Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.T...Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.Therefore,the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated.In this review,we analyzed the challenges and critical points of the current anti-Aβtherapeutic strategies.In addition to Aβ,multiple pathological events such as tau hyperphosphorylation,oxidative stress,and neuroinflammation,which are involved in AD pathogenesis and synergistically drive disease progression,could be important targets for AD treatment.Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis.Systemic perspective addressing the disease pathogenesis within and outside the brain,as well as the multidomain intervention targeting risk factors and comorbidities,are important approaches for the therapeutic solutions of AD.展开更多
As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of ne...As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.展开更多
β－淀粉样蛋白（β－amyloid protein ，Aβ）在脑内的异常聚集在阿尔茨海默病（Alzheimer disease ，AD）的发生、发展中扮演着重要的角色。AD患者脑内Aβ代谢失衡，过量的Aβ蛋白会自发形成聚集体，引起神经细胞功能障碍、死亡，最...β－淀粉样蛋白（β－amyloid protein ，Aβ）在脑内的异常聚集在阿尔茨海默病（Alzheimer disease ，AD）的发生、发展中扮演着重要的角色。AD患者脑内Aβ代谢失衡，过量的Aβ蛋白会自发形成聚集体，引起神经细胞功能障碍、死亡，最终导致痴呆。目前研究显示Aβ聚集体主要为寡聚体，原纤维及纤维3种聚集形式，这3种聚集形式的构象不尽相同，对神经细胞造成的损伤方式也有所不同。进一步了解Aβ聚集体的分子结构，有助于对Aβ致病分子机制的认识，为以Aβ为靶点的AD抑制剂开发提供理论基础，本文针对最近关于Aβ聚集体分子结构的研究的前沿进展作一综述。展开更多
BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is impor...BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.AIM To explore novel hub genes for IPF therapy.METHODS Here,we used public datasets to identify differentially expressed genes between IPF patients and healthy donors.Potential targets were considered based on multiple bioinformatics analyses,especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide,forced vital capacity,and patient survival rate.The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.RESULTS We found that TDO2 was upregulated in IPF patients and predicted poor prognosis.Surprisingly,single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts,indicating that TDO2 may participate in the regulation of proliferation and survival.Therefore,we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β(TGF-β)-induced pulmonary fibrosis.Furthermore,the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation.These findings suggest that TDO2 may be a potential target for IPF treatment.Based on transcription factors-microRNA prediction and scRNA-seq analysis,elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.CONCLUSION We provided new target genes prediction and proposed blocking TGF-βproduction as a potential treatment for IPF.展开更多
Bacteria producingβ-lactamases have become a major issue in the global public health field.To restrain the development of drug resistance and reduce the abuse of antibiotics,it is very important to rapidly identify b...Bacteria producingβ-lactamases have become a major issue in the global public health field.To restrain the development of drug resistance and reduce the abuse of antibiotics,it is very important to rapidly identify bacteria producingβ-lactamases and put forward a reasonable treatment plan.Here,an integrated microfluidic chip-mass spectrometry system was proposed for rapid screening ofβ-lactamaseproducing bacteria and optimization ofβ-lactamase inhibitor dosing concentration.The concentration gradient generator followed by an array of bacterial culture chambers,as well as micro-solid-phase extraction columns was designed for sample pretreatment before mass analysis.By using the combination system,the process of the hydrolysis of antibiotics byβ-lactamase-producing bacteria could be analyzed.To validate the feasibility,four antibiotics and two antibiotic inhibitors were investigated using three strains including negative control,SHV-1 and TEM-1 strains.SHV-1 and TEM-1 strains were successfully distinguished as theβ-lactamase producing strains.And the acquired optimal concentrations ofβ-lactamase inhibitors were in accordance with the results by that obtained from the traditional microdilution broth method.The total analysis time only needed around 2 h,which was faster than conventional methods that require a few days.The technique presented herein provides an easy and rapid protocol forβ-lactamase resistance related studies,which is important for the inhibition of antimicrobial resistance development and the reduction of antibiotics abuse.展开更多
To investigate the epidemiological status of extended spectrum β lactamase (ESBL) producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) and the drug resistance profiles of such organisms ...To investigate the epidemiological status of extended spectrum β lactamase (ESBL) producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) and the drug resistance profiles of such organisms Methods A total of 282 clinical isolates of E coli and 180 of K pneumoniae were collected from different districts of Zhejiang Province Inhibitor potentiated broth dilution tests were performed for detecting extended spectrum β lactamases Etests were performed to detect the drug resistance of these strains against nine commonly used antibiotics Results The prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 34 0% and 38 3%, respectively The average prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 35 7% The resistance prevalence of extended spectrum β lactamase producing strains to ceftazidime and cefotaxime was 40% and 26% respectively, so were those to cefepime, cefoxitin, piperacillin tazobactam, cefoperazone sulbactam, amikacin and ciprofloxacin All these strains were sensitive to imipenem Conclusion The results in this study showed that the prevalence of extended spectrum β lactamases was high, while extended spectrum β lactamase producing strains were resistant to most antimicrobial agents except imipenem展开更多
基金supported by the National Natural Science Foundation of China(91749206,81930028,81625007,81870860,31921003)。
文摘Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.Therefore,the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated.In this review,we analyzed the challenges and critical points of the current anti-Aβtherapeutic strategies.In addition to Aβ,multiple pathological events such as tau hyperphosphorylation,oxidative stress,and neuroinflammation,which are involved in AD pathogenesis and synergistically drive disease progression,could be important targets for AD treatment.Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis.Systemic perspective addressing the disease pathogenesis within and outside the brain,as well as the multidomain intervention targeting risk factors and comorbidities,are important approaches for the therapeutic solutions of AD.
