ABSTRACT
Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.T260A, p.R422W, and p.R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‒49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‒17.9%, which was significantly higher than that (6.9%‒7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
Subject(s)
Humans , Apoptosis Inducing Factor/metabolism , NAD/metabolism , Dimerization , ApoptosisABSTRACT
@#Objective To investigate the effect of enteral nutritional support beginning at different time on aspiration events and immune function in the early post-traumatic (within 14 days) period in patients with severe traumatic brain injury.Methods From June, 2018, to February, 2021, 75 patients with acute traumatic brain injury admitted in the Department of Neurosurgery of the Second People's Hospital of Lianyungang were randomly divided into early feeding group (24 to 48 hours, n=35) and delayed feeding group (48 to 120 hours, n=40). The 14-day reflux rate, aspiration rate, incidence of aspiration pneumonia, immune indexes and complications were compared between two groups.Results There was no significant difference in the reflux rate, aspiration rate and the incidence of aspiration pneumonia between the two groups (P > 0.05). The levels of IgG, IgA, and complements C3 and C4 were significantly higher in the early feeding group than in the delayed feeding group (|t| > 1.720, P<0.001). The incidence of non-aspiratory lung infections was significantly lower in the early feeding group than in the delayed feeding group (χ2=4.728, P<0.05).Conclusion Initiating enteral nutrition within 24 to 48 hours after injury may preserve immune function and reduce the incidence of non-aspiratory lung infections in patients with severe traumatic brain injury.