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1.
Int J Mol Sci ; 24(3)2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36768628

ABSTRACT

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.


Subject(s)
Brain Ischemia , Proto-Oncogene Proteins c-akt , Mice , Animals , Proto-Oncogene Proteins c-akt/metabolism , Activating Transcription Factor 3/genetics , Activating Transcription Factor 3/metabolism , Carrier Proteins/metabolism , Brain Ischemia/genetics , Brain Ischemia/metabolism , Mice, Knockout , Brain Infarction/genetics , RNA, Small Interfering/genetics , Cerebral Infarction , Palmitoyl-CoA Hydrolase/metabolism
2.
J Mol Neurosci ; 71(9): 1761-1771, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34355355

ABSTRACT

Aberrant expression of microRNAs (miRNAs) has been linked with ischemic brain injury (IBI), but the mechanistic actions behind the associated miRNAs remain to be determined. Of note, miR-129-5p was revealed to be downregulated in the serum of patients with IBI. In silico prediction identified a putative target gene, siah E3 ubiquitin protein ligase 1 (SIAH1), of miR-129-5p. Accordingly, this study plans to clarify the functional relevance of the interplay of miR-129-5p and SIAH1 in IBI. IBI was modeled by exposing human hippocampal neuronal cells to oxygen-glucose deprivation (OGD) in vitro and by occluding the middle cerebral artery (MCAO) in a mouse model in vivo. Apoptosis of hippocampal neuronal cells was assessed by annexin V-FITC/PI staining and TUNEL staining. The area of cerebral infarction was measured using TTC staining, along with neurological scoring on modeled mice. Loss of hippocampal neuronal cells in the peri-infarct area was monitored using Nissl staining. Downregulated miR-129-5p expression was found in OGD-induced hippocampal neuronal cells and MCAO-treated mice. Mechanistically, miR-129-5p was validated to target and inhibit SIAH1 through the application of dual-luciferase reporter assay. Additionally, enforced miR-129-5p inhibited the apoptosis of OGD-induced cells and decreased the cerebral infarct area, neurological scores and apoptosis of hippocampal neuronal cells by downregulating SIAH1 and activating the mTOR signaling pathway. Taken together, the results of this study reveal the important role and underlying mechanism of miR-129-5p in IBI, providing a promising biomarker for preventive and therapeutic strategies.


Subject(s)
Brain Infarction/metabolism , MicroRNAs/metabolism , Nuclear Proteins/genetics , TOR Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/genetics , Adult , Aged , Animals , Apoptosis , Brain Infarction/genetics , Brain Infarction/pathology , Cells, Cultured , Female , Hippocampus/cytology , Hippocampus/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs/genetics , Middle Aged , Neurons/metabolism , Nuclear Proteins/metabolism , Signal Transduction , Ubiquitin-Protein Ligases/metabolism
3.
Mol Biol Rep ; 48(5): 3955-3962, 2021 May.
Article in English | MEDLINE | ID: mdl-34019199

ABSTRACT

Ischemic infarctions occur under the influence of genetic and environmental factors. In our study, the role of ischemia-modified albumin and thiol balance, which are new markers in determining oxidative damage together with MTHFR gene polymorphisms and homocysteine levels, in the development of SBI was investigated. White matter lesions in the magnetic resonance imaging (MRI) results of the patients were evaluated according to the Fazekas scale and divided into groups (Grade 0, 1, 2, and 3). Homocysteine, folate, B12, IMA, total thiol, and native thiol were measured by biochemical methods. The polymorphisms in MTHFR genes were investigated by the RT-PCR method. According to our results, a significant difference was found between the groups in age, homocysteine, folate, IMA, total thiol, and native thiol parameters (p < 0.05). When we compared the groups in terms of genotypes of the C677T gene, we found a significant difference in TT genotype between grades 0/3 and 1/3 (p < 0.05). We determined that homocysteine and IMA levels increased and folate levels decreased in CC/TT and CT/TT genotypes in the C677T gene (p < 0.05). Considering our results, the observation of homocysteine and IMA changes at the genotype level of the MTHFR C677T gene and between the groups, and the deterioration of thiol balance between the groups suggested that these markers can be used in the diagnosis of silent brain infarction.


