treatment resulted in mitochondrial membrane potential decreased, and Cytochrome C release, eventually leading to cell apoptosis rate increase. HFE pretreatment could significantly alleviate the above abnormal phenomena. To examine the mechanism of protection, the expression of critical molecules in the mitochondrial apoptosis pathway was examined. The levels of Bcl‐2 was inhibited, and the levels of Bax, Caspase‐9, Cleaved Caspase‐9, and Cleaved caspase‐3 were upregulated after MC‐LR treatment. HFE reduced MC‐LR‐induced apoptosis via reversing the expression of key proteins and genes in the mitochondrial apoptotic pathway. Hence, HFE could alleviate MC‐LR induced hepatotoxicity by reducing oxidative stress and apoptosis.

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p53‐Dependent pathway and the opening of mPTP mediate the apoptosis of co‐cultured Sertoli‐germ cells induced by microcystin‐LR

Cited by 13 publications

References 61 publications

Reactive Oxygen Species Damage Bovine Endometrial Epithelial Cells via the Cytochrome C-mPTP Pathway

Reactive Oxygen Species Damage Bovine Endometrial Epithelial Cells via the Cytochrome C-mPTP Pathway

A Review of Common Cyanotoxins and Their Effects on Fish

Hawthorn fruit extract protect against MC‐LR‐induced hepatotoxicity by attenuating oxidative stress and apoptosis

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