During the traumatic brain injury(TBI),improved expression of circulatory miR-21 serves as a diagnostic feature.Low levels of exosome-miR-21 in the brain can effectively improve neuroinflammation and bloodebrain barri...During the traumatic brain injury(TBI),improved expression of circulatory miR-21 serves as a diagnostic feature.Low levels of exosome-miR-21 in the brain can effectively improve neuroinflammation and bloodebrain barrier(BBB)permeability,reduce nerve apoptosis,restore neural function and ameliorate TBI.We evaluated the role of macrophage derived exosomes-miR-21(M-Exos-miR-21)in disrupting BBB,deteriorating TBI,and Rg1 interventions.IL-1β-induced macrophages(ⅡA)-Exos-miR-21 can activate NF-kB signaling pathway and induce the expressions of MMP-1,-3 and-9 and downregulate the levels of tight junction proteins(TJPs)deteriorating the BBB.Rg1 reduced miR-21-5 p content in ⅡA-Exos(RⅡA-Exos).The interaction of NMIIAe HSP90 controlled the release of Exos-miR-21,this interaction was restricted by Rg1.Rg1 could inhibit the Exos-miR-21 release in peripheral blood flow to brain,enhancing TIMP3 protein expression,MMPs proteolysis,and restricting TJPs degradation thus protected the BBB integrity.Conclusively,Rg1 can improve the cerebrovascular endothelial injury and hold the therapeutic potential against TBI disease.展开更多
Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of ...Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains unknown.Here,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia.Furthermore,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.展开更多
Objective:In this study,the influence of puerarin,paeoniflorin,and menthol on the structure and barrier function of tight junctions(TJs)in MadineDarby canine kidney epithelial(MDCK)and MDCK-multi-drug resistance 1(MDR...Objective:In this study,the influence of puerarin,paeoniflorin,and menthol on the structure and barrier function of tight junctions(TJs)in MadineDarby canine kidney epithelial(MDCK)and MDCK-multi-drug resistance 1(MDR1)cells was evaluated to determine the mechanisms by which the drugs cross the bloodebrain barrier(BBB).Method:Cells were treated with puerarin,paeoniflorin,and menthol followed by immunohistochemical staining with occludin,claudin-1,and F-actin.The cells were then observed using laser-scanning confocal microscopy.Average optical density(AOD)of the immunofluorescence images of the proteins were analyzed using ImageJ software while Transepithelial electrical resistance(TEER)was measured using an epithelial voltohmmeter.Results:Confocal microscopy revealed that puerarin-and paeoniflorin-treated tight junction proteins were conspicuous while menthol suppressed their expression.Correspondingly,AOD values of cells treated with puerarin or paeoniflorin,or both showed no difference compared to the control group(P>.05)while the menthol group value was downregulated.In 3 h,TEER of cells not treated with menthol were similar to the control group,while treatment with menthol significantly decreased TEER value(P<.05).In addition,application of menthol decreased TEER in MDCK cells earlier than in MDCK-MDR1 cells.Conclusion:Menthol but not puerarin and paeoniflorin may enhance paracellular transport and improve drug penetration of the BBB by disrupting the structure and,thereby,weakening the barrier function of TJs.展开更多
Background:Scalp combing,as an ancient method of health care,has been used for thousands of years in traditional Chinese medicine.Although this method is considered to be beneficial for the blood circulation of the he...Background:Scalp combing,as an ancient method of health care,has been used for thousands of years in traditional Chinese medicine.Although this method is considered to be beneficial for the blood circulation of the head,the underlying mechanisms remain unclear.Methods:Both human participants and mice were used in this study.In participants,the scalp was stimulated by combing continuously for 5 min,and the temperature was measured using infrared thermal imaging before and after stimulation.In mice,the temperature was determined before and at 5,15,and 30 min after a 5-min scalp mechanical stimulation(SMS).Additionally,the vasculature of the mice was labeled with retro-orbital fluorescein isothiocyanate-dextran injection,and the capillaries were observed directly under a confocal microscope.Using in vivo CLARITY imaging and the spectrofluorometric detection of Evans Blue dye extravasation,the bloodebrain barrier permeability was assessed.Results:SMS increased the temperature of the left ear significantly in human(P=.0247)while can slightly increase the temperature of the right ear and the face without significant difference(P>.05).Moreover,SMS can significantly slow the decrease in the temperature of the external auditory canal at 5 min(P=.0153)and in body temperature at 15 min(P=.0295)after SMS whereas no significant difference in body temperature at 30 min(P>.05)compared with control mice.Furthermore,capillaries of the ear with a diameter of less than 8 mm were significantly dilated(P=.0006)following SMS and the number of dextran dots was higher at 15 min(P>.05)and 30 min(F=10.98,P=.037)after SMS intervention compared with control mice.Conclusion:Our study provides strong evidence to support the notion that scalp combing can improve extra-and intracranial blood circulation under healthy conditions.展开更多