Subject(s)
Brain Infarction/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Adult , Aged , Alleles , Biomarkers/blood , Brain Infarction/metabolism , Female , Folic Acid/blood , Gene Frequency/genetics , Genotype , Homocysteine/blood , Humans , Magnetic Resonance Imaging/methods , Male , Methylenetetrahydrofolate Reductase (NADPH2)/metabolism , Middle Aged , Oxidative Stress/genetics , Oxidative Stress/physiology , Polymorphism, Genetic/genetics , Serum Albumin , White Matter/diagnostic imaging
4.
Sci Rep ; 11(1): 7464, 2021 04 02.
Article in English | MEDLINE | ID: mdl-33811249

ABSTRACT

Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.


Subject(s)
Metformin/therapeutic use , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Stroke/drug therapy , Stroke/prevention & control , Adenylate Kinase/metabolism , Animals , Apoptosis/drug effects , Body Weight , Brain Infarction/blood , Brain Infarction/complications , Brain Infarction/drug therapy , Brain Infarction/genetics , Enzyme Activation/drug effects , Female , Gene Expression Regulation , Gliosis/blood , Gliosis/complications , Gliosis/drug therapy , Infarction, Middle Cerebral Artery/blood , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/genetics , Ischemic Preconditioning , Macrophages/drug effects , Macrophages/pathology , Metformin/blood , Metformin/pharmacology , Mice, Inbred C57BL , Microglia/drug effects , Microglia/pathology , Models, Biological , NF-kappa B/metabolism , Neurons/drug effects , Neurons/pathology , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/genetics , Stroke/genetics
5.
J Pediatr Hematol Oncol ; 43(8): e1173-e1176, 2021 11 01.
Article in English | MEDLINE | ID: mdl-33625081

ABSTRACT

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.


Subject(s)
Drug Hypersensitivity/pathology , Homozygote , Mercaptopurine/adverse effects , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyrophosphatases/genetics , Antimetabolites, Antineoplastic , Brain Infarction/chemically induced , Brain Infarction/genetics , Brain Infarction/pathology , Child, Preschool , Drug Hypersensitivity/etiology , Humans , Infections/chemically induced , Infections/genetics , Infections/pathology , Lymphohistiocytosis, Hemophagocytic/chemically induced , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Mucositis/chemically induced , Mucositis/genetics , Mucositis/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Sepsis/chemically induced , Sepsis/genetics , Sepsis/pathology
6.
Acta Biochim Biophys Sin (Shanghai) ; 53(2): 170-178, 2021 Feb 04.
Article in English | MEDLINE | ID: mdl-33372676

ABSTRACT

It has been widely accepted that autophagic cell death exacerbates the progression of cerebral ischemia/reperfusion (I/R). Our previous study revealed that overexpression of reticulon protein 1-C (RTN1-C) is involved in cerebral I/R injury. However, the underlying mechanisms have not been studied intensively. This study was designed to evaluate the effect of RTN1-C on autophagy under cerebral I/R. Using an in vitro oxygen-glucose deprivation followed by reoxygenation and a transient middle cerebral artery occlusion model in rats, we found that the expression of RTN1-C protein was significantly upregulated. We also revealed that RTN1-C knockdown suppressed overactivated autophagy both in vivo and in vitro, as indicated by decreased expressions of autophagic proteins. The number of Beclin-1/propidium iodide-positive cells was significantly less in the LV-shRTN1-C group than in the LV-shNC group. In addition, rapamycin, an activator of autophagy, aggravated cerebral I/R injury. RTN1-C knockdown reduced brain infarct volume, improved neurological deficits, and attenuated cell vulnerability to cerebral I/R injury after rapamycin treatment. Taken together, our findings demonstrated that the modulation of autophagy from RTN1-C may play vital roles in cerebral I/R injury, providing a potential therapeutic treatment for ischemic brain injury.


