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1.
Exp Neurol ; 347: 113867, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34582837

RESUMO

Blood-brain barrier (BBB) disruption is one of the most important pathological manifestations of ischemic stroke. Reducing BBB collapse is effective in alleviating brain parenchymal injury and cognitive dysfunction. Our previous study reported that Sigma-1 receptor (Sig-1R) activation in cerebral microvascular endothelial cells (CMECs) ameliorated BBB impairment, but the detailed mechanism remains unclear. In this study, we investigated Sig-1R activation as a BBB integrity promoter via many post ischemic stroke pathways. Sig-1R activation in BBB-associated astrocytes can increase glia-derived neurotrophic factor (GDNF) secretion in bilateral common carotid artery occlusion (BCCAO) mice. Upregulated GDNF activates its receptors in CMECs to promote BBB integrity, and activated Sig-1R in CMECs facilitates this process. In vitro experiments have found that Sig-1R activation in CMECs promotes the interaction between the GDNF α1 receptor and transduction rearrangement gene, increasing PI3K-AKT-junction protein signaling pathway expression. Sig-1R activation could be an effective therapeutic method for preventing BBB damage in ischemic stroke and other neurological conditions.


Assuntos
Barreira Hematoencefálica/patologia , Receptores sigma/metabolismo , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/patologia , Animais , Barreira Hematoencefálica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
2.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34846535

RESUMO

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC's suppression of post-WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC's potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.


Assuntos
Corpo Caloso/metabolismo , Isquemia/metabolismo , Oligodendroglia/metabolismo , Proteína C/metabolismo , Substância Branca/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Corpo Caloso/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibrinolíticos/metabolismo , Fibrinolíticos/farmacologia , Humanos , Isquemia/fisiopatologia , Isquemia/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteína C/farmacologia , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/prevenção & controle
3.
Exp Neurol ; 347: 113913, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34752785

RESUMO

INTRODUCTION: Neural stem cell (NSC) transplantation offers great potential for treating ischemic stroke. Clinically, ischemia followed by reperfusion results in robust cerebrovascular injury that upregulates proinflammatory factors, disrupts neurovascular units, and causes brain cell death. NSCs possess multiple actions that can be exploited for reducing the severity of neurovascular injury. Our previous studies in young adult mice showed that human NSC transplantation during the subacute stage diminishes stroke pathophysiology and improves behavioral outcome. METHODS: We employed a well-established and commonly used stroke model, middle cerebral artery occlusion with subsequent reperfusion (MCAO/R). Here, we assessed the outcomes of hNSC transplantation 48 h post-MCAO (24 h post-transplant) in aged mouse brains in response to stroke because aging is a crucial risk factor for cerebral ischemia. Next, we tested whether administration of the integrin α5ß1 inhibitor, ATN-161, prior to hNSC transplantation further affects stoke outcome as compared with NSCs alone. RNA sequencing (RNA-seq) was used to assess the impact of hNSC transplantation on differentially expressed genes (DEGs) on a transcriptome-wide level. RESULTS: Here, we report that hNSC-engrafted brains with or without ATN-161 showed significantly reduced infarct size, and attenuated the induction of proinflammatory factors and matrix metalloproteases. RNA-seq analysis revealed DEGs and molecular pathways by which hNSCs induce a beneficial post-stroke outcome in aged stroke brains. 811 genes were differentially expressed (651 downregulated and 160 upregulated) in hNSC-engrafted stroke brains. Functional pathway analysis identified enriched and depleted pathways in hNSC-engrafted aged mouse stroke brains. Depletion of pathways following hNSC-engraftment included signaling involving neuroinflammation, acute phase response, leukocyte extravasation, and phagosome formation. On the other hand, enrichment of pathways in hNSC-engrafted brains was associated with PPAR signaling, LXR/RXR activation, and inhibition of matrix metalloproteases. Hierarchical cluster analysis of DEGs in hNSC-engrafted brains indicate decreased expression of genes encoding TNF receptors, proinflammatory factors, apoptosis factors, adhesion and leukocyte extravasation, and Toll-like receptors. CONCLUSIONS: Our study is the first to show global transcripts differentially expressed following hNSC transplantation in the subacute phase of stroke in aged mice. The outcome of our transcriptome study would be useful to develop new therapies ameliorating early-stage stroke injury.


