Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using tri...Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using triphenylphosphonium cation(TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel(PTX) nanocrystals(NCs) against drugresistant cancer cells. Evaluations were performed on 2 D monolayer and 3 D multicellular spheroids(MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs,the targeted PTX NCs showed the strongest cytotoxicity against both2 D MCF-7 and MCF-7/ADR cells,which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.展开更多
Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerativ...Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerative diseases,cardiovascular diseases,metabolic diseases,musculoskeletal diseases,and immune system diseases.Although the development of modern medicine has promoted human health and greatly extended life expectancy,with the aging of society,a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals.Current research on aging focuses on elucidating how various endogenous and exogenous stresses(such as genomic instability,telomere dysfunction,epigenetic alterations,loss of proteostasis,compromise of autophagy,mitochondrial dysfunction,cellular senescence,stem cell exhaustion,altered intercellular communication,deregulated nutrient sensing)participate in the regulation of aging.Furthermore,thorough research on the pathogenesis of aging to identify interventions that promote health and longevity(such as caloric restriction,microbiota transplantation,and nutritional intervention)and clinical treatment methods for aging-related diseases(depletion of senescent cells,stem cell therapy,antioxidative and anti-inflammatory treatments,and hormone replacement therapy)could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.展开更多
DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We genera...DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury.Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart failure.Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions.Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart failure.We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure.These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.展开更多
文摘Mitochondria are currently known as novel targets for treating cancer,especially for tumors displaying multidrug resistance(MDR). This present study aimed to develop a mitochondriatargeted delivery system by using triphenylphosphonium cation(TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel(PTX) nanocrystals(NCs) against drugresistant cancer cells. Evaluations were performed on 2 D monolayer and 3 D multicellular spheroids(MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs,the targeted PTX NCs showed the strongest cytotoxicity against both2 D MCF-7 and MCF-7/ADR cells,which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.
基金supported by funds from the National Key R&D Program of China(2018YFC2000100 and 2021YFE0114200)the National Natural Science Foundation of China(81770228,81770858,81600618,and 82271597)+1 种基金the Beijing Natural Science Foundation(7212086)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-050).
文摘Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerative diseases,cardiovascular diseases,metabolic diseases,musculoskeletal diseases,and immune system diseases.Although the development of modern medicine has promoted human health and greatly extended life expectancy,with the aging of society,a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals.Current research on aging focuses on elucidating how various endogenous and exogenous stresses(such as genomic instability,telomere dysfunction,epigenetic alterations,loss of proteostasis,compromise of autophagy,mitochondrial dysfunction,cellular senescence,stem cell exhaustion,altered intercellular communication,deregulated nutrient sensing)participate in the regulation of aging.Furthermore,thorough research on the pathogenesis of aging to identify interventions that promote health and longevity(such as caloric restriction,microbiota transplantation,and nutritional intervention)and clinical treatment methods for aging-related diseases(depletion of senescent cells,stem cell therapy,antioxidative and anti-inflammatory treatments,and hormone replacement therapy)could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.
基金supported by grants from the National Key R&D Program of China(2021YFE0114200,2018YFC2000100)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-050)+4 种基金the Project funded by China Postdoctoral Science Foundation(2023M732704)the National Natural Science Foundation of China(81770228,82370584,81470427 and U23A20470)the Beijing Natural Science Foundation(7232141,7212086)the Beijing Hospital Clinical Research 121 Project(121-2016004)the National High Level Hospital Clinical Research Funding(BJ-2021-199,BJ-2023-156,BJ-2019-159).
文摘DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor activity.Although DDX17 is abundantly expressed in the myocardium,its role in heart is not fully understood.We generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury.Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart failure.Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions.Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart failure.We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure.These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.
