Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

Ruhl, Douglas S.; Du, Tingting; Choi, Jeong-Hwan; Li, Sihan; Reed, Robert M.; Freeman, M.H.; Hashisaki, George T.; Lukens, John R.; Shin, Jung-Bum

doi:10.1101/332031

Cited by 2 publications

(2 citation statements)

References 73 publications

(95 reference statements)

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“…Thus, both necroptosis and apoptosis contributed to alcohol-mediated osteopenia, and necroptosis performed the main inducement. The combination of necroptosis and apoptosis also occurred simultaneously in the process of dexamethasoneinduced MC3T3-E1 cell death [55] and affected the outcomes in liver diseases [56] and other inflammation or tissue damage [57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis

Guo

Huang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.

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Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis

Guo

Huang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Previous studies [4][5][6] proposed that aminoglycosides might enter hair cells via a mechanoelectrical transducer channel or endocytosis. The exact mechanisms behind the ototoxicity of aminoglycosides remain unclear, but possible mechanisms include oxidative stress, autophagy, caspase-dependent apoptosis, and programmed cell necrosis that depends on receptorinteracting proteins [7]. Previous studies [8,9] suggested that oxidative stress might be the main contributor to aminoglycoside-induced hearing impairment.…”

Section: Introductionmentioning

confidence: 99%

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells

et al. 2021

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Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.

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Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

Abstract: 13Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 2 publications

References 73 publications

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis

Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells

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