基金the National Natural Science Foundation of China (Grant No. 20471011)
文摘As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.
文摘β－淀粉样蛋白（β－amyloid protein ，Aβ）在脑内的异常聚集在阿尔茨海默病（Alzheimer disease ，AD）的发生、发展中扮演着重要的角色。AD患者脑内Aβ代谢失衡，过量的Aβ蛋白会自发形成聚集体，引起神经细胞功能障碍、死亡，最终导致痴呆。目前研究显示Aβ聚集体主要为寡聚体，原纤维及纤维3种聚集形式，这3种聚集形式的构象不尽相同，对神经细胞造成的损伤方式也有所不同。进一步了解Aβ聚集体的分子结构，有助于对Aβ致病分子机制的认识，为以Aβ为靶点的AD抑制剂开发提供理论基础，本文针对最近关于Aβ聚集体分子结构的研究的前沿进展作一综述。
文摘BACKGROUND Idiopathic pulmonary fibrosis(IPF)is a progressive interstitial lung disease with a high mortality rate.On this basis,exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.AIM To explore novel hub genes for IPF therapy.METHODS Here,we used public datasets to identify differentially expressed genes between IPF patients and healthy donors.Potential targets were considered based on multiple bioinformatics analyses,especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide,forced vital capacity,and patient survival rate.The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.RESULTS We found that TDO2 was upregulated in IPF patients and predicted poor prognosis.Surprisingly,single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts,indicating that TDO2 may participate in the regulation of proliferation and survival.Therefore,we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β(TGF-β)-induced pulmonary fibrosis.Furthermore,the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation.These findings suggest that TDO2 may be a potential target for IPF treatment.Based on transcription factors-microRNA prediction and scRNA-seq analysis,elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.CONCLUSION We provided new target genes prediction and proposed blocking TGF-βproduction as a potential treatment for IPF.
基金supported by Research and Development Program in Key Areas of Guangdong Province,China(No.2019B020209009)Natural Science Foundation of Guangdong Province,China(Nos.2020A1515010660 and 2022A1515011437)Shenzhen Fundamental Research and Discipline Layout project(No.JCYJ20180508152244835)。
文摘Bacteria producingβ-lactamases have become a major issue in the global public health field.To restrain the development of drug resistance and reduce the abuse of antibiotics,it is very important to rapidly identify bacteria producingβ-lactamases and put forward a reasonable treatment plan.Here,an integrated microfluidic chip-mass spectrometry system was proposed for rapid screening ofβ-lactamaseproducing bacteria and optimization ofβ-lactamase inhibitor dosing concentration.The concentration gradient generator followed by an array of bacterial culture chambers,as well as micro-solid-phase extraction columns was designed for sample pretreatment before mass analysis.By using the combination system,the process of the hydrolysis of antibiotics byβ-lactamase-producing bacteria could be analyzed.To validate the feasibility,four antibiotics and two antibiotic inhibitors were investigated using three strains including negative control,SHV-1 and TEM-1 strains.SHV-1 and TEM-1 strains were successfully distinguished as theβ-lactamase producing strains.And the acquired optimal concentrations ofβ-lactamase inhibitors were in accordance with the results by that obtained from the traditional microdilution broth method.The total analysis time only needed around 2 h,which was faster than conventional methods that require a few days.The technique presented herein provides an easy and rapid protocol forβ-lactamase resistance related studies,which is important for the inhibition of antimicrobial resistance development and the reduction of antibiotics abuse.
文摘To investigate the epidemiological status of extended spectrum β lactamase (ESBL) producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) and the drug resistance profiles of such organisms Methods A total of 282 clinical isolates of E coli and 180 of K pneumoniae were collected from different districts of Zhejiang Province Inhibitor potentiated broth dilution tests were performed for detecting extended spectrum β lactamases Etests were performed to detect the drug resistance of these strains against nine commonly used antibiotics Results The prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 34 0% and 38 3%, respectively The average prevalence of extended spectrum β lactamases in E coli and K pneumoniae was 35 7% The resistance prevalence of extended spectrum β lactamase producing strains to ceftazidime and cefotaxime was 40% and 26% respectively, so were those to cefepime, cefoxitin, piperacillin tazobactam, cefoperazone sulbactam, amikacin and ciprofloxacin All these strains were sensitive to imipenem Conclusion The results in this study showed that the prevalence of extended spectrum β lactamases was high, while extended spectrum β lactamase producing strains were resistant to most antimicrobial agents except imipenem