Subject(s)
Autophagy , Brain Infarction/metabolism , Nerve Tissue Proteins/metabolism , Reperfusion Injury/metabolism , Animals , Brain Infarction/genetics , Brain Infarction/pathology , Gene Deletion , Male , Nerve Tissue Proteins/genetics , Rats , Rats, Sprague-Dawley , Reperfusion Injury/genetics , Reperfusion Injury/pathology
7.
Cereb Cortex ; 31(1): 248-266, 2021 01 01.
Article in English | MEDLINE | ID: mdl-32954425

ABSTRACT

Loss of cognitive function with aging is a complex and poorly understood process. Recently, clinical research has linked the occurrence of cortical microinfarcts to cognitive decline. Cortical microinfarcts form following the occlusion of penetrating vessels and are considered to be restricted to the proximity of the occluded vessel. Whether and how such local events propagate and affect remote brain regions remain unknown. To this end, we combined histological analysis and longitudinal diffusion tensor imaging (DTI), following the targeted-photothrombotic occlusion of single cortical penetrating vessels. Occlusions resulted in distant tissue reorganization across the mouse brain. This remodeling co-occurred with the formation of a microglia/macrophage migratory path along subcortical white matter tracts, reaching the contralateral hemisphere through the corpus callosum and leaving a microstructural signature detected by DTI-tractography. CX3CR1-deficient mice exhibited shorter trail lengths, differential remodeling, and only ipsilateral white matter tract changes. We concluded that microinfarcts lead to brain-wide remodeling in a microglial CX3CR1-dependent manner.


Subject(s)
Brain Infarction/pathology , Macrophages/pathology , Microglia/pathology , White Matter/pathology , Animals , Brain Infarction/diagnostic imaging , Brain Infarction/genetics , CX3C Chemokine Receptor 1/genetics , Cell Movement , Corpus Callosum/diagnostic imaging , Corpus Callosum/pathology , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging , Intracranial Thrombosis/diagnostic imaging , Intracranial Thrombosis/genetics , Intracranial Thrombosis/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Pathways/diagnostic imaging , Neural Pathways/pathology , White Matter/diagnostic imaging
8.
Biomed Pharmacother ; 132: 110870, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33080468

ABSTRACT

To explore the present treatment strategies for ischemic stroke lowered by ischemia-reperfusion (I/R) injury, to hypothesize the effect of d-Carvone on cerebral I/R brain injury induced neuroinflammation through oxidative stress markers mechanism via NRLP3 and TLR4 marker expressions in rat model. The rats were divided into four groups: Sham, I/R vehicle, I/R + D-carvone (10 mg/kg/bw), I/R + D-carvone (20 mg/kg/bw). Supplementation of d-carvone at dose of 10 and 20 m/kg/bw increased the water content, reduced infract volume, attenuated neurological score depicts, furthermore it had antioxidative, anti-inflammatory, and anti-apoptotic effects against cerebral I/R brain injury. In the brain tissues decreased proinflammatory cytokines IL-1ß and TNF-α reduced interleukins IL-6, IL-4, IL-10 & VEGF dose dependently, and mRNA expressions of NLRP3, caspase -1, TNF-α, ASC, IL-1ß and TLR3 down regulated in cerebral I/R induced rats. Finally d- carvone can successfully improve the cerebral I/R induced rats neuroinflammation, in the hippocampus and cortical areas of the brain finally reduces cerebral I/R induced injury. These results were hypothesized that d-carvone contributed to cerebral stroke associated with the TLR3, giving an excellent therapeutic approach for cerebral I/R brain injury.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain Infarction/prevention & control , Brain/drug effects , Cyclohexane Monoterpenes/pharmacology , Inflammation Mediators/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neuroprotective Agents/pharmacology , Reperfusion Injury/prevention & control , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , Brain/metabolism , Brain/pathology , Brain Infarction/genetics , Brain Infarction/metabolism , Brain Infarction/pathology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Male , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Oxidative Stress/drug effects , Rats, Wistar , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism
9.
Mol Med Rep ; 21(4): 1973-1983, 2020 04.
Article in English | MEDLINE | ID: mdl-32319632