The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system.However,the challenge of practical and precise targeting of malignant ...The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system.However,the challenge of practical and precise targeting of malignant cells persists.To address this,engineered nanoparticles(NPs)have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions,owing to their small size,low immunogenicity,and ease of surface modification.This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy,encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness.Moreover,it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities.Finally,the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy,which could shape the path for future advancements in this promising field.展开更多
The neurovascular unit(NVU)is highly responsible for cerebral homeostasis and its dysfunc-tion emerges as a critical contributor to Alzheimer’s disease(AD)pathology.Hence,rescuing NVU dysfunction might be a viable ap...The neurovascular unit(NVU)is highly responsible for cerebral homeostasis and its dysfunc-tion emerges as a critical contributor to Alzheimer’s disease(AD)pathology.Hence,rescuing NVU dysfunction might be a viable approach to AD treatments.Here,we fabricated a self-regulated muti-func-tional nano-modulator(siR/PIO@RP)that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy.The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state(low/high RAGE expression)of the target site via a feedback loop.siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy,such as reducing cerebral Ab load,relieving neuroinflammation,and alleviating the dysfunction of NVU.Overall,the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.展开更多
基金supported by National Natural Science Foundation of China(81601034 and 31850410476)Anhui Provincial Science Fund for Distinguished Young Scholars(2008085J39,China)+5 种基金Focus on Research and Development Projects in Anhui Province(1804a0802225,China)State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources(CMEMR2020B13,Guangxi Normal University,China)the Natural Science Foundation of Anhui Educational Committee(KJ2018ZD044 and KJ2020A0728,China)Key Disciplines of Pharmacy(2019xjzdxk2,China)the Back-up Candidates for Academic and Technical Leaders of Suzhou University(2018XJHB06,China)Key Research Project of Suzhou University(2019yzd06,China)。
文摘During the traumatic brain injury(TBI),improved expression of circulatory miR-21 serves as a diagnostic feature.Low levels of exosome-miR-21 in the brain can effectively improve neuroinflammation and bloodebrain barrier(BBB)permeability,reduce nerve apoptosis,restore neural function and ameliorate TBI.We evaluated the role of macrophage derived exosomes-miR-21(M-Exos-miR-21)in disrupting BBB,deteriorating TBI,and Rg1 interventions.IL-1β-induced macrophages(ⅡA)-Exos-miR-21 can activate NF-kB signaling pathway and induce the expressions of MMP-1,-3 and-9 and downregulate the levels of tight junction proteins(TJPs)deteriorating the BBB.Rg1 reduced miR-21-5 p content in ⅡA-Exos(RⅡA-Exos).The interaction of NMIIAe HSP90 controlled the release of Exos-miR-21,this interaction was restricted by Rg1.Rg1 could inhibit the Exos-miR-21 release in peripheral blood flow to brain,enhancing TIMP3 protein expression,MMPs proteolysis,and restricting TJPs degradation thus protected the BBB integrity.Conclusively,Rg1 can improve the cerebrovascular endothelial injury and hold the therapeutic potential against TBI disease.
基金supported by the National Natural Science Foundation of China(81973512,81822041,21977116,and 81673305)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013,China)+7 种基金Science&Technology Major Project of Zhongshan City(No.2019A4020,China)Double First-Class Project of China Pharmaceutical University(CPU2018GY06,CPU2018GY18,and CPU2018GY20,China)the Open Project of State Key Laboratory of Natural Medicines(SKLNMZZCX 201824 and SKLNMZZ202029,China)the Open Project Program of the State Key Laboratory of Drug Research(SIMM2004KF-08,China)the Open Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Traditional Chinese Pharmacology,China)Zhejiang Chinese Medical University(No.ZYAOX2018001,China)State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(SKL-HIDCA-2018-1,China)supported by the Six Talent Peaks Project of Jiangsu Province to Tao Pang
文摘Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains unknown.Here,we show that LFHP-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity,but also reduced the interaction of PGAM5 with NRF2,which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia.Furthermore,LFHP-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.
