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The age-related hearing loss allele (Cdh23 ahl ) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23 ahl allele to the wild-type Cdh23 + allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23 ahl allele to Cdh23 + , suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23 ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23 + allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

An MSM/Ms strain was established using Japanese wild mice, which exhibit resistance to several phenotypes associated with aging, such as obesity, inflammation, and tumorigenesis, compared to common inbred mouse strains. MSM/Ms strain is resistant to age-related hearing loss, and their auditory abilities are sustained for long durations. The age-related hearing loss 3 ( ahl3 ) locus contributes to age-related hearing in MSM/Ms strain. We generated ahl3 congenic strains by transferring a genomic region on chromosome 17 from MSM/Ms mice into C57BL/6J mice. Although C57BL/6J mice develop age-related hearing loss because of the ahl allele of the cadherin 23 gene, the development of middle- to high-frequency hearing loss was significantly delayed in an ahl3 congenic strain. Moreover, the novel age-related hearing loss 10 ( ahl10 ) locus associated with age-related hearing resistance in MSM/Ms strain was mapped to chromosome 12. Although the resistance effects in ahl10 congenic strain were slightly weaker than those in ahl3 congenic strain, slow progression of age-related hearing loss was confirmed in ahl10 congenic strain despite harboring the ahl allele of cadherin 23. These results suggest that causative genes and polymorphisms of the ahl3 and ahl10 loci are important targets for the prevention and treatment of age-related hearing loss.

C57BL/6J mice have long been studied as a model of age-related hearing loss (ARHL). In C57BL/6J mice, ARHL begins in the high-frequency range at 3 months of age and spreads toward low frequencies by 10 months of age. We previously confirmed that c.753A>G genome editing of an ahl allele (c.753A) in the cadherin 23 gene (Cdh23) suppressed the onset of ARHL until 12 months of age. We further investigated the hearing phenotypes of the original and genome-edited C57BL/6J-Cdh23 +/+ (c.753G/G) mice until 24 months of age. The hearing tests revealed that most of the C57BL/6J mice maintained good hearing levels until 14 months of age following genome editing of a Cdh23 ahl allele. However, the hearing levels of the C57BL/6J-Cdh23 +/+ mice gradually declined, and severe ARHL developed with increasing age. ARHL in the C57BL/6J mice was correlated with degeneration of the stereocilia in cochlear hair cells. The stereocilia degeneration was rescued in the C57BL/6J-Cdh23 +/+ mice at 12 months of age, but the stereocilia bundles exhibited abnormal phenotypes similar to those of the original C57BL/6J mice at more advanced ages. Therefore, genome editing of Cdh23 ahl did not completely suppress ARHL in C57BL/6J mice. We also compared the hearing levels of C57BL/6J-Cdh23 +/+ mice with those of C3H/HeN and MSM/Ms mice, which carry the Cdh23 + allele. The severity and onset patterns of ARHL in the C57BL/6J-Cdh23 +/+ mice differed from those observed in other Cdh23 +/+ mice. Therefore, we hypothesize that other susceptible and/or resistant alleles of ARHL exist in the genetic backgrounds of these mice., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of the present study was to investigate the immune-enhancing activity of selenizing Codonopsis pilosula polysaccharide (sCPPS5) in nonspecific immune response. In in vitro experiment, the results showed that sCPPS5 could promote the phagocytic uptake, NO production, and TNF-α and IL-6 secretion of RAW264.7 cells. sCPPS5 could also strongly increase the IκB-α degradation in the cytosol and the translocation of NF-κB p65 subunit into the nucleus of RAW264.7 cells. In the vivo experiment, sCPPS5 at medium doses could significantly improve the phagocytic index of peritoneal macrophages and induce the secretion of TNF-α and IL-6. Moreover, the effect of sCPPS5 was significantly better than Codonopsis pilosula polysaccharide (CPPS). These results indicated that selenylation modification could significantly enhance the immune-enhancing activity of CPPS in the nonspecific immune response.