Cellular models of stress resistance may pave ways to fight neurodegenerative diseases

Alzheimer's disease(AD),the most common form of neurodegeneration,is characterized by selective neuronal vulnerability and brain regionselective neuron demise.The entorhinal cortex and hippoc,ampal CA1 projection neurons are at greater risk in AD whereas other regions display resistance to neurodegeneration.Interestingly,the cerebellum,a phylogenetically very old region,is affected only very late in the disease progression.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Transient extreme insulin resistance in a critically ill patient:A case report

BACKGROUND Acute hyperglycemia due to insulin resistance is common in critically ill patients,typically managed with insulin infusion.However,the occurrence of transient extreme insulin resistance(EIR)requiring exceptional high-dose insulin is rare.CASE SUMMARY We present the case of a 68-year-old woman with pneumonia who suffered an out-of-hospital cardiac arrest,subsequently developing transient EIR following a new episode of sepsis.Remarkably,insulin resistance rapidly reversed when the insulin infusion rate peaked at 960 units/hour(a total of 18224 units on that day),and it was promptly titrated down to zero upon achieving the target glucose level.CONCLUSION Exceptional high-dose insulin infusion may be required in critically ill patients with stress-related EIR,which is typically transient.Clinicians should be aware of the phenomenon and cautious to avoid hypoglycemia and fluid overload during the steep titration of high-dose insulin infusion.

Combined BRAF G469A mutation and echinoderm microtubule associated protein like-4-anaplastic lymphoma kinase rearrangement with resistance:A case report and review of literature

BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.

Selenoprotein P1 as a biomarker of insulin resistance in pediatric obesity:Insights and implications

This editorial discusses the findings of Elbarky et al on the role of selenoprotein P1(SEPP1)in pediatric obesity and insulin resistance.Their study uncovered si-gnificantly lower SEPP1 Levels in children who were obese compared with hea-lthy peers,demonstrating a negative correlation between SEPP1 levels and mea-sures of adiposity and insulin resistance.These findings suggest that SEPP1 is a biomarker useful in the early identification of insulin resistance in pediatric populations.This editorial emphasizes the clinical implications of the study and calls for further research to validate and explore the role of SEPP1 in metabolic health.

Efficacy of antimicrobials in preventing resistance in solid organ transplant recipients:A systematic review of clinical trials

BACKGROUND In the absence of effective antimicrobials,transplant surgery is not viable,and antirejection immunosuppressants cannot be administered,as resistant infections compromise the life-saving goal of organ transplantation.AIM To evaluate the efficacy of antimicrobials in preventing resistance in solid organ transplant recipients.METHODS A systematic review was conducted using a search methodology consistent with the preferred reporting items for systematic reviews and meta-analyses.This review included randomized clinical trials that evaluated the efficacy of antimicrobial agents(prophylactic or therapeutic)aimed at preventing antimicrobial resistance.The search strategy involved analyzing multiple databases,including PubMed/MEDLINE,Web of Science,Embase,Scopus,and SciELO,as well as examining gray literature sources on Google Scholar.A comprehensive electronic database search was conducted from the databases’inception until May 2024,with no language restrictions.RESULTS After the final phase of the eligibility assessment,this systematic review ultimate-ly included 7 articles.A total of 2318 patients were studied.The most studied microorganisms were cytomegalovirus,although vancomycinresistant enterococci,Clostridioides difficile,and multidrug-resistant Enterobacterales were also analyzed.The antimicrobials used in the interventions were mainly maribavir,valganciclovir,gancic-lovir,and colistin-neomycin.Of concern,all clinical trials showed significant proportions of resistant microorga-nisms after the interventions,with no statistically significant differences between the groups(mean resistance 13.47%vs 14.39%),except for two studies that demonstrated greater efficacy of maribavir and valganciclovir(mean resistance 22.2%vs 41.1%in the control group;P<0.05).The total reported deaths in three clinical trials were 75,and there were 24 graft rejections in two studies.CONCLUSION All clinical trials reported significant proportions of antimicrobial-resistant microorganisms following interventions.More high-quality randomized clinical trials are needed to corroborate these results.