Assuntos
Envelhecimento/genética , Células-Tronco Neurais/fisiologia , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/terapia , Transcriptoma/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Células Cultivadas , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Infarto Cerebral/terapia , Feto , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/transplante , Oligopeptídeos/administração & dosagem , Acidente Vascular Cerebral/metabolismo , Transcriptoma/efeitos dos fármacos
4.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948237

RESUMO

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as 'selective neuronal loss', and in brain areas remote from, but connected to, the infarct, known as 'secondary neurodegeneration'. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release "find-me" signals such as ATP, (ii) expose "eat-me" signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.


Assuntos
Encéfalo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Fagocitose , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Microglia/patologia , Neurônios/patologia , Acidente Vascular Cerebral/patologia
5.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638567

RESUMO

Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.


Assuntos
Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Levodopa/farmacologia , Levodopa/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação para Baixo/efeitos dos fármacos , Proteína GAP-43/metabolismo , Infarto da Artéria Cerebral Média/complicações , Masculino , Camundongos , Proteínas Nogo/genética , Proteínas Nogo/metabolismo , Receptores Nogo/metabolismo , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos Wistar , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Trombose/complicações
6.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638996

RESUMO

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.


Assuntos
Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Ativadores de Enzimas/administração & dosagem , Histona Desacetilase 1/metabolismo , Neurônios/metabolismo , Substâncias Protetoras/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Masculino , Força Muscular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
7.
Nat Commun ; 12(1): 6112, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34671051

RESUMO

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.


Assuntos
Interneurônios/fisiologia , Acidente Vascular Cerebral/terapia , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Clozapina/análogos & derivados , Clozapina/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Camundongos , Inibição Neural/efeitos dos fármacos , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Recuperação de Função Fisiológica , Córtex Somatossensorial/citologia , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/fisiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia
8.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575875

RESUMO

Mitochondrial dysfunction during ischemic stroke ultimately manifests as ATP depletion. Mitochondrial ATP synthase upon loss of mitochondrial membrane potential during ischemia rapidly hydrolyses ATP and thus contributes to ATP depletion. Increasing evidence suggests that inhibition of ATP synthase limits ATP depletion and is protective against ischemic tissue damage. Bedaquiline (BDQ) is an anti-microbial agent, approved for clinical use, that inhibits ATP synthase of Mycobacteria; however recently it has been shown to act on mitochondrial ATP synthase, inhibiting both ATP synthesis and hydrolysis in low micromolar concentrations. In this study, we investigated whether preconditioning with BDQ can alleviate ischemia/reperfusion-induced brain injury in Wistar rats after middle cerebral artery occlusion-reperfusion and whether it affects mitochondrial functions. We found that BDQ was effective in limiting necrosis and neurological dysfunction during ischemia-reperfusion. BDQ also caused inhibition of ATPase activity, mild uncoupling of respiration, and stimulated mitochondrial respiration both in healthy and ischemic mitochondria. Mitochondrial calcium retention capacity was unaffected by BDQ preconditioning. We concluded that BDQ has neuroprotective properties associated with its action on mitochondrial respiration and ATPase activity.


