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Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

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Neural Regeneration Research 2024年第4期19卷 881-886页

作者： Fan Bu Jia-Wei Min Md Abdur Razzaque Ahmad El Hamamy Anthony Patrizz Li Qi Akihiko Urayama Jun Li Department of Neurology University of Texas Health Science Center Department of Neurology&Psychology The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain *** is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following *** evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced *** studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke ***,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic *** found that as mice aged,Rac1 expression declined in the *** overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–*** was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by *** a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial ***,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after *** work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

关键词： aging angiogenesis brain-derived neurotrophic factor(BDNF) cerebral ischemia cognitive recovery neurite Pak1 Rac1 sensorimotor recovery

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TRP Channels in Stroke

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Neuroscience Bulletin 2024年第8期40卷 1141-1159页

作者： Pengyu Zong Cindy XLi Jianlin Feng Mara Cicchetti Lixia Yue Department of Cell Biology Calhoun Cardiology CenterSchool of Medicine(UConn Health)University of ConnecticutFarmingtonCT 06030USA Institute for the Brain and Cognitive Sciences University of Connecticut337 Mansfield RoadUnit 1272StorrsCT 06269USA Present Address:Department of Neuroscience University of Pittsburgh4200 Fifth AvePittsburghPA 15260USA

Ischemic stroke is a devastating disease that affects millions of patients ***,there are no effective medications for mitigating brain injury after ischemic *** channels are evolutionally ancient biosensors that detect external stimuli as well as tissue or cellular *** date,many members of the TRP superfamily have been reported to contribute to ischemic brain injury,including the TRPC subfamily(1,3,4,5,6,7),TRPV subfamily(1,2,3,4)and TRPM subfamily(2,4,7).These TRP channels share structural similarities but have distinct channel functions and *** activation during ischemic stroke can be beneficial,detrimental,or even *** this review,we focus on discussing the interesting features of stroke-related TRP channels and summarizing the underlying cellular and molecular mechanisms responsible for their involvement in ischemic brain injury.

关键词： Stroke TRP channels-Neuronal death Immune cell infiltration Blood-brain barrier Glial activation

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New evidence for the epigenetic regulation of skeletal stem cells

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Science Bulletin 2024年第13期69卷 2004-2006页

作者： Liming Zhao Jun Xiao Charles K.F.Chan Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of MedicineStanford CA 94305USA Department of Surgery Division of Plastic and Reconstructive SurgeryStanford University School of MedicineStanford CA 94305USA Department of Orthopaedic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Skeletal stem cells(SSCs)are crucial for skeletal development and regeneration,yet the epigenetic regulation of these cells remains poorly *** studies have delineated the epigenetic landscape across the developmental trajectory of SSCs,highlighting the involvement of Ptip in regulating SSC *** skeletal system undergoes dynamic remodeling throughout *** stem cells(SSCs),residing within the skeleton and lineage-restricted,serve as a cellular reserve to foster development and maintain skeletal *** categorized within the broader mesenchymal stromal/stem cells(MSCs).

关键词： skeletal involvement maintain

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Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

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Improving lung allograft function in the early post-operative period through the inhibition of pyroptosis

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Medical Review 2024年第5期4卷 384-394页

作者： Doug A.Gouchoe Zhentao Zhang Jung-Lye Kim Yong Gyu Lee Bryan A.Whitson Hua Zhu Department of Surgery Division of Cardiac SurgeryThe Ohio State University Wexner Medical CenterColumbusOHUSA COPPER Laboratory The Ohio State University Wexner Medical CenterColumbusOHUSA Cardiac Surgery The Ohio State University Wexner Medical CenterColumbusOH 43210USA

Lung transplantation is the only deﬁnitive ther-apy for end-stage pulmonary *** than 20%of offered lungs are successfully transplanted due to a limited ischemic time window and poor donor lung quality man-ifested by pulmonary edema,hypoxia,or ***,poor donor organ recovery and utilization are signiﬁcant barriers to wider implementation of the life-saving therapy of *** ischemia reperfusion injury(IRI)is often identiﬁed as the underlying molecular insult leading to immediate poor lung function in the post-operative period,this injury encompasses several pathways of cellular injury in addition to the recruitment of the innate immune system to the site of injury to propagate this inflammatory *** is a central molecular inflammatory pathway that is the most signiﬁcant contributor to injury in this early post-operative *** is another form of pro-grammed cell death and is often associated with *** mitigation of pyroptosis in the early post-operative period following lung transplantation is a potential novel way to prevent poor allograft function and improve outcomes for all *** we detail the pyroptotic pathway,its importance in lung transplantation,and several therapeutic modalities that can mitigate this harmful inflammatory pathway.

关键词： lung transplantation pyroptosis ischemia reperfusion injury IRI ex vivo lung perfusion EVLP

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Therapeutic nucleic acids in regenerative medicine and tissue repair

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Nano Research 2024年第10期17卷 8942-8976页

作者： Qimanguli Saiding Duotian Qin Soohwan An Dylan Neal Patel Muhammad Muzamil Khan Na Kong Wei Tao Center for Nanomedicine and Department of Anesthesiology Brigham and Women’s HospitalHarvard Medical SchoolBostonMassachusetts 02115USA

In the vanguard of biomedical innovation,regenerative medicine emerges as a transformative paradigm,concentrating its efforts on rectifying tissue deficits and functional aberrations in patients through the strategic augmentation of endogenous cellular *** to this approach is nucleic acid therapy,which offers a novel pathway for tissue regeneration by modulating key signaling *** one of the most effective ways to regulate cell function,nucleic acids are crucial for various tissue regeneration;however,their in vivo therapeutic applications face substantial challenges,including nuclease degradation,cell membrane impermeability,and targeted intracellular ***-based gene delivery systems offer a solution for stable and localized drug delivery by enabling the controlled overexpression of therapeutic nucleic acids,producing functional regulatory *** review presents examples of nucleic acid applications in regenerative medicine,highlighting the synergy between nucleic acids and biomaterial *** underlines the importance of nucleic acid delivery techniques,the choice of therapeutic nucleic acids,and biomaterials for advancing tissue *** latest developments in designing nucleic acid biomaterial-based delivery vehicles are explored,the mechanism of nucleic acids in tissue regeneration is elucidated,and their limitations are discussed while considering future directions for the clinical translation of nucleic acid-based therapeutics.