ABSTRACT

Silent brain infarction (SBI) is a cerebral infarction identified through brain imaging. In particular, studies have shown that the presence of SBI in elderly patients increases their risk of cognitive dysfunction, impairment and dementia. However, little research has been published on the relevance of SBI to these risks for the Korean population. The association between potassium voltage­gated channel subfamily Q member 2 (KCNQ2), transcription factor 4 (TCF4) and regulator of G­protein signaling 18 (RGS18) genotypes and SBI were investigated using whole­exome sequencing and PCR restriction fragment length polymorphism (RFLP) analysis. The study population included 407 patients with SBI (171 males) and 401 control subjects (172 males). Genotyping was performed using PCR RFLP. Interestingly, TCF4 rs9957668T>C polymorphisms were associated with SBI prevalence [TT vs. CC: adjusted odds ratio (AOR), 1.815, 95% confidence intervals (CI), 1.202­2.740; TT vs. TC+CC: AOR, 1.492, 95% CI, 1.066­2.088; TT+TC vs. CC: AOR, 1.454, 95% CI, 1.045­2.203]. The combination of KCNQ2 rs73146513A>G and TCF4 rs9957668T>C genotypes was associated with increasing SBI prevalence (AG/CC: AOR, 3.719, 95% CI, 1.766­7.833; AA/CC: AOR, 3.201, 95% CI, 1.387­7.387). The present study showed that TCF4 rs9957668T>C polymorphisms may be risk factors for SBI. Therefore, the TCF4 rs9957668T>C polymorphism may serve as a biomarker for increased risk of SBI in the Korean population.


Subject(s)
Brain Infarction/genetics , Exome Sequencing , Genetic Association Studies , Genetic Predisposition to Disease , KCNQ2 Potassium Channel/genetics , Polymorphism, Single Nucleotide/genetics , RGS Proteins/genetics , Transcription Factor 4/genetics , Alleles , Case-Control Studies , Female , Gene Frequency/genetics , Humans , Male , Middle Aged
10.
Headache ; 60(1): 217-228, 2020 01.
Article in English | MEDLINE | ID: mdl-31579941

ABSTRACT

Migraine and stroke are among the most prevalent and disabling neurological diseases. Epidemiologic studies showed that there is an association between migraine and stroke. Migraineurs, especially those with aura, are more likely to develop subclinical infarct-like lesions in the brain and are at risk for cryptogenic or cardioembolic stroke. Migrainous headache can be found at the onset of acute ischemic stroke in some patients, and in rare instances, an infarction can be directly attributed to a prolonged migraine aura, ie, migrainous infarction. Importantly, recent studies suggest that in the event of cerebral artery occlusion, even a history of migraine is sufficient to accelerate infarct progression and worsen outcomes. The mechanisms underlying the migraine-stroke connection are multifactorial, with genetic predisposition, aura-related electrophysiological mechanisms (cortical spreading depolarization), and cerebral microembolism being the most convincing ones at this point. Here, we provide a comprehensive overview on recent imaging studies that have helped us better understand the complex association between migraine and stroke.


Subject(s)
Brain Infarction , Migraine Disorders , Neuroimaging , Stroke , Brain Infarction/diagnostic imaging , Brain Infarction/epidemiology , Brain Infarction/genetics , Brain Infarction/pathology , Comorbidity , Disease Susceptibility , Humans , Migraine Disorders/diagnostic imaging , Migraine Disorders/epidemiology , Migraine Disorders/genetics , Migraine Disorders/physiopathology , Stroke/diagnostic imaging , Stroke/epidemiology , Stroke/genetics , Stroke/physiopathology
11.
J Cereb Blood Flow Metab ; 40(3): 639-655, 2020 03.
Article in English | MEDLINE | ID: mdl-30834805

ABSTRACT

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα-epidermal growth factor receptor (EGFR)-was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGFα directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.


Subject(s)
Brain Infarction/metabolism , Oligodendroglia/metabolism , Transforming Growth Factor alpha/metabolism , White Matter/metabolism , Animals , Brain Infarction/genetics , Brain Infarction/pathology , Disease Models, Animal , Mice , Mice, Knockout , Oligodendroglia/pathology , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Transforming Growth Factor alpha/genetics , White Matter/pathology
12.
J Ethnopharmacol ; 248: 112319, 2020 Feb 10.
Article in English | MEDLINE | ID: mdl-31639488

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Apoptosis plays an important role in cerebral ischemia-reperfusion injury and triggers a series of pathological changