Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction

Physical exercise is of great significance for maintaining human health.Exercise can provide varying degrees of benefits to cognitive function at all stages of life cycle.Currently,with the aging of the world’s population and increase of life expectancy,cognitive dysfunction has gradually become a disease of high incidence,which is accompanied by neurodegenerative diseases in elderly individuals.Patients often exhibit memory loss,aphasia and weakening of orientation once diagnosed,and are unable to have a normal life.Cognitive dysfunction largely affects the physical and mental health,reduces the quality of life,and causes a great economic burden to the society.At present,most of the interventions are aimed to maintain the current cognitive level and delay deterioration of cognition.In contrast,exercise as a nonpharmacological therapy has great advantages in its nontoxicity,low cost and universal application.The molecular mechanisms underlying the effect of exercise on cognition are complex,and studies have been extensively centered on neural plasticity,the direct target of exercise in the brain.In addition,mitochondrial stability and energy metabolism are essential for brain status.Meanwhile,the organ-brain axis responds to exercise and induces release of cytokines related to cognition.In this review,we summarize the latest evidence on the molecular mechanisms underlying the effects of exercise on cognition,and point out directions for future research.

Rational design and crystallographic analysis of novel isoform-selective TRKA inhibitors for cancer therapy

To the Editor:Tropomyosin receptor kinase A/B/C(TRKA/B/C)are encoded by neurotrophic tyrosine receptor kinase 1/2/3(NTRK1/2/3),respectively.NTRK gene fusions are the most common drivers of malignancies.Additionally,TRKA is the most common oncogene in TRK family,which is detected in 7.4%of human tumors.

Therapeutic potential of alkaloid extract from Codonopsis Radix in alleviating hepatic lipid accumulation: insights into mitochondrial energy metabolism and endoplasmic reticulum stress regulation in NAFLD mice

Alkaloids are a class of naturally occurring bioactive compounds that are widely distributed in various food sources and Traditional Chinese Medicine.This study aimed to investigate the therapeutic effects and underlying mechanisms of alkaloid extract from Codonopsis Radix(ACR)in ameliorating hepatic lipid accumulation in a mouse model of non-alcoholic fatty liver disease(NAFLD)induced by a high-fat diet(HFD).The results revealed that ACR treatment effectively mitigated the abnormal weight gain and hepatic injury associated with HFD.Furthermore,ACR ameliorated the dysregulated lipid metabolism in NAFLD mice,as evidenced by reductions in serum triglyceride,total cholesterol,and low-density lipoprotein levels,accompanied by a concomitant increase in the high-density lipoprotein level.ACR treatment also demonstrated a profound anti-oxidative effect,effectively alleviating HFD-induced oxidative stress and promoting ATP production.These effects were achieved through the up-regulation of the activities of mitochondrial electron transfer chain complexes Ⅰ,Ⅱ,Ⅳ,and Ⅴ,in addition to the activation of the AMPK/PGC-1α pathway,suggesting that ACR exhibits therapeutic potential in alleviating the HFD-induced dysregulation of mitochondrial energy metabolism.Moreover,ACR administration mitigated HFD-induced endoplasmic reticulum(ER)stress and suppressed the overexpression of ubiquitin-specific protease 14(USP14)in NAFLD mice.In summary,the present study provides compelling evidence supporting the hepatoprotective role of ACR in alleviating lipid deposition in NAFLD by improving energy metabolism and reducing oxidative stress and ER stress.These findings warrant further investigation and merit the development of ACR as a potential therapeutic agent for NAFLD.

Protein tyrosine phosphatases:emerging role in cancer therapy resistance

Background:Tyrosine phosphorylation of intracellular proteins is a posttranslational modification that plays a regulatory role in signal transduction during cellular events.Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases(PTPs)contributed their role as a convergent node to mediate cross-talk between signaling pathways.In the context of cancer,PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy.This is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor microenvironment.Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors,reversing drug resistance that was responsible for clinical failures during cancer therapy.Areas covered:This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint therapy.Expert opinion:This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor regression.Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease

Parkinson’s disease(PD),known as one of the most universal neurodegenerative diseases,is a serious threat to the health of the elderly.The current treatment has been demonstrated to relieve symptoms,and the discovery of new small-molecule compounds has been regarded as a promising strategy.Of note,the homeostasis of the autolysosome pathway(ALP)is closely associated with PD,and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD.Thus,pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far.In this review,we focus on summarizing several autophagy-associated targets,such as AMPK,m TORC1,ULK1,IMPase,LRRK2,beclin-1,TFEB,GCase,ERRα,C-Abelson,and as well as their relevant small-molecule compounds in PD models,which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