Assuntos
Diarilquinolinas/farmacologia , Inibidores Enzimáticos/farmacologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Respiração Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroproteção/efeitos dos fármacos , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
9.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576163

RESUMO

Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs, in an animal model of transient focal ischemia and demonstrated that its anti-inflammatory, pro-angiogenic, and phagocytosis inducing functions are responsible for the neuroprotective effects. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motifs (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S), and their neuroprotective efficacy was examined in a rat middle cerebral artery occlusion (MCAO) model. Intranasal administration of all four peptides significantly reduced infarct volume; OPNpt7R (VPNGRGD), the 7-amino-acid peptide containing an RGD motif, was determined to be the most potent, with efficacy comparable to that of OPNpt20. Additionally, sensory-motor functional deficits of OPNpt7R-administered MCAO animals were significantly improved, as indicated by the modified neurological severity scores and rotarod test. Notably, the expression of M1 markers was suppressed, whereas that of M2 markers (Arginase 1, CD206, and VEGF) was significantly enhanced in OPNpt7R-treated primary microglia cultures. Inflammation resolution by OPNpt7R was further confirmed in MCAO animals, in which upregulation of anti-inflammatory cytokines (Arg1, IL-10, IL-4, and CD36) and enhanced efferocytosis were detected. Moreover, studies using three mutant peptides (OPNpt7R-RAA or OPNpt7R-RAD, where RGD was replaced with RAA or RAD, respectively, and OPNpt7R-sc containing scrambled sequences) revealed that the RGD motif plays a vital role in conferring neuroprotection. In conclusion, the RGD-containing OPN heptamer OPNpt7R exhibits neuroprotective effects in the post-ischemic brain by suppressing M1 markers and augmenting M2 polarization of microglia and the RGD motif plays a critical role in these activities.


Assuntos
Microglia/metabolismo , Neuroproteção/fisiologia , Osteopontina/metabolismo , Animais , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Neuroproteção/genética , Ratos , Acidente Vascular Cerebral/metabolismo
10.
Hematology ; 26(1): 684-690, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34493173

RESUMO

BACKGROUND: Sickle cell anaemia affects about 4 million people across the globe, making it an inherited disorder of public health importance. Red cell lysis consequent upon haemoglobin crystallization and repeated sickling leads to anaemia and a baseline strain on haemopoiesis. Vaso-occlusion and haemolysis underlies majority of the chronic complications of sickle cell. We evaluated the clinical and laboratory features observed across the various clinical phenotypes in adult sickle cell disease patients. METHODS: Steady state data collected prospectively in a cohort of adult sickle cell disease patients as out-patients between July 2010 and July 2020. The information included epidemiological, clinical and laboratory data. RESULTS: About 270 patients were captured in this study (165 males and 105 females). Their ages ranged from 16 to 55 years, with a median age of 25 years. Sixty-eight had leg ulcers, 43 of the males had priapism (erectile dysfunction in 8), 42 had AVN, 31 had nephropathy, 23 had osteomyelitis, 15 had osteoarthritis, 12 had cholelithiasis, 10 had stroke or other neurological impairment, 5 had pulmonary hypertension, while 23 had other complications. Frequency of crisis ranged from 0 to >10/year median of 2. Of the 219 recorded, 148 of the patients had been transfused in the past, while 71 had not. CONCLUSION: The prevalence of SLU, AVN, priapism, nephropathy and the other complications of SCD show some variations from other studies. This variation in the clinical parameters across different clinical phenotypes indicates an interplay between age, genetic and environmental factors.


Assuntos
Anemia Falciforme , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Colelitíase/etiologia , Colelitíase/metabolismo , Colelitíase/patologia , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Úlcera da Perna/epidemiologia , Úlcera da Perna/etiologia , Úlcera da Perna/metabolismo , Úlcera da Perna/patologia , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/metabolismo , Osteomielite/patologia , Priapismo/epidemiologia , Priapismo/etiologia , Priapismo/metabolismo , Priapismo/patologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
11.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360881

RESUMO

Intracerebral hemorrhage (ICH) is a major public health problem and devastating subtype of stroke with high morbidity and mortality. Notably, there is no effective treatment for ICH. Neuroinflammation, a pathological hallmark of ICH, contributes to both brain injury and repair and hence, it is regarded as a potential target for therapeutic intervention. Recent studies document that microRNAs, small non-coding RNA molecules, can regulate inflammatory brain response after ICH and are viable molecular targets to alter brain function. Therefore, there is an escalating interest in studying the role of microRNAs in the pathophysiology of ICH. Herein, we provide, for the first time, an overview of the microRNAs that play roles in ICH-induced neuroinflammation and identify the critical knowledge gap in the field, as it would help design future studies.