Impact of Genetic Diversity of Uropathogenic Escherichia coli and Klebsiella pneumoniae Strains on the Dissemination of Extended Spectrum Beta-Lactam Resistance Genes in Côte d’Ivoire

The increase and spread of bacterial resistance to extended-spectrum beta-lactam antibiotics are reported in many infections and are a real public health problem worldwide. Drug pressure is a factor that favors the emergence of a population of better adapted bacteria. However, there is no literature highlighting the genetic diversity and evolutionary structure of E. coli and K. pneumoniae in an environment with high selection pressure in Côte d’Ivoire. The objective of this study was to evaluate the genetic diversity of E. coli and K. pneumoniae strains circulating at the HKB Hospital in Abobo and at the Daloa Regional Hospital and its impact on the dissemination of extended spectrum beta-lactam resistance genes. A total of 39 strains isolated from the urinary tract of infected patients, including 30 strains of E. coli and 9 strains of K. pneumoniae were studied. A total of 39 strains isolated from the urinary tract of infected patients, including 30 strains of E. coli and 9 strains of K. pneumoniae were studied. From genomic DNA extracts, ESBL resistance genes were amplified by PCR and sequenced, in addition to genetic typing by ERIC-PCR. The data obtained were submitted to genetic and bioinformatics analyses. The results have shown a genetic diversity important in E. coli and K. pneumoniae with diversity indexs (SID) ranging from 0.5 to 0.77. The genetic structure of the bacterial species studied has shown a clonal distribution of strains with clones expressing TEM-9 and CTX-M-15 variants. Also, this clonal structure was correlated with the spread of resistance genes in E. coli and K. pneumoniae. The spread of resistant clones is a factor that might limit the fight against antibiotic resistance.

Beta-lactam antibiotic resistance among Escherichia coli isolates from patients with urinary tract infections in Vietnam:A systematic review and meta-analysis

Objective:To investigate the evolving patterns of antimicrobial resistance against beta-lactam antibiotics in Escherichia coli isolates from urinary tract infection patients in Vietnam,covering the period from 2005 to 2022.Methods:29 Descriptive studies published between 2010 and 2022 in English and Vietnamese were included in the analysis.Data on resistance rates to beta-lactam antibiotics,including cephalosporins and carbapenems,were extracted and analyzed.Weighted pooled resistance rates were calculated using random-effects models.Annual trends in resistance were assessed using linear regression analysis.Results:Among the beta-lactam antibiotics studied,Escherichia coli exhibited varying levels of resistance,with cephalosporins showing higher resistance rates compared to carbapenems.Weighted pooled resistance rates were 66%for cefotaxime,65%for ceftriaxone,54%for ceftazidime,and 56%for cefepime.In contrast,carbapenems demonstrated lower resistance rates,with weighted pooled resistance rates ranging from 3%to 4%for meropenem,ertapenem,and imipenem.Resistance rates were also observed for amoxicillin/clavulanate(35%),ticarcillin/clavulanate(26%),and piperacillin/tazobactam(12%).Significant annual increases in resistance were noted for imipenem(0.56%,P<0.001).Conclusions:This study highlights the critical issue of antimicrobial resistance in urinary tract infections in Vietnam and emphasizes the importance of prudent antibiotic use and the regular monitoring of resistance patterns.These insights are useful for guiding healthcare professionals in optimizing treatment strategies and for policymakers in formulating evidence-based clinical guidelines to combat antibiotic resistance effectively.

The influence of resistance exercise training prescription variables on skeletal muscle mass,strength,and physical function in healthy adults:An umbrella review

Purpose:The aim of this umbrella review was to determine the impact of resistance training(RT)and individual RT prescription variables on muscle mass,strength,and physical function in healthy adults.Methods:Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,we systematically searched and screened eligible systematic reviews reporting the effects of differing RT prescription variables on muscle mass(or its proxies),strength,and/or physical function in healthy adults aged>18 years.Results:We identified 44 systematic reviews that met our inclusion criteria.The methodological quality of these reviews was assessed using A Measurement Tool to Assess Systematic Reviews;standardized effectiveness statements were generated.We found that RT was consistently a potent stimulus for increasing skeletal muscle mass(4/4 reviews provide some or sufficient evidence),strength(4/6 reviews provided some or sufficient evidence),and physical function(1/1 review provided some evidence).RT load(6/8 reviews provided some or sufficient evidence),weekly frequency(2/4 reviews provided some or sufficient evidence),volume(3/7 reviews provided some or sufficient evidence),and exercise order(1/1 review provided some evidence)impacted RT-induced increases in muscular strength.We discovered that 2/3 reviews provided some or sufficient evidence that RT volume and contraction velocity influenced skeletal muscle mass,while 4/7 reviews provided insufficient evidence in favor of RT load impacting skeletal muscle mass.There was insufficient evidence to conclude that time of day,periodization,inter-set rest,set configuration,set end point,contraction velocity/time under tension,or exercise order(only pertaining to hypertrophy)influenced skeletal muscle adaptations.A paucity of data limited insights into the impact of RT prescription variables on physical function.Conclusion:Overall,RT increased muscle mass,strength,and physical function compared to no exercise.RT intensity(load)and weekly frequency impacted RT-induced increases in muscular strength but not muscle hypertrophy.RT volume(number of sets)influenced muscular strength and hypertrophy.

Biomass-enhanced Janus sponge-like hydrogel with salt resistance and highstrength for efficient solar desalination

Interfacial solar-driven evaporation technology shows great potential in the field of industrial seawater desalination, and the development ofefficient and low-cost evaporation materials is key to achieving large-scale applications. Hydrogels are considered to be promising candidates;however, conventional hydrogel-based interfacial solar evaporators have difficulty in simultaneously meeting multiple requirements, including ahigh evaporation rate, salt resistance, and good mechanical properties. In this study, a Janus sponge-like hydrogel solar evaporator (CPAS) withexcellent comprehensive performance was successfully constructed. The introduction of biomass agar (AG) into the polyvinyl alcohol (PVA)hydrogel backbone reduced the enthalpy of water evaporation, optimized the pore structure, and improved the mechanical properties. Meanwhile, by introducing hydrophobic fumed nano-silica aerogel (SA) and a synergistic foaming-crosslinking process, the hydrogel spontaneouslyformed a Janus structure with a hydrophobic surface and hydrophilic bottom properties. Based on the reduction of the evaporation enthalpy andthe modulation of the pore structure, the CPAS evaporation rate reached 3.56 kg m^(-2) h^(-1) under one sun illumination. Most importantly, owingto the hydrophobic top surface and 3D-interconnected porous channels, the evaporator could work stably in high concentrations of salt-water(25 wt% NaCl), showing strong salt resistance. Efficient water evaporation, excellent salt resistance, scalable preparation processes, and low-costraw materials make CPAS extremely promising for practical applications.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy.Prior research has illuminated reasons behind drug resistance,including increased drug efflux,alterations in drug targets,and abnormal activation of oncogenic pathways.However,there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment(TME).Recent studies on extracellular vesicles(EVs)have provided valuable insights.EVs are membrane-bound particles secreted by all cells,mediating cell-to-cell communication.They contain functional cargoes like DNA,RNA,lipids,proteins,and metabolites from mother cells,delivered to other cells.Notably,EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs.This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance,covering therapeutic approaches like chemo-therapy,targeted therapy,immunotherapy and even radiotherapy.Detecting Ev-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance.Additionally,targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance.We highlight the importance of conducting in-depth mechanistic research on EVs,their cargoes,and functional ap-proaches specifically focusing on EV subpopulations.These efforts will significantly advance the devel-opment of strategies to overcome drug resistance in anti-tumor therapy.

Reversal of tamoxifen resistance by artemisinin in ER+breast cancer:bioinformatics analysis and experimental validation

Breast cancer is the leading cause of cancer-related deaths in women worldwide,with Hormone Receptor(HR)+being the predominant subtype.Tamoxifen(TAM)serves as the primary treatment for HR+breast cancer.However,drug resistance often leads to recurrence,underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates.Artemisinin(ART)has demonstrated efficacy in inhibiting the growth of drug-resistant cells,positioning art as a viable option for counteracting endocrine resistance.This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation.Five characterized genes(ar,cdkn1a,erbb2,esr1,hsp90aa1)and seven drug-disease crossover genes(cyp2e1,rorc,mapk10,glp1r,egfr,pgr,mgll)were identified using WGCNA crossover analysis.Subsequent functional enrichment analyses were conducted.Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and-sensitized patients.scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells,suggesting artemisinin’s specific impact on tumor cells in estrogen receptor(ER)-positive BC tissues.Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes.These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.

Drug resistance mechanisms in cancers:Execution of prosurvival strategies

One of the quintessential challenges in cancer treatment is drug resistance.Several mechanisms of drug resistance have been described to date,and new modes of drug resistance continue to be discovered.The phenomenon of cancer drug resistance is now widespread,with approximately 90% of cancer-related deaths associated with drug resistance.Despite significant advances in the drug discovery process,the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy.Therefore,understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities.In the present review,I discuss the different mechanisms of drug resistance in cancer cells,including DNA damage repair,epithelial to mesenchymal transition,inhibition of cell death,alteration of drug targets,inactivation of drugs,deregulation of cellular energetics,immune evasion,tumor-promoting inflammation,genome instability,and other contributing epigenetic factors.Furthermore,I highlight available treatment options and conclude with future directions.

Selenium–nitrogen-co-doped carbon dots increase rice seedling growth and salt resistance

Soil salinity seriously affects the utilization of farmland and threatens the crop production.Here,a selenium-nitrogen-co-doped carbon dots was developed,which increased rice seedling growth and alleviated its inhibition by salt stress by foliar spraying.The treatment activated Ca^(2+)and jasmonic acid signaling pathways and increased iron homeostasis,antioxidant defense,and cell wall development of rice seedlings.It could be used to increase crop resistance to environmental stress.

Identification of Fusarium wilt resistance gene SiRLK1 in Sesamum indicum L.

