The research and development of innovative drug have progressed remarkably, but the long development circle and high failure rate have become the bottleneck. Drug repurposing, discovering new indications of approved drugs, is a strategy to overcome these obstacles. By exploring new indications for approved drugs, rapid progress has been made in basic research and clinical translation in recent years. Rich resources of drugs, proven security, efficient development workflow and reduced cost are core advantages of this strategy, making the strategy a crucial direction of optimizing the pipeline of drug research and development. This review systematically summarizes drug repurposing cases that have received clinical approval over the past five years, and proposes core strategies for drug repurposing, including approaches based on targets, pathways, drug similarity, post-treatment phenotypes, and clinical side effects, aiming to provide some strategic guidance for drug repurposing efforts.

BACKGROUND:Pyroptosis participate in the degradation of the extracellular matrix of chondrocytes,synovial inflammation and pain,and plays an important role in the prevention and treatment of osteoarthritis.In addition,exercise can inhibit the occurrence of pyroptosis to regulate the progression of osteoarthritis,which has become a research hot spot in the prevention and treatment of osteoarthritis. OBJECTIVE:To summarize the regulatory role of pyroptosis in osteoarthritis and the mechanism of exercise-mediated pyroptosis in osteoarthritis. METHODS:PubMed and CNKI databases were searched during 1992 to 2024 with the keywords"pyroptosis,osteoarthritis,chondrocyte pyroptosis,synovial cell pyroptosis,exercise"in English and Chinese,respectively.Finally,71 relevant articles were selected according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)Osteoarthritis is a chronic degenerative joint disease characterized by the breakdown of cartilage extracellular matrix,synovial inflammation,and subchondral bone remodeling.This condition often leads to organic lesions,bone pain,and functional impairment.(2)Pyroptosis,a distinct programmed cell death mechanism,involves cell lysis and the release of inflammatory cytokines,triggering a robust inflammatory response,and is closely related to the development of osteoarthritis.Pyroptosis can result in the release of numerous inflammatory factors,thereby activate the nuclear factor kappa-B transcription and increase pyroptosis protein production,and in turn exacerbate the occurrence and development of osteoarthritis.Therefore,pyroptosis can be a new direction for the prevention and treatment of osteoarthritis.(3)Exercise has been shown to down-regulate the pyroptosis protein signaling pathway and inhibit the expression of related inflammatory factors,thereby playing a pivotal role in osteoarthritis prevention and treatment.Aerobic and anaerobic exercises can delay the pathological process of osteoarthritis by inhibiting the occurrence of pyroptosis.Moderate-intensity aerobic exercise is most effective in improving osteoarthritis by inhibiting pyroptosis signaling pathways,while anaerobic exercise can have beneficial effects on osteoarthritis by improving muscle mass.

To analyze potential adverse drug events(ADEs) associated with ustekinumab and upadacitinib in the treatment of inflammatory bowel disease(IBD) based on an international authoritative database, thereby providing evidence for clinical medication safety.

Objective:To investigate the active ingredients and targets of Compound Gastritis Mixture(CGM)in the treatment of chronic atrophic gastritis(CAG)by network pharmacology method,and to validate the potential mechanism combined with molecular docking technology and cellular experiments.Methods:The Traditional Chinese Medicine System Analysis Platform(TCMSP)and Swiss Target Prediction databases were used to select the herbal ingredients of CGM and the corresponding targets;the GeneCards and Online Mendelian Inheritance in Man(OMIM)database were used to screen the targets of CAG;the common targets of CGM and CAG were analyzed from the Venny2.1.0 platform;STRING online platform was used to construct protein-protein interaction(PPI)networks for common drug-disease targets and screen the core targets.Cytoscape 3.9.1 software was used to construct the drug-disease-target network and screen the drug core components;Gene Ontology(GO)fuctional,Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis were used to analyze the common targets of CGM and CAG;and AutoDock analysis software was used to perform molecular docking analysis of predicted main components of the drugs and core targets.The gastric mucosal epithelial cells GES-1 were induced by lipopolysaccharide(LPS)to construct CAG cell model.The GES-1 cells were divided into blank group(10%serum complete medium),model group(10 mg·L-1 LPS),and different concentrations of CGM groups(50,100,200,400,800 and 1 600 g·L-1 CGM+10 mg·L-1 LPS),and cells were incubated for 12,24,and 48 h.The cell counting kit-8(CCK-8)assay was used to detect the proliferation activities of GES-1 cells.The GES-1 cells were divided into blank group(10%serum complete medium),model group(10 mg·L-1 LPS)and CGM group(1 600 g·L-1 CGM+10 mg·L-1 LPS).Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of interleukin(IL)-6,tumor necrosis factor(TNF),serine/threonine protein kinase 1(AKT1),IL-1β,and epidermal growth factor receptor(EGFR)mRNA in the cells in various groups.Results:A total of 198 ingredients of CGM were screened,and 128 common targets with CAG were identified.The main herbal ingredients of CGM in treatment of CAG were quercetin,kaempferol,and lluteolin,which mainly acted on the core targets of IL-6,TNF,AKT1,IL-1β,and EGFR.The GO function enrichment analysis results showed that the top 15 targets mainly focused on biological processes(BP)such as apoptosis,inflammatory response and cell proliferation,mainly included cellular components(CC)such as cytoplasm,cell surface and macromolecular complexes,and mainly exerted molecular functions(MF)such as proteins,enzymes and ubiquitin-protein ligases.A total of 158 pathways were obtained from KEGG signaling pathway enrichment analysis,mainly involved cancer-related pathways,TNF signaling pathways,viral infection,programmed cell death-ligand 1(PD-L1)/programmed cell death protein-1(PD-1)pathways,apoptosis,NOD-like receptor signaling pathways,Toll-like receptor signaling pathways,EGFR,and IL-17 signaling pathways.The binding energies of the core targets IL-6,TNF,IL-1β,AKT1,and EGFR with main herbal ingredients quercetin,kaempferol,and luteolin were<-5 kcal·mol-1.The CCK-8 assay results showed that compared with blank group,after 24 and 48 h of cell culture,the proliferation activities of the cells in model group were significantly decreased(P<0.01),and the inhibition of the proliferation activity was more obvious after 48 h;therefore,48 h was selected for the modeling time;compared with model group,the proliferation activities of cells in 800 and 1 600g·L-1 GCM groups were significantly decreased(P<0.01),and the promotion of cell proliferation activity was more obvious in 1 600g·L-1 GCM group,so the intervening concentration of this drug was selected for the subsequent experiments.The RT-qPCR method results showed that compared with blank group,the expression levels of IL-6,TNF,IL-1β,AKT1,and EGFR mRNA in the cells in model group were significantly increased(P<0.01);compared with model group,the expression levels of IL-6,IL-1β,AKT1 and EGFR mRNA in the cells in CGM group were significantly decreased(P<0.01).Conclusion:CGM may play a role in the prevention and treatment of CAG through multiple ingredients such as quercetin,kaempferol and lignocerol,acting on the multiple target proteins such as IL-6,TNF,AKT1,IL-1β,and EGFR,as well as involving a variety of"inflammatory-cancer-related"pathways.