Assuntos
Hemorragia Cerebral/metabolismo , Encefalite/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais/genética , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia
12.
Biochim Biophys Acta Gen Subj ; 1865(11): 129977, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34391832

RESUMO

BACKGROUND: Phosphotyrosine Binding (PTB) Domains, usually found on scaffold proteins, are pervasive in many cellular signaling pathways. These domains are the second-largest family of phosphotyrosine recognition domains and since their initial discovery, dozens of PTB domains have been structurally determined. SCOPE OF REVIEW: Due to its signature sequence flexibility, PTB domains can bind to a large variety of ligands including phospholipids. PTB peptide binding is divided into classical binding (canonical NPXY motifs) and non-classical binding (all other motifs). The first atypical PTB domain was discovered in cerebral cavernous malformation 2 (CCM2) protein, while only one third in size of the typical PTB domain, it remains functionally equivalent. MAJOR CONCLUSIONS: PTB domains are involved in numerous signaling processes including embryogenesis, neurogenesis, and angiogenesis, while dysfunction is linked to major disorders including diabetes, hypercholesterolemia, Alzheimer's disease, and strokes. PTB domains may also be essential in infectious processes, currently responsible for the global pandemic in which viral cellular entry is suspected to be mediated through PTB and NPXY interactions. GENERAL SIGNIFICANCE: We summarize the structural and functional updates in the PTB domain over the last 20 years in hopes of resurging interest and further analyzing the importance of this versatile domain.


Assuntos
Doença de Alzheimer/metabolismo , Diabetes Mellitus/metabolismo , Hipercolesterolemia/metabolismo , Fosfotirosina/metabolismo , Acidente Vascular Cerebral/metabolismo , Sítios de Ligação , Humanos , Fosfotirosina/química
13.
Sci Rep ; 11(1): 16354, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381129

RESUMO

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.


Assuntos
Histona Desacetilase 1/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sobrevivência Celular/fisiologia , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Epigênese Genética/fisiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Ratos , Ratos Sprague-Dawley
14.
Biomed Res Int ; 2021: 9988534, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458374

