NADPH oxidase 3-associated oxidative stress and caspase 3-dependent apoptosis in the cochleae of D-galactose-induced aged rats

Du, Zhongtao; Li, Shuo; Li, Lin; Yang, Qiong; Zhang, Hongwei; Gao, Chengde

doi:10.3892/mmr.2015.4430

Cited by 12 publications

(9 citation statements)

References 54 publications

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“…Several studies indicate that loss of V-ATPase triggers apoptosis by increasing ROS. High levels of ROS result in mitochondrial membrane depolarization, release of cytochrome C and activation of apoptotic machinery that includes caspases ( Lin and Beal, 2006 ; Du et al, 2015 ; Wang et al, 2017 ). However, we observed a decrease in CellROX signals in the atp6v1f −/− mutant hair cells, indicating that elevated levels of ROS is not a cause of hair cell death in these mutants.…”

Section: Discussionmentioning

confidence: 99%

Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts

Santra

Amack

2021

Disease Models &Amp; Mechanisms

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The vacuolar type H+-ATPase (V-ATPase) is a ubiquitous membrane-bound, multi-subunit proton pump that regulates pH of cellular compartments. V-ATPase activity is known to modulate several cellular processes, but cell type-specific V-ATPase functions remain poorly understood. Patients with mutations in specific V-ATPase subunits can develop sensorineural deafness, but underlying mechanisms are unclear. Here, we show that V-ATPase mutations disrupt formation of zebrafish neuromasts, which serve as a model system to investigate the underpinnings of hearing loss. Neuromasts consist of support cells surrounding mechanosensory hair cells that function similarly to hair cells in the mammalian inner ear. In V-ATPase mutant zebrafish embryos, neuromasts are small, malformed, and contain pyknotic nuclei that denote dying cells. Using molecular markers and live imaging, we find that loss of V-ATPase induces hair cells, but not neighboring support cells, to undergo caspase-independent necrosis-like cell death. This is the first demonstration that loss of V-ATPase can lead to necrosis-like cell death in a specific cell type in vivo. Mechanistically, loss of V-ATPase reduces mitochondrial membrane potential in hair cells, which has previously been associated with necrotic cell death. Modulating the mitochondrial permeability transition pore, which regulates mitochondrial membrane potential, improves hair cell survival. These results have implications for understanding causes of sensorineural deafness, and more broadly, reveal functions for V-ATPase in regulating mitochondrial function and promoting survival of a specific cell type in vivo.

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Section: Discussionmentioning

confidence: 99%

Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts

Santra

Amack

2021

Disease Models &Amp; Mechanisms

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“…Large amounts of evidence have confirmed that chronic systemic administration of D-gal can induce aging-related changes, including the corruption of spatial learning, memory impairment, lowered antioxidant enzyme activities and increased production of ROS [30]. Therefore, chronic injection of D-gal has been demonstrated as an effective way to establish an animal model for studying cognitive disorders and aging, as well as drug testing [31]. The present study evaluated the effects of leonurine on D-gal-induced aging mice, and the results demonstrated that leonurine prevented aging.…”

Section: Discussionmentioning

confidence: 99%

Leonurine ameliorates D-galactose-induced aging in mice through activation of the Nrf2 signalling pathway

Chen

Zhou

2019

Aging

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Aging is a complex physiological phenomenon associated with oxidative stress damage. The objective of this study was to investigate the potential effects of leonurine on D-galactose-induced aging in mice and its possible mechanisms. In this study, we first tested the antioxidant activity of leonurine in vitro. A subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of leonurine. The results showed that treatment with 150 mg·kg-1 leonurine could improve the mental condition, organic index, and behavioural impairment; significantly increase the activities of antioxidative enzymes including SOD, CAT, and T-AOC; and ameliorate the advanced glycation end product (AGE) level and histopathological injury. Furthermore, the Western blotting data revealed that leonurine supplementation noticeably modulated the suppression of the Nrf2 pathway and upregulated the downstream expression of HO-1 and NOQ1 in aging mice. Additionally, leonurine treatment activated Nrf2 nuclear translocation in both aging mice and normal young mice, and the expression levels of Nrf2 in normal young mice was higher than those in naturally aging mice. In conclusion, our findings suggest that leonurine is a promising agent for attenuating the aging process, and the underlying molecular mechanisms depend on activating the Nrf2 pathway.

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“…7 A). Previous studies have linked cisplatin-induced upregulation of iNOS , NOX3 and KIM-1 to cause oxidative damage to the cochlea 47 – 49 . Similarly, we observed increases in these genes in the cochlea following infection with adenoviral vector expressing RGS17 .…”

Section: Resultsmentioning

confidence: 99%

Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

Dhukhwa

Aameri

Sheth

et al. 2021

Sci Rep

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Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.

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NADPH oxidase 3-associated oxidative stress and caspase 3-dependent apoptosis in the cochleae of D-galactose-induced aged rats

Cited by 12 publications

References 54 publications

Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts

Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts

Leonurine ameliorates D-galactose-induced aging in mice through activation of the Nrf2 signalling pathway

Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

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