关键词： tissue repair nucleic acids biomaterials delivery systems regenerative medicine

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骨骼干细胞表观遗传调控的新证据（英文）

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Science Bulletin 2024年第13期 2004-2006页

作者：赵黎明肖骏 Charles K.F.Chan Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine Department of Surgery Division of Plastic and Reconstructive Surgery Stanford University School of Medicine Department of Orthopaedic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Skeletal stem cells (SSCs) are crucial for skeletal development and regeneration, yet the epigenetic regulation of these cells remains poorly understood. Recent studies have delineated the epigenetic landscape across the developmental trajectory of SSCs,highlighting the involvement of Ptip in regulating SSC *** skeletal system undergoes dynamic remodeling throughout life. Skeletal stem cells (SSCs), residing within the skeleton and lineage-restricted, serve as a cellular reserve to foster development and maintain skeletal homeostasis. Historically categorized within the broader mesenchymal stromal/stem cells (MSCs), SSCs have been differentiated due to MSCs’ recognized heterogeneity, which has generated inconsistencies and controversies in the field [1].

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Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

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Neural Regeneration Research 2016年第3期11卷 372-385页

作者： Kenneth Maiese Cellular and Molecular Signaling Newark NJ USA

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this *** impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic *** mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth *** a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this *** studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

关键词： Akt AMP activated protein kinase(AMPK) apoptosis Alzheimer’s disease autophagy β-cell cancer cardiovascular disease caspase CCN family diabetes mellitus epidermal growth factor erythropoietin fibroblast growth factor forkhead transcription factors Fox O FRAP1 hamartin(tuberous sclerosis 1)/tuberin(tuberous sclerosis 2)(TSC1/TSC2) insulin mechanistic target of rapamycin(mTOR) m TOR Complex 1(m T ORC1) m TOR Complex 2(m TORC2) nicotinamide nicotinamide adenine dinucleotide(NAD+) non-communicable diseases oxidative stress phosphoinositide 3-kinase(PI 3-K) programmed cell death silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1) sirtuin stem cells wingless Wnt Wnt1 inducible signaling pathway protein 1(WISP1)

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Oxidative stress and stress signaling: menace of diabetic cardiomyopathy

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Acta Pharmacologica Sinica 2005年第8期26卷 908-917页

作者： Loren E WOLD Asli F CEYLAN-ISIK Jun REN Department of Pharmacology Physiology and Therapeutics University of North Dakota Grand Forks ND 58203 USA Center for Cardiovascular Research and Alternative Medicine University of Wyoming Laramie WY 82071 USA Department of Pharmacology Physiology and Therapeutics University of North Dakota Grand Forks ND 58203 USA Center for Cardiovascular Research and Alternative Medicine University of Wyoming Laramie WY 82071 USA

Cardiovascular disease is the most common cause of death in the diabetic population and is currently one of the leading causes of death in the United States and other industrialized countries. The health care expenses associated with cardiovascular disease are staggering, reaching more than US$350 billion in 2003. The risk factors for cardiovascular disease include high fat/cholesterol levels, alcoholism, smoking, genetics, environmental factors and hypertension, which are commonly used to gauge an individual's risk of cardiovascular disease and to track their progress during therapy. Most recently, these factors have become important in the early prevention of cardiovascular diseases. Oxidative stress, the imbalance between reactive oxygen species production and breakdown by en- dogenous antioxidants, has been implicated in the onset and progression of car- diovascular diseases such as congestive heart failure and diabetes-associated heart dysfunction (diabetic cardiomyopathy). Antioxidant therapy has shown promise in preventing the development of diabetic heart complications. This review focuses on recent advances in oxidative stress theory and antioxidant therapy in diabetic cardiomyopathy, with an emphasis on the stress signaling pathways hypothesized to be involved. Many of these stress signaling pathways lead to activation of reactive oxygen species, major players in the development and progression of diabetic cardiomyopathy.

关键词： diabetes: heart cardiomyopathy oxidative stress: signal transduction

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Neural stem cells:mechanisms and modeling

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Protein & Cell 2012年第7期3卷 251-261页

作者： Jun Yao Yangling Mu Fred H.Gage Laboratory of Genetics The Salk Institute for Biological StudiesLa JollaCA 92037USA

In the adult brain,neural stem cells have been found in two major niches:the hippocampus and the olfactory *** derived from these stem cells contribute to learning,memory,and the autonomous repair of the brain under pathological ***,the physi-ology of adult neural stem cells has become a signifi-cant component of research on synaptic plasticity and neuronal *** addition,the recently developed induced pluripotent stem cell technique provides a powerful tool for researchers engaged in the patho-logical and pharmacological study of neuronal *** this review,we briefly summarize the research progress in neural stem cells in the adult brain and in the neuropathological application of the induced pluripotent stem cell technique.

关键词： neural stem cell hippocampus olfactory bulb induced pluripotent stem cell neurodegenerative dis-ease neurodevelopmental disorder

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