RESUMO

To explore the effect of miR-1 on neuronal apoptosis in rats with stroke through the ERK signaling pathway. Methods. Forty male rats (180-220 g) were selected and randomly divided into the sham, model, miR-1 inhibitor, and miR-1 mimic groups (10 rats per group) by average body weight. Cerebral ischemia/reperfusion (I/R) models were established using a modified middle cerebral artery wire thrombosis (MCAO) method in rats in the model group, miR-1 inhibitor group, and miR-1 mimic group. After the successful model establishment, the miR-1inhibitor group and miR-1 mimic group were intravenously injected with miR-1 inhibitor and miR-1 mimic, respectively, once a day for 3 days. The sham and model groups were given the same dose of normal saline. TTC staining was applied to detect the cerebral infarct size and calculate the infarct volume. Histopathological changes in the hippocampus of rat brains were observed by HE staining. Flow cytometry was used to detect neuronal apoptosis in rat brains. The mRNA expressions of miR-1, ERK1/2, Bcl-2, and Bax in rat brain tissues were determined by QRT PCR, and the protein levels of ERK1/2, Bcl-2, Bax, and caspase-3 were determined by Western blot analysis. Results. Compared with the sham group, the neurological impairment score, cerebral infarct size, and volume of rats in the model group were significantly increased (p < 0.05). Compared with the model group, the neurological impairment score, cerebral infarct size, and volume were significantly increased in the miR-1 mimic group and significantly decreased in the miR-1 inhibitor group (p < 0.05). In the model group, the hippocampal tissue of rats had malaligned cells, neuron cell atrophy became smaller, the intercellular spaces became larger, and vacuoles appeared. Compared with the model group, the miR-1 inhibitor group could effectively alleviate the pathological changes in the hippocampus, and the miR-1 mimic group could significantly add to the pathological changes in the rat hippocampus. Compared with the sham group, the mRNA expression of miR-1 and Bax in the brain of model rats increased significantly (p < 0.05), and the mRNA expression of ERK1/2 decreased significantly; Compared with the model group, the miR-1 and Bax mRNA expressions in the brain tissues of rats in the miR-1 inhibitor group were significantly decreased, the ERK1/2 and bcl-2 mRNA expressions were significantly increased, and the miR-1 and Bax mRNA expressions in the brain tissues of rats in the miR-1 inhibitor group were significantly decreased, and the Bcl-2 mRNA expression was significantly increased (p < 0.05). Compared with the sham group, neuronal apoptosis was increased in the brain tissues of rats in the model group and miR-1 mimic group. Compared with the model group, neuronal apoptosis was decreased in the brain tissues of rats in the miR-1 inhibitor group. Compared with the sham group, the ERK1/2 proteins in the model group were significantly decreased, the Bcl-2, Bax, and caspase-3 proteins were significantly increased, and the ERK1/2, Bcl-2, Bax, and caspase-3 proteins in the miR-1 inhibitor group and miR-1 mimic group were significantly increased. Compared with the model group, the protein levels of ERK1/2 and Bcl-2 in the miR-1 inhibitor group were significantly increased, the proteins of Bax and caspase-3 were significantly decreased, and the protein levels of ERK1/2 and Bcl-2 in the miR-1 inhibitor group were significantly increased (p < 0.05). Conclusions. miR-1 can interfere with neuronal apoptosis in rats with stroke through the ERK signaling pathway.


Assuntos
Isquemia Encefálica/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , MicroRNAs/genética , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
15.
Sci Rep ; 11(1): 16780, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408211

RESUMO

There are no clinical interventions to prevent post-injury epilepsy, a common and devastating outcome after brain insults. Epileptogenic events that run from brain injury to epilepsy are poorly understood. Previous studies in our laboratory suggested Proechimys, an exotic Amazonian rodent, as resistant to acquired epilepsy development in post-status epilepticus models. The present comparative study was conducted to assess (1) stroke-related brain responses 24-h and 30 days after cortical photothrombosis and (2) post-stroke epilepsy between Proechimys rodents and Wistar rats, a traditional animal used for laboratory research. Proechimys group showed smaller volume of ischemic infarction and lesser glial activation than Wistar group. In contrast to Wistar rats, post-stroke decreased levels of pro-inflammatory cytokines and increased levels of anti-inflammatory mediators and growth factors were found in Proechimys. Electrophysiological signaling changes assessed by cortical spreading depression, in vitro and in vivo, showed that Wistar's brain is most severely affected by stroke. Chronic electrocorticographic recordings showed that injury did not lead to epilepsy in Proechimys whereas 88% of the Wistar rats developed post-stroke epilepsy. Science gains insights from comparative studies on diverse species. Proechimys rodents proved to be a useful animal model to study antiepileptogenic mechanisms after brain insults and complement conventional animal models.


Assuntos
Epilepsia/metabolismo , Floresta Úmida , Estado Epiléptico/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Ratos , Ratos Wistar
16.
FASEB J ; 35(9): e21835, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34449927