Development of small molecule extracellular signal-regulated kinases(ERKs) inhibitors for cancer therapy

The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase 1/2(ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

Establishment of the Psychometric Properties of a Disaster Resilience Measuring Tool for Healthcare Rescuers in China:A Cross-Sectional Study

The aim of this study was to test the validity and reliability of a tool for measuring the disaster resilience of healthcare disaster rescuers.A cross-sectional study involving 936 healthcare disaster rescuers of the Sichuan Disaster Response Team was conducted to establish the psychometric properties of the disaster resilience measuring tool(DRMT).Item analysis,exploratory factor analysis,confirmatory factor analysis,and correlation analysis were adopted to analyze the data.Item analysis showed that all but three items had the critical ratio over 3,which indicates adequate discriminability for inclusion in the measuring tool.The exploratory factor analysis showed that 65.93%of the total variance was explained by four factors—self-efficacy,social support,positive growth,and altruism.The confirmatory factor analysis showed goodness of fit for the four-factor model:CMIN/DF(2.846),GFI(0.916≥0.90),CFI(0.949≥0.90),AGFI(0.891≥0.80),and RMSEA(0.063≤0.08).Criterion validity demonstrated significant associations of the DRMT and the Connor-Davidson Resilience Scale(P<0.01,r=0.566).Convergent validity was established by correlation with stress(P<0.05,r=-0.095),depression(P<0.01,r=-0.127),posttraumatic stress disorder-PCL-C(P<0.05,r=-0.100),compassion satisfaction(P<0.01,r=0.536),and burnout(P<0.01,r=-0.330).The DRMT demonstrated adequate internal consistency(Cronbach’s alpha>0.84)and stability over the two-week study period(intraclass correlation coefficient>0.85),and a cut-off point of 61 was suggested.The disaster resilience measuring tool has satisfactory psychometric properties and is a valid,reliable,and valuable instrument for assessing disaster resilience in healthcare rescue workers.The scale needs to be tested further among other populations and those from other cultures.

The roles of computer-aided drug synthesis in drug development

With the improvements in computer computing ability,data accumulation and rapid algorithm development,the integration of artificial intelligence(AI)and drug synthesis has been accelerated,significantly improving the design and synthesis of drug molecules.Recently,data-driven computer-aided synthesis tools have been quickly and widely applied in retrosynthetic analysis,reaction prediction and automated synthesis,which can effectively accelerate the process of drug discovery and development and improve the quality of designed and synthesized drug molecules.Here,we review the development and applications of computer-aided synthesis technology and introduce recent advances in computer-aided drug development from three aspects:computer-aided drug design,computer-aided drug synthesis route design and computer-aided intelligent drug synthesis machines.Furthermore,the challenges and opportunities of computer-aided drug synthesis technology are discussed.

Small molecules targeting protein-protein interactions for cancer therapy

Protein-protein interactions(PPIs)are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases.Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases,especially tumours.Encouragingly,selective PPI-based therapeutic agents have been rapidly advancing over the past decade,providing promising perspectives for novel therapies for patients with cancer.In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects,focusing on PPIs in disease,drug design and discovery strategies,structure-activity relationships,inherent dilemmas,and future directions.

MCDB: A comprehensive curated mitotic catastrophe database for retrieval, protein sequence alignment, and target prediction

Mitotic catastrophe(MC)is a form of programmed cell death induced by mitotic process disorders,which is very important in tumor prevention,development,and drug resistance.Because rapidly increased data for MC is vigorously promoting the tumor-related biomedical and clinical study,it is urgent for us to develop a professional and comprehensive database to curate MC-related data.Mitotic Catastrophe Database(MCDB)consists of 1214 genes/proteins and 5014 compounds collected and organized from more than 8000 research articles.Also,MCDB defines the confidence level,classification criteria,and uniform naming rules for MC-related data,which greatly improves data reliability and retrieval convenience.Moreover,MCDB develops protein sequence alignment and target prediction functions.The former can be used to predict new potential MC-related genes and proteins,and the latter can facilitate the identification of potential target proteins of unknown MC-related compounds.In short,MCDB is such a proprietary,standard,and comprehensive database for MC-relate data that will facilitate the exploration of MC from chemists to biologists in the fields of medicinal chemistry,molecular biology,bioinformatics,oncology and so on.The MCDB is distributed on http://www.combio-lezhang.online/MCDB/indexhtml/.