Mitochondria play a multidimensional role in the function and the vitality of the neurological system.From the generation of neural stem cells to the maintenance of neurons and their ultimate demise,mitochondria play ...Mitochondria play a multidimensional role in the function and the vitality of the neurological system.From the generation of neural stem cells to the maintenance of neurons and their ultimate demise,mitochondria play a critical role in regulating our neural pathways'homeostasis,a task that is critical to our cognitive health and neurological well-being.Mitochondria provide energy via oxidative phosphorylation for the neurotransmission and generation of an action potential along the neuron's axon.This paper will first review and examine the molecular subtleties of the mitochondria's role in neurogenesis and neuron vitality,as well as outlining the impact of defective mitochondria in neural aging.The authors will then summarize neurodegenerative diseases related to either neurogenesis or homeostatic dysfunction.Because of the significant detriment neurodegenerative diseases have on the quality of life,it is essential to understand their etiology and ongoing molecular mechanics.The mitochondrial role in neurogenesis and neuron vitality is essential.Dissecting and understanding this organelle's role in the genesis and homeostasis of neurons should assist in finding pharmaceutical targets for neurodegenerative diseases.展开更多
Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversi...Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily(MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1 p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.展开更多
Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and ...Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.展开更多
基金supported by a grant from the National Institutes for Health(K22-HL135051,to NS)。
文摘Mitochondria play a multidimensional role in the function and the vitality of the neurological system.From the generation of neural stem cells to the maintenance of neurons and their ultimate demise,mitochondria play a critical role in regulating our neural pathways'homeostasis,a task that is critical to our cognitive health and neurological well-being.Mitochondria provide energy via oxidative phosphorylation for the neurotransmission and generation of an action potential along the neuron's axon.This paper will first review and examine the molecular subtleties of the mitochondria's role in neurogenesis and neuron vitality,as well as outlining the impact of defective mitochondria in neural aging.The authors will then summarize neurodegenerative diseases related to either neurogenesis or homeostatic dysfunction.Because of the significant detriment neurodegenerative diseases have on the quality of life,it is essential to understand their etiology and ongoing molecular mechanics.The mitochondrial role in neurogenesis and neuron vitality is essential.Dissecting and understanding this organelle's role in the genesis and homeostasis of neurons should assist in finding pharmaceutical targets for neurodegenerative diseases.
基金supported by the National Key Research and Development Program of China (2020YFA0907800)the National Natural Science Foundation of China (31720103901)+2 种基金the “111” Project of China (B18022)the Fundamental Research Funds for the Central Universities (22221818014S)the Open Project Funding of the State Key Laboratory of Bioreactor Engineering,the Shandong Taishan Scholar Award,and the Novo Nordisk Foundation (NNF10CC1016517)。
文摘Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance(MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily(MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1 p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.
基金the National Program on Key Basic Research Project(973program,2013CB734000)in part by grants from the National Natural Science Foundation of China[31670052,31430002,31320103911,31400090,81302678 and 31125002]+2 种基金the Ministry of Science and Tech-nology of the People’s Republic of China[2011ZX09102-011-11,2013ZX10005004-005]China Ocean Mineral Resources R&D Association(Grant No.DY125-15-T-07)the European Union’s Seventh Framework Programme(FP7/2007-2013)under grant agreement no.312184.
文摘Multi-drug resistance of pathogenic microorganisms is becoming a serious threat,particularly to immunocompromised populations.The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies.Unfortunately,with traditional drug discovery approaches,only echinocandins was approved by FDA as a new class of antifungals in the past two decades.Drug efflux is one of the major contributors to multi-drug resistance,the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance.In this study,we combined structure-based virtual screening and whole-cell based mechanism study,identified a natural product,beauvericin(BEA)as a drug efflux pump modulator,which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette(ABC)transporters;meantime,BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species(ROS).It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole(KTC)and could cure the murine model of disseminated candidiasis.Toxicity evaluation of BEA,including acute toxicity test,Ames test,and hERG(human ether-a-go-go-related gene)test promised that BEA can be harnessed for treatment of candidiasis,especially the candidiasis caused by ABC overexpressed multi-drug resistant C.albicans.
