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2,3,4',5‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside ameliorates gentamicin‑induced ototoxicity by modulating autophagy
Yu-Hsuan Wen1, Hui-Yi Lin2, Jia-Ni Lin3
1Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan, R.O.C.
Abstract:
Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram‑negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5‑tetrahydroxystilbene‑2‑O‑β‑D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC‑2. MTT assay demonstrated that gentamicin reduced UB/OC‑2 cell viability and western blotting showed that gentamicin upregulated autophagy‑related proteins, such as Beclin, autophagy related 5 and LC3‑II. THSG significantly attenuated gentamicin‑induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy‑related proteins. Reverse‑transcription‑quantitative (RT‑q) PCR and western blotting showed that THSG against gentamicin‑induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP‑activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin‑induced ototoxicity in UB/OC‑2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.
Insights
This study shows that 2,3,4
Area of Science:
- Pharmacology
- Ototoxicity research
- Cell biology
Background:
- Gentamicin, an aminoglycoside antibiotic, is effective against gram-negative bacteria but causes ototoxicity.
- Autophagy pathway activation is implicated in gentamicin-induced auditory hair cell damage.
- Developing strategies to mitigate gentamicin ototoxicity is crucial for its clinical utility.
Purpose of the Study:
- To investigate the otoprotective mechanism of 2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) against gentamicin-induced ototoxicity in vitro.
- To elucidate the role of autophagy and the Sesn2/AMPK/mTOR pathway in THSG's protective effects.
Main Methods:
- Utilized the mouse cochlear cell line UB/OC-2 for in vitro experiments.
- Assessed cell viability using MTT assay and cytotoxicity via LDH release.
- Analyzed autophagy-related protein expression (Beclin, autophagy related 5, LC3-II) and Sesn2 using western blotting and RT-qPCR.
Main Results:
- Gentamicin exposure reduced UB/OC-2 cell viability and upregulated autophagy markers.
- THSG treatment attenuated gentamicin-induced cytotoxicity and reduced LDH release.
- THSG suppressed gentamicin-induced autophagy by downregulating Sesn2 expression, involving the AMPK/mTOR signaling pathway.
Conclusions:
- THSG demonstrates otoprotective effects against gentamicin-induced ototoxicity in cochlear cells.
- THSG mitigates ototoxicity by inhibiting autophagy through the Sesn2/AMPK/mTOR pathway.
- THSG shows potential as a therapeutic agent for preventing gentamicin-induced hearing damage.