Objective To investigate whether aberrant DNA methylation of ubiquinol-cytochrome C reductase core protein 1(UQCRC1)is related to cognitive impairment caused by neonatal sevoflurane exposure.Methods A total of 94 SPF C57 mice of either sex,aged 6 d,and weighing 4～6 g,were randomly divided into 7 groups:control group(Con,n=6),sevoflurane-6 and-24 h exposure groups(Sev-6 and-24 h,n=6),control+DMSO group(Con+DMSO,n=19),control+5-aza-2'-deoxycytidine(5-AZA,methylation inhibitor)group(Con+5-AZA,n=19),sevoflurane+DMSO group(Sev+DMSO group,n=19),and sevoflurane+5-AZA group(Sev+5-AZA group,n=19).From 6 to 8 d after birth,the mice of the Sev-6 and-24 h exposure groups were exposed to 3％sevoflurane daily(with 97％oxygen,2 L/min,2 h per day),while those from the Con groups were given exposure of 100％oxygen(2 L/min,2 h per day).For the mice of the 5-AZA and DMSO groups,1 mg/kg of 5-AZA or an equal volume of DMSO was injected intraperitoneally 30 min before daily exposure.In 6 and 24 h after the last exposure to sevoflurane,6 mice from the Con,Sev-6 h,and Sev-24 h groups were euthanized for biochemical analysis,and in 24 h post-exposure,6 mice from the Con+DMSO,Con+5-AZA,Sev+DMSO,and Sev+5-AZA groups were randomly selected for biochemical analysis,while another 3 mice from above each group were also randomly selected for morphological analysis.The remaining 10 mice in these groups underwent behavioral testing(open field test,novel object test,and Y-maze test)at 30～33 d after birth to assess cognitive function,and were euthanized in 24 h after the final behavioral test.RT-qPCR and Western blotting were used to detect the hippocampal expression of UQCRC1,DNA methyltransferases(Dnmts),and methyl CpG binding protein 2(Mecp2)at mRNA and protein levels,respectively.Immunofluorescence assay was employed to observe the distribution and expression of UQCRC1 in the hippocampus.Bisulfite sequencing PCR(BSP)was applied to measure the methylation in the UQCRC1 promoter region.Results Compared with the Con group,the mRNA and protein levels of UQCRC1 were down-regulated(P<0.05),and the mRNA level of Dnmts was up-regulated(P<0.05)in both the Sev-6 h and Sev-24 h exposure groups,while the methylation level in the UQCRC1 promoter region was enhanced in the Sev-24 h exposure group(P<0.05).Additionally,the Sev+5-AZA group had obviously increased mRNA and protein levels of UQCRC1(P<0.05),and notable improvement in cognitive impairment(P<0.05)when compared with the Sev+DMSO group.Conclusion Hypermethylation of UQCRC1 promoter region and thus down-regulating its mRNA and protein expression might be the main mechanism by which repeated neonatal sevoflurane exposure induces cognitive impairment later in life.

Objective:Ménière's disease（MD） is a common disorder of the inner ear. The fluctuating clinical symptoms and the absence of gold standards for diagnosis have posed serious problems for clinical diagnosis and treatment over the years. With the development of science and technology, artificial intelligence （AI） has been widely used in the field of medicine, and the potential of AI application to MD is demonstrated. The purpose of this review is to outline the use of AI in MD. Initially, specific instances where AI aids in differentiating MD from other causes of vertigo are presented. Furthermore, the role of AI in the evaluation of Endolymphatic Hydrops （EH）, particularly through imaging and biochemical assays, is highlighted due to its correlation with MD. Additionally, the effectiveness of AI in managing MD patients and forecasting disease progression is examined. In conclusion, the prevalent challenges hindering the clinical integration of AI in MD treatment are discussed, alongside potential strategies to surmount these barriers.
Humans ; Meniere Disease/diagnosis* ; Artificial Intelligence ; Endolymphatic Hydrops/diagnosis*