文摘Objective:In this study,the influence of puerarin,paeoniflorin,and menthol on the structure and barrier function of tight junctions(TJs)in MadineDarby canine kidney epithelial(MDCK)and MDCK-multi-drug resistance 1(MDR1)cells was evaluated to determine the mechanisms by which the drugs cross the bloodebrain barrier(BBB).Method:Cells were treated with puerarin,paeoniflorin,and menthol followed by immunohistochemical staining with occludin,claudin-1,and F-actin.The cells were then observed using laser-scanning confocal microscopy.Average optical density(AOD)of the immunofluorescence images of the proteins were analyzed using ImageJ software while Transepithelial electrical resistance(TEER)was measured using an epithelial voltohmmeter.Results:Confocal microscopy revealed that puerarin-and paeoniflorin-treated tight junction proteins were conspicuous while menthol suppressed their expression.Correspondingly,AOD values of cells treated with puerarin or paeoniflorin,or both showed no difference compared to the control group(P>.05)while the menthol group value was downregulated.In 3 h,TEER of cells not treated with menthol were similar to the control group,while treatment with menthol significantly decreased TEER value(P<.05).In addition,application of menthol decreased TEER in MDCK cells earlier than in MDCK-MDR1 cells.Conclusion:Menthol but not puerarin and paeoniflorin may enhance paracellular transport and improve drug penetration of the BBB by disrupting the structure and,thereby,weakening the barrier function of TJs.
基金The work was supported by the National Natural Science Foundation of China(81904049 and 81973690)Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine(CACM-2018-QNRC2-C06).
文摘Background:Scalp combing,as an ancient method of health care,has been used for thousands of years in traditional Chinese medicine.Although this method is considered to be beneficial for the blood circulation of the head,the underlying mechanisms remain unclear.Methods:Both human participants and mice were used in this study.In participants,the scalp was stimulated by combing continuously for 5 min,and the temperature was measured using infrared thermal imaging before and after stimulation.In mice,the temperature was determined before and at 5,15,and 30 min after a 5-min scalp mechanical stimulation(SMS).Additionally,the vasculature of the mice was labeled with retro-orbital fluorescein isothiocyanate-dextran injection,and the capillaries were observed directly under a confocal microscope.Using in vivo CLARITY imaging and the spectrofluorometric detection of Evans Blue dye extravasation,the bloodebrain barrier permeability was assessed.Results:SMS increased the temperature of the left ear significantly in human(P=.0247)while can slightly increase the temperature of the right ear and the face without significant difference(P>.05).Moreover,SMS can significantly slow the decrease in the temperature of the external auditory canal at 5 min(P=.0153)and in body temperature at 15 min(P=.0295)after SMS whereas no significant difference in body temperature at 30 min(P>.05)compared with control mice.Furthermore,capillaries of the ear with a diameter of less than 8 mm were significantly dilated(P=.0006)following SMS and the number of dextran dots was higher at 15 min(P>.05)and 30 min(F=10.98,P=.037)after SMS intervention compared with control mice.Conclusion:Our study provides strong evidence to support the notion that scalp combing can improve extra-and intracranial blood circulation under healthy conditions.
基金supported by grants from Karolinska Institute Network Medicine Global Alliance Collaborative Grant(C24401073,Sweden)China Postdoctoral Science Foundation(2021M703602)Natural Science Foundation of Liaoning Province(2022-BS-137,China).
文摘The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system.However,the challenge of practical and precise targeting of malignant cells persists.To address this,engineered nanoparticles(NPs)have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions,owing to their small size,low immunogenicity,and ease of surface modification.This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy,encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness.Moreover,it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities.Finally,the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy,which could shape the path for future advancements in this promising field.
基金supported by Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China)111 Project(B18035,China)the National Natural Science Foundation of China(No.82373801,China).
文摘The neurovascular unit(NVU)is highly responsible for cerebral homeostasis and its dysfunc-tion emerges as a critical contributor to Alzheimer’s disease(AD)pathology.Hence,rescuing NVU dysfunction might be a viable approach to AD treatments.Here,we fabricated a self-regulated muti-func-tional nano-modulator(siR/PIO@RP)that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy.The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state(low/high RAGE expression)of the target site via a feedback loop.siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy,such as reducing cerebral Ab load,relieving neuroinflammation,and alleviating the dysfunction of NVU.Overall,the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.
