Noise-induced hearing loss is a worldwide public health issue that is characterized by temporary or permanent changes in hearing sensitivity. This condition is closely linked to inflammatory responses, and interventions targeting the inflammatory gene tumor necrosis factor-alpha (TNFα) are known to mitigate cochlear noise damage. TNFα-induced proteins (TNFAIPs) are a family of translucent acidic proteins, and TNFAIP6 has a notable association with inflammatory responses. To date, there have been few reports on TNFAIP6 levels in the inner ear. To elucidate the precise mechanism, we generated transgenic mouse models with conditional knockout of Tnfaip6 (Tnfaip6 cKO). Evaluation of hair cell morphology and function revealed no significant differences in hair cell numbers or ribbon synapses between Tnfaip6 cKO and wild-type mice. Moreover, there were no notable variations in hair cell numbers or hearing function in noisy environments. Our results indicate that Tnfaip6 does not have a substantial impact on the auditory system.
Animals ; Mice, Knockout ; Hair Cells, Auditory, Inner/pathology* ; Mice ; Mice, Transgenic ; Hearing Loss, Noise-Induced ; Evoked Potentials, Auditory, Brain Stem/physiology*

OBJECTIVE To develop an individualized medication list for elderly patients by evidence-based pharmacy method， and to support clinical decisions on rational use of METHODS　Firstly， drugs with risk genetic information were screened out by systematically reviewing evidence-based pharmacy information. Secondly， researchers investigated the included drugs in lists from different data E- sources. Drugs included in three or more data sources and drugs proposed by the expert committee were then included in the medication list. Thirdly， for the drugs included in two data sources， researchers designed questionnaires to investigate the necessity of drug-related gene testing. According to the scoring results of the expert questionnaire， drugs with higher scores were included in the list. Data sources included real-world data （list of high frequency medication in hospitals， high frequency medication for elderly outpatients and inpatients in National Health Care Claims Data， drugs related to frequent medication errors and so on） and evidence-based pharmacy evidence （the websites of Clinical Pharmacogenomics Implementation Consortium， Dutch Pharmacogenetics Working Group， Food and Drug Administration and so on）. RESULTS　The study obtain 68 drugs with risk genetic information which were included in three data sources. Combined with 23 drugs proposed by the expert committee， a list containing 74 drugs was preliminarily formed after de-duplication. A total of 37 drugs included in two databases with risk genetic information were scored through the questionnaire survey to form a supplementary list of 26 drugs. This is the final composition of the list of 100 drugs developed in this study. Among them， there are 43 drugs for the central nervous system， 15 drugs for the cardiovascular system， 12 anti-tumor drugs and so on. Twelve drugs were included in six or more data sources， which mainly consisted of drugs for digestive system， all proton pump inhibitors. CONCLUSION　In this study， a list of 100 commonly used drugs which require individualized medication for the elderly was developed by evidence-based pharmacy method. The drug list will be updated in time as available evidence changes， and can provide guidance for rational use of medicines for elderly patients.

Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.
Alzheimer Disease ; metabolism ; pathology ; Amyloid beta-Peptides ; metabolism ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; chemistry ; genetics ; metabolism ; Brain ; metabolism ; Cells, Cultured ; Chloride Channels ; genetics ; metabolism ; Disease Models, Animal ; HEK293 Cells ; Humans ; Lysosomes ; genetics ; metabolism ; Mice ; Mice, Transgenic ; Microglia ; cytology ; metabolism ; Mutagenesis, Site-Directed ; Peptides ; analysis ; chemistry ; Protein Binding ; RNA Interference ; Sirtuin 1 ; antagonists & inhibitors ; genetics ; metabolism