Sesame Fusarium wilt(SFW),caused by Fusarium oxysporum f.sp.sesami(Fos),is one of the most devastating diseases affecting sesame cultivation.Deciphering the genetic control of SFW resistance is pivotal for effective disease management in sesame.An inheritance study on a cross between the highly resistant variety Yuzhi 11 and the highly susceptible accession Sp1 using a Fos pathogenicity group 1 isolate indicated that resistance was conferred by a single dominant allele.The target locus was located in a 1.24 Mb interval on chromosome 3 using a combination of cross-population association mapping and bulked segregant analysis.Fine genetic mapping further narrowed the interval between 21,350 and 21,401 kb.The locus Sindi_0812400 was identified as the SFW resistance gene and officially designated SiRLK1.This gene encodes a specific malectin/receptor-like protein kinase with three putative tandem kinase domains and is considered a kinase fusion protein.Sequence analysis revealed that a high proportion(49.44%)of variants within the locus was located within the kinase domainⅢ,and several of which were evidently associated with the diversity in SFW response,indicating the critical role of kinase domainⅢin expression of disease resistance.These findings provide valuable information for further functional analysis of SFW resistance genes and marker-assisted resistance breeding in sesame.

Molecular Characterization and Correlation with β-lactam Resistance of Streptococcus pneumonia Isolates in Hangzhou,China

Penicillin-binding proteins（PBPs） are the target of β-lactam antibiotics（the major treatment for Streptococcus pneumoniae infections）,and mutations in PBPs are considered as a primary mechanism for the development of β-lactam resistance in S.pneumoniae.This study was conducted to investigate the mutations in the PBPs of clinical S.pneumoniae isolates in Hangzhou,China,in correlation with β-lactam resistance.Results showed that 19 F was the predominant serotype（7/27） and 14 of the S.pneumoniae isolates were resistant to both penicillin G and cephalosporin.Genotyping results suggested that β-lactam-resistant isolates primarily exhibited single-site mutations in both the STMK and SRNVP motifs of pbp1 a in combination with double-site mutations in the STMK motif of pbp2 x,which might be the primary mechanisms underlying the β-lactam resistance of the isolates in this study.

CircTHSD4 promotes the malignancy and docetaxel (DTX) resistance in prostate cancer by regulating miR-203/HMGA2 axis

Objective:Circular ribose nudeic acids(circRNAs)are implicated in tumor progression and drug resistance of prostate cancer(PCa).The current work explored the function of circ_0005203(aircTHSD4)in the malignancy and docetaxel(DTX)resistance of PCa.Methods:circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real time reverse transcription quantitative polymerase chain reaction(RT-qPCR).In addition,a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells.In addition,we performed a Western blot(WB)assay to detect high mobility.group A2 protein(HMGA2)levels.Besides,functional associations of two molecules were investigated through dual luciferase reporter assay.Cell Counting Kit(CCK)-8,colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells,whereas flow cytometry was performed to determine cell apoptosis.Furthermore,a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells.Results:According to RT-qPCR results,circTHSD4 was up-regulated within PCa tissues and cells,which predicted the dismal prognostic outcome of PCa cases.circTHSD4 silencing within PCa cells markedly suppressed cell growth,migration,and colony fomation.circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model.Further,circTHSD4 silencing enhanced docetaxel(DTX)sensitivity in PCa cells.Furthermore,we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR 203.Conclusion:Together,our findings suggest that cirCTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR 203/HMGA2 axis.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Greatly enhanced corrosion/wear resistances of epoxy coating for Mg alloy through a synergistic effect between functionalized graphene and insulated blocking layer

The poor corrosion and wear resistances of Mg alloys seriously limit their potential applications in various industries.The conventional epoxy coating easily forms many intrinsic defects during the solidification process,which cannot provide sufficient protection.In the current study,we design a double-layer epoxy composite coating on Mg alloy with enhanced anti-corrosion/wear properties,via the spin-assisted assembly technique.The outer layer is functionalized graphene(FG)in waterborne epoxy resin(WEP)and the inner layer is Ce-based conversion(Ce)film.The FG sheets can be homogeneously dispersed within the epoxy matrix to fill the intrinsic defects and improve the barrier capability.The Ce film connects the outer layer with the substrate,showing the transition effect.The corrosion rate of Ce/WEP/FG composite coating is 2131 times lower than that of bare Mg alloy,and the wear rate is decreased by~90%.The improved corrosion resistance is attributed to the labyrinth effect(hindering the penetration of corrosive medium)and the obstruction of galvanic coupling behavior.The synergistic effect derived from the FG sheet and blocking layer exhibits great potential in realizing the improvement of multi-functional integration,which will open up a new avenue for the development of novel composite protection coatings of Mg alloys.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.