Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery ...Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.展开更多
Objective： To observe the clinical efficacy of Xin＇anning Nasal Drop （XAND,心安宁滴鼻剂） in treating coronary heart disease with unstable angina pectoris （CHD-UAP）. Methods： Sixty patients with CHD-UAP were ass...Objective： To observe the clinical efficacy of Xin＇anning Nasal Drop （XAND,心安宁滴鼻剂） in treating coronary heart disease with unstable angina pectoris （CHD-UAP）. Methods： Sixty patients with CHD-UAP were assigned, according to the randomizing number table, to two groups, the control group treated with conventional Western medicine, and the treated group treated with conventional Western medicine plus XAND. The clinical efficacy and the changes of S-T segment in resting EKG and total ischemia burden （TIB） in 24-h dynamic EKG were observed. Results： The clinical efficacy, including the effect of angina alleviation, its initiation, and the effect of TOM syndrome score reduction, were significantly superior in the treated group to those in the control group （ P〈0.05 or P〈0.01 ）. The degree and extent of myocardial ischemia were significantly improved in both groups （ P〈0.01 ）, but the improvement in the treated group was better than that in the control group （ P〈0.05）. Moreover, it was worth mentioning that the immediate effect in the treated group was better than that in the control group, and the reduction of TIB, the improvement in heart rate and myocardial oxygen consumption （ immediately after the first administration or by the end of the therapeutic course）, and systolic blood pressure after treatment in the former were all superior to those in the latter, showing significant difference （ P〈0.05 or P〈0.01 ）. Conclusion： XAND has a quick effect in alleviating angina in patients with CHD-UAP, and it is worthy of further studies and spreading in clinical practice.展开更多
Adequate drug delivery across the blood–brain barrier(BBB) is a critical factor in treating central nervous system(CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is t...Adequate drug delivery across the blood–brain barrier(BBB) is a critical factor in treating central nervous system(CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization,the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2(LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine(PLL)and negatively charged surface of fibers;this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.展开更多
基金supported by the National Natural Science Foundation(52273133,52303190,82271223,82271220,82301369)Shanghai Municipal Health and Family Planning Commission(2022XD055)+3 种基金Shanghai Nat-ural Science Foundation(25ZR1402458)Shanghai Municipal Health Commission(20244Z0007)Shanghai Municipal Committee of Science and Technology(23XD1422900)Hongkou district Health Commission(Hongwei2401-03,HKLCFC202405,HKLCYQ2024-02,HKLCYQ2024-04).
文摘Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.
文摘Objective： To observe the clinical efficacy of Xin＇anning Nasal Drop （XAND,心安宁滴鼻剂） in treating coronary heart disease with unstable angina pectoris （CHD-UAP）. Methods： Sixty patients with CHD-UAP were assigned, according to the randomizing number table, to two groups, the control group treated with conventional Western medicine, and the treated group treated with conventional Western medicine plus XAND. The clinical efficacy and the changes of S-T segment in resting EKG and total ischemia burden （TIB） in 24-h dynamic EKG were observed. Results： The clinical efficacy, including the effect of angina alleviation, its initiation, and the effect of TOM syndrome score reduction, were significantly superior in the treated group to those in the control group （ P〈0.05 or P〈0.01 ）. The degree and extent of myocardial ischemia were significantly improved in both groups （ P〈0.01 ）, but the improvement in the treated group was better than that in the control group （ P〈0.05）. Moreover, it was worth mentioning that the immediate effect in the treated group was better than that in the control group, and the reduction of TIB, the improvement in heart rate and myocardial oxygen consumption （ immediately after the first administration or by the end of the therapeutic course）, and systolic blood pressure after treatment in the former were all superior to those in the latter, showing significant difference （ P〈0.05 or P〈0.01 ）. Conclusion： XAND has a quick effect in alleviating angina in patients with CHD-UAP, and it is worthy of further studies and spreading in clinical practice.
基金supported by the National Key Research and Development Program of China (2020YFA0908200)the National Natural Science Foundation of China (82271204, 81771138, and32000937)+1 种基金the Shanghai Municipal Health Commission(20204Y0354)Sanming Project of Medicine in Shenzhen(SZSM202211007)。
文摘Adequate drug delivery across the blood–brain barrier(BBB) is a critical factor in treating central nervous system(CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization,the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2(LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine(PLL)and negatively charged surface of fibers;this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.
