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Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo

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Acta Pharmaceutica Sinica B 2022年第1期12卷 167-181页

作者： Benyu Nan Zirui Zhao Kanglun Jiang Xi Gu Huawei Li Xinsheng Huang Department of Otorhinolaryngology-Head and Neck Surgery Zhongshan HospitalFudan UniversityShanghai 200030China Department of Otorhinolaryngology-Head and Neck Surgery Wenzhou Medical UniversityAffiliated Hospital 2Wenzhou 325000China Department of Otolaryngology Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghai 200437China Department of Otolaryngology the First Affiliated Hospital of Fujian Medical UniversityFuzhou 350005China ENT Institute and Department of Otorhinolaryngology Eye&ENT HospitalState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200031China Institutes of Biomedical Sciences Fudan UniversityShanghai 200031China NHC Key Laboratory of Hearing Medicine(Fudan University) Shanghai 200031China The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science Fudan UniversityShanghai 200031China

Astaxanthine(AST) has important biological activities including antioxidant and antiinflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss(CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2(NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathwayusing quantitative PCR and Western blotting. The levels of reactive oxygen species(ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial ***, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

关键词： Astaxanthine Cisplatin Hearing loss Mitochondrial ototoxicity Reactive oxygen species Apoptosis

Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4149-4163页

作者： Xinyun Jian Cheng Wang Shijuan Wu Guo Sun Chuan Huang Chengbing Qiu Yuanzheng Liu Peter FLeadlay Dong Liu Zixin Deng Fuling Zhou Yuhui Sun Department of Hematology Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery(Ministry of Education) Wuhan UniversityWuhan 430071China School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China School of Life Sciences Co-Innovation Center of NeuroregenerationNantong Laboratory of Development and DiseasesNantong UniversityNantong 226019China Department of Biochemistry University of CambridgeCambridge CB21GAUK Department of Biochemistry and Molecular Biology Biomedicine Discovery InstituteMonash UniversityClayton VIC 3800Australia ARC Centre of Excellence for Innovations in Protein and Peptide Science Monash UniversityClayton VIC 3800Australia

Aminoglycosides(AGs)are a class of antibiotics with a broad spectrum of ***,their use is limited by safety concerns associated with nephrotoxicity and ototoxicity,as well as drug *** address these issues,semi-synthetic approaches for modifying natural AGs have generated new generations of AGs,however,with limited types of modification due to significant challenges in *** study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid *** was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase(GT)in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs,therefore referred to as genkamicins(GKs).The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK *** compounds display retained antimicrobial activity against a panel of World Health Organization(WHO)critical priority pathogens,and GK-C2a,in particular,demonstrates low ototoxicity compared to clinical drugs in zebrafish *** study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

关键词： Antibiotic Aminoglycoside biosynthesis Biosynthetic engineering ototoxicity

PGC-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4413-4430页

作者： Bin Chen Cheng Cheng Yunhao Wu Siyu Li Mo Han Le Zhen Ying Peng Suhan Guo Kaidi Shen Xia Gao Renjie Chai Guangji Wang Fang Zhou Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Department of Otolaryngology Head and Neck Surgery Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210096China Co-Innovation Center of Neuroregeneration Nantong UniversityNantong 226001China Medical Science and Technology Innovation Center Shandong First Medical University&Shandong Academy of Medical SciencesJinan 250117China State Key Laboratory of Digital Medical Engineering Department of Otolaryngology Head and Neck SurgeryZhongda HospitalSchool of Life Sciences and TechnologyAdvanced Institute for Life and HealthJiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSoutheast UniversityNanjing 210096China Department of Neurology Aerospace Center HospitalSchool of Life ScienceBeijing Institute of TechnologyBeijing 100081China

ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics(gentamicin,amikacin,neomycin)and platinum anti-tumor drugs(cisplatin,carboplatin).The inner ear and kidney share similarities in drug deposition and toxicity,but the underlying pathophysiological mechanisms remain *** the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy.A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two *** primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets(LDs)and more interactions between mitochondria and LDs,leading to a sequence of disturbances in lipid metabolism,such as increased lipid ROS and the blocked transfer of fatty acids from LDs to ***-1αdeficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs,as indicated by the exacerbated disturbance of dynamic LD turnover,increased level of oxidized lipids and decreased use of fatty *** investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria-LD interactions in drug-induced ototoxicity and nephrotoxicity,potentially providing novel avenues for intervention strategies.

关键词： Mitochondria Neomycin Nephrotoxicity ototoxicity Lipid metabolism Triacylglycerol PGC-1α PLIN3

Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity

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Journal of Otology 2017年第1期12卷 1-8页

作者： Zewen Gao Ye Chen Min-Xin Guan Division of Clinical Genetics and Genomics The Children's HospitalZhejiang University School of Medicine Institute of Genetics Zhejiang University and Department of GeneticsZhejiang University School of Medicine

Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.

