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

doi:10.1007/s11684-021-0864-3

Front. Med.

2022, Vol. 16

Issue (4) : 637-650 https://doi.org/10.1007/s11684-021-0864-3

RESEARCH ARTICLE

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

Gaogan Jia, Huanyu Mao, Yanping Zhang, Yusu Ni(

), Yan Chen(

)

ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai 200031, China

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Abstract

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.

Keywords apigenin aminoglycosides ototoxicity oxidative stress Nrf2 signaling pathway

Corresponding Author(s): Yusu Ni,Yan Chen

About author:

Tongcan Cui and Yizhe Hou contributed equally to this work.

Just Accepted Date: 19 August 2021 Online First Date: 16 December 2021 Issue Date: 02 September 2022

Cite this article:

Gaogan Jia,Huanyu Mao,Yanping Zhang, et al. Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells[J]. Front. Med., 2022, 16(4): 637-650.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0864-3
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I4/637

Tab.1 Primers used in qPCR

Fig.1 Apigenin protected cochlear hair cells from neomycin ototoxicity. (A) Chemical structure of apigenin. (B) Diagram of the experimental process. Cochlear sensory epithelia were isolated from C57/BL6 neonatal mice and cultured in vitro for 12 h followed by neomycin treatment at the concentration of 1 mmol/L for 6 h. The cochlear explants recovered for another 24 h before they were harvested with the withdrawal of neomycin. (C) Representative images of immunofluorescence with anti-Myo7a antibody (red) and DAPI (blue) from the apical, middle, and basal turns of the cochleae. Myo7a was used as a marker of cochlear hair cells. The samples were divided into five groups: Cont (control), Neo (1 mmol/L neomycin only), and neomycin co-treated with different concentrations of apigenin. Scale bar= 100 μm. (D) Quantification of Myo7a-positive hair cells per 100 μm from different groups. Data are shown as mean±SD. **** P<0.0001. n = 6.

Fig.2 Apigenin did not affect the antibiotic efficacy of neomycin and the uptake of aminoglycosides. (A) Representative images of the disc diffusion test for groups of PBS, 20 μmol/L API, 1 mmol/L neomycin, 20 μmol/L API+ 1 mmol/L neomycin, and 50 μmol/L API+ 1 mmol/L neomycin. Scale bar= 5 mm. (B) Statistical data of inhibitory areas. (C) Representative images of Atoh1-EGFP (green), Texas Red-conjugated gentamycin (GTTR, red), and DAPI (blue) fluorescence in the mid-base turns of the cochleae. GTTR was used to assess the uptake of aminoglycosides. Atoh1-EGFP-positive cells were cochlear hair cells. The samples were divided into three groups: Cont (control), GTTR (50 μmol/L GTTR only), and API+ GTTR (20 μmol/L apigenin+ 50 μmol/L GTTR). (D) Statistical data of Atoh1-EGFP- and GTTR double-positive cells in the cochlear middle and basal turns. Scale bar= 100 μm. Data are shown as mean±SD. ns, no significant difference. n = 6.

Fig.3 Apigenin suppressed oxidative stress induced by neomycin in the hair cells. (A) Representative images of staining with anti-Myo7a antibody (green), MitoSOX (red), and DAPI (blue) from the middle turns of the cochleae. MitoSOX Red was used as a marker in evaluating ROS level. Scale bar= 100 μm. (B and C) Quantification of Myo7a and MitoSOX double-positive hair cells per 100 μm from the middle and basal turns. The samples were divided into five groups: Cont (control), Neo (1 mmol/L neomycin only), API 10 μmol/L+ Neo (10 μmol/L apigenin+ 1 mmol/L neomycin), API 20 μmol/L+ Neo (20 μmol/L apigenin+ 1 mmol/L neomycin), and API 50 μmol/L+ Neo (50 μmol/L apigenin+ 1 mmol/L neomycin). Data are shown as mean±SD. **** P<0.0001. n = 6. (D) Representative images of DCFH-DA (green) and Hoechst (blue) staining from the mid-base turn of the cochleae. DCFH-DA was used as an indicator of intracellular ROS. The samples were divided into three groups: Cont (control), Neo (1 mmol/L neomycin only), and API+ Neo (20 μmol/L apigenin+ 1 mmol/L neomycin). Scale bar= 100 μm. (E) Fluorescent quantitation of DCFH-DA from the mid-base turn. Data are shown as mean±SD. *** P<0.001. n = 6.

Fig.4 Apigenin attenuated neomycin-induced apoptosis in the hair cells. (A) Representative images of staining with anti-Myo7a antibody (red), TUNEL (green), and DAPI (blue) from the middle turn of the cochleae. TUNEL staining confirmed the presence of apoptotic cells. The samples were divided into three groups: Cont (control), Neo (1 mmol/L neomycin only), and API+ Neo (20 μmol/L apigenin+ 1mmol/L neomycin). Scale bar= 100 μm. (B and C) Quantification of Myo7a and TUNEL double-positive hair cells per 100 μm. Data are shown as mean±SD. **** P<0.0001. n = 6.

Fig.5 Apigenin upregulated Nrf2 signaling in the cochlear explants. (A and B) Relative mRNA levels of antioxidant-related genes in the cochlear explants after 3 (A) or 6 (B) h of neomycin injury with or without apigenin. qPCR data were normalized to Actb and presented as the fold of control levels. The samples were divided into four groups: Cont (control), Neo (1 mmol/L neomycin only), API+ Neo (20 μmol/L apigenin+ 1 mmol/L neomycin), and ML385+ API+ Neo (5 μmol/L ML385+ 20 μmol/L apigenin+ 1 mmol/L neomycin). Data were shown as mean±SD. *P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001. (C) Representative images of immunostaining with anti-parvalbumin antibody (green), anti-Nrf2 antibody (red), and DAPI (blue). Parvalbumin was used as a marker of cochlear hair cells. Scale bar= 100 μm.

Fig.6 Nrf2 signaling mediated the protective effect of apigenin against neomycin-induced oxidative stress and apoptosis. (A) Representative images of immunostaining with anti-Myo7a antibody (red), TUNEL (green), and DAPI (blue) from the middle turns of the cochleae. (B and C) Quantification of Myo7a and TUNEL double-positive hair cells from the middle and basal turns of the cochleae. (D) Representative images of immunostaining with anti-Myo7a antibody (green), MitoSOX (red), and DAPI (blue) from the middle turns of the cochleae. (E and F) Quantification of Myo7a and MitoSOX double-positive hair cells per 100 μm from the middle and basal turns of the cochleae. Scale bar= 100 μm. Data are shown as mean±SD. *P<0.05, **** P<0.0001. n = 6.

Fig.7 Apigenin alleviated the neomycin-induced loss of hair cells by targeting Nrf2 signaling. (A) Representative images of immunofluorescence with anti-Myo7a antibody (red) and DAPI (blue) from the apical, middle, and basal turns of the cochleae. Scale bar= 100 μm. (B) Quantification of Myo7a-positive hair cells in the apical, middle, and basal turns of the cochleae from different groups. Data are shown as mean±SD. *P<0.05, **P<0.01, ****P<0.0001. n = 6.

Fig.8 Schematic of the underlying mechanism of the protective effect of apigenin against neomycin ototoxicity. Apigenin relieved aminoglycoside-induced ototoxicity by reducing oxidative stress and inhibiting apoptosis by activating the Nrf2 axis.

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