RESUMO

Circulating neutrophil extracellular traps (NETs) resistant to t-PA have not been studied completely although NETs in thrombi may contribute to tissue plasminogen activator (t-PA) resistance. This research intended to elucidate whether circulating NETs are associated with t-PA resistance and the underlying mechanism. The levels of NETs were detected in the circulating neutrophils, ischemic brain tissue of acute ischemic stroke (AIS) patients, and transient middle cerebral artery occlusion (tMCAO) models. NET formation in blood, thrombi, and ischemic brain tissue of mice were analyzed by immunofluorescence. Exposed phosphatidylserine (PS) was assessed using flow cytometry and confocal microscopy. Procoagulant activity (PCA) was evaluated using fibrin formation assays, thrombin, and purified coagulation complex. The plasma levels of NETs in AIS patients were significantly higher than those in healthy individuals. After thrombolysis, a significant increase was noted in NET markers in no-improvement patients, while the changes in improvement patients were not significant. Importantly, NETs were decorated with von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) in the blood and thrombi, which could reverse the fibrinolytic effects. In addition, NETs activated platelets (PLTs) and endothelial cells (ECs), stimulating a procoagulant phenotype and facilitating vWF and PAI-1 release. DNase I, activated protein C (APC), and sivelestat markedly inhibited these effects. Furthermore, targeting NETs protected mice from tMCAO-induced cerebral ischemia, possibly by regulating vWF and PAI-1. In summary, NETs may contribute to t-PA resistance in AIS through activation of PLTs and ECs. Strategies against NETs may present a promising therapeutic approach to improve the thrombolysis efficiency of t-PA in AIS patients.


Assuntos
Isquemia Encefálica/metabolismo , Armadilhas Extracelulares/metabolismo , AVC Isquêmico/metabolismo , Neutrófilos/metabolismo , Acidente Vascular Cerebral/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Idoso , Animais , Coagulação Sanguínea/fisiologia , Plaquetas/metabolismo , Células Endoteliais/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosfatidilserinas/metabolismo , Trombina/metabolismo , Trombose/metabolismo
17.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203368

RESUMO

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.


Assuntos
Encéfalo/metabolismo , Antígeno CD47/metabolismo , Doença de Gaucher/metabolismo , Esclerose Múltipla/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Humanos , Inflamação/metabolismo
18.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299322

RESUMO

Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA's thrombolytic role within the vasculature is beneficial, tPA's non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA's detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.


Assuntos
AVC Isquêmico/terapia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Fibrinolíticos/administração & dosagem , Humanos , AVC Isquêmico/metabolismo , Metaloendopeptidases/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/terapia , Transplante de Células-Tronco/tendências , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia , Ativador de Plasminogênio Tecidual/uso terapêutico
19.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201646

RESUMO

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin-angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the ß-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by ß-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Lesões Encefálicas Traumáticas/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Humanos , Aneurisma Intracraniano/metabolismo , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , beta-Arrestinas/agonistas , beta-Arrestinas/metabolismo
20.
Biomed Pharmacother ; 139: 111621, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243599

RESUMO

Alterations in xanthine oxidase activity are known to be pathologically influential on coronary artery disease (CAD), but the association between purine-related blood metabolites and CAD has only been partially elucidated. We performed global metabolomics profiling and network analysis on blood samples from the Wonju and Pyeongchang (WP) cohort study (n = 2055) to elucidate the importance of purine related metabolites associated with potential CAD risk. Then, 5 selected serum metabolites were quantified from the WP cohort, Shinchon cohort (n = 259), and Shinchon case control (n = 424) groups to develop machine learning models for 10-year risk prediction, relapse within 10 years and diagnosis of the disease via 100 repeated 5-fold cross-validations of logistic models. The combination of purine metabolite levels or only xanthine levels in blood could be applied for machine learning model development for major adverse cardiac and cerebrovascular event (MACCE, cerebrovascular death, nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and stroke) risk prediction, relapse of MACCEs among patients with myocardial infarction history and diagnosis of stable CAD. In particular, our research provided initial evidence that blood xanthine and uric acid levels play different roles in the development of machine learning models for primary/secondary prevention or diagnosis of CAD. In this research, we determined that purine-related metabolites in blood are applicable to machine learning model development for CAD risk prediction and diagnosis. Also, our work advances current CAD biomarker discovery strategies mainly relying on clinical features; emphasizes the differential biomarkers in first/secondary prevention or diagnosis studies.


Assuntos
Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Purinas/metabolismo , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Intervenção Coronária Percutânea/métodos , Prognóstico , Medição de Risco/métodos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
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