关键词： Aminoglycosides ototoxicity Genetic susceptibility Mitochondrial DNA mutations

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Arsenic ototoxicity

Journal of Otology 2016年第1期11卷 13-17页

作者： Gülin Gokcen Kesici Yenimahalle Education and Research Hospital Department of Otolaryngology Head and Neck Surgery

High levels of arsenic are found in many parts of the world and more than 100 million people may have been exposed to it. There is growing evidence to indicate that arsenic has a deleterious effect on the auditory sys... 详细信息

关键词： Arsenic Exposure assessment ototoxicity

Gene expression in cisplatin ototoxicity and protection with p53 inhibitor

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Journal of Otology 2009年第2期4卷 61-70页

作者： Donald Coling Richard Salvi Center for Hearing & Deafness 137 Cary HallUniversity at Buffalo

Cisplatin damages cochlear hair cells and spiral ganglion neurons through cell death signaling pathways that are not fully understood. We used focused apoptosis gene microarrays to study early changes in gene expres- sion in cochlear cultures from P3 neonatal rats treated with cisplatin (0.2 mM). After 12 hours of cisplatin treat- ment, more than 50% of the 96 genes on the array showed a significant decrease in expression, consistent with widespread cell death. However, after 3 hours of cisplatin treatment, 10 genes showed significant increase in ex- pression in total cochlear tissue. In experiments with subsets of cochlear tissues, at 3h, cisplatin induced increased expression of 12 genes in the cochlear sensory epithelium (basilar membrane) and 11 genes in the spiral ganglion (tissue of Rosenthal’s canal, containing the spiral ganglion). These included pro- and anti-apoptotic genes in- volved in the p53 signaling pathway, TNF receptor family, NF-kappaB pathway, death domain family, death effec- tor domain family, Bcl-2 family, CARD family, TRAF family, and GTP signal transduction. Although the changes in gene expression showed an overlap between basilar membrane and spiral ganglion, other changes, which may reflect the unique response of each tissue, were also observed. Pifithrin-α blocked cisplatin-induced up-regulation of genes in the p53 signaling pathway when assayed by both superarray and real time PCR. The data add to our understanding of the involvement of p53 in cisplatin-induced ototoxicity and otoprotection, conferred by the p53 inhibitor Pifithrin-α.

关键词： cisplatin p53 Pifithrin-α gene expression ototoxicity cochlea hair cells spiral ganglion neurons

Partial Protection by Lipoic Acid Against Carboplantin-induced ototoxicity in Rats

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Biomedical and Environmental Sciences 2005年第3期18卷 198-206页

作者： KAZIM HUSAIN CRAIG WHITWORTH SATU M. SOMANI LEONARD P. RYBAK Departments of Surgery Southern Illinois University School of Medicine Springfield IL 62794 USADepartments of Surgery Southern Illinois University School of Medicine Springfield IL 62794 USADepartments of Pharmacology Southern Illinois University School of Medicine Springfield IL 62794 USADepartments of Surgery Southern Illinois University School of Medicine Springfield IL 62794 USA

Objective To investigate the alterations in auditory brainstem evoked responses (ABRs) and the changes of carboplatin-induced ototoxicity in the cochlear oxidant/antioxidant systems and otoprotection by an antioxidant lipoate. Methods Male wistar rats were divided into four groups and treated as follows: 1) vehicle (saline) control, 2) carboplatin (256 mg/kg, i.p.), 3) lipoate (100 mg/kg, i.p.), 4) lipoate + carboplatin. Post-treatment ABRs were performed after four days and rats were sacrificed with their cochleae harvested and analyzed. Results Carboplatin significantly elevated ABR threshold above the pretreatment thresholds. Lipoate+carboplatin treated rats showed decreased elevation of hearing threshold. Carboplatin significantly depleted cochlear reduced to oxizized glutathione (GSH/GSSG) ratio, whereas lipoate+carboplatin treatment increased GSH/GSSG ratio. Carboplatin significantly decreased cochlear copper zinc-superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST) activities and enzyme protein expressions and a significant increase in Mn-SOD activity, protein expression and malondialdehyde (MDA) level. Cochlear antioxidant enzyme activities, enzyme protein expressions and MDA level were partially restored in lipoate+carboplatin treated rats, compared to carboplatin alone. Conclusion Carboplatin-induced ototoxicity is related to impairment of cochlear antioxidant system and otoprotection conferred by lipoate is associated with partial sparing of the cochlear antioxidant defense system.

关键词： Carboplatin Alpha-lipoic acid ototoxicity Antioxidants Rats

ototoxicity induced by kanamycin in iron-deficient young rats

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Journal of Medical Colleges of PLA(China) 1991年第1期6卷 78-83页

作者：迟放鲁萧轼之李兆基江德胜孙爱华 Department of Otolaryngology Changhai HospitalSecond Military Medical UniversityShanghai 200433

Using auditory electrophysiological,histopathological,enzymehistochemical and scanning electron microscopic techniques,we observed thechanges of function and structure of cochlea in iron-deficient growing rats receiv-ing kanamycin *** results showed that at an equal dose ofkanamycin,hearing loss and hair cell damage were more serious,and incidence ofhearing loss was much higher in iron-deficient rats than in normal *** of succinate dehydrogenase activity of cochlea induced by interaction ofkanamycin and iron deficiency was more obvious than that by either one of *** deficiency can increase the sensitivity of cochlea to *** resultsindicated that iron deficiency may be one of the reasons for high incidence ofototoxic deafness in children,and it should be cautious when using such drugs inchildren with iron-deficient anemia.

关键词： kanamycin ototoxicity iron deficiency hearing loss cochlea

Calpain mediated cisplatin-induced ototoxicity in mice

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Neural Regeneration Research 2013年第21期8卷 1995-2002页

作者： Liang Chang Aimei Wang Party and Government Affairs Office Jinzhou Central Hospital Department of Physiology Liaoning Medical University

Ototoxic drug-induced apoptosis of inner ear cells has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cell apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cells. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin （2.5, 3.5, 4.5, 5.5 mg/kg）. Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cells, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an increased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cisplatin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role.

关键词： neural regeneration biological factor cisplatin mice cochlea apoptosis calpain auditory brainstem response ototoxicity immunofluorescence staining image analysis technique western blotting grants-supported paper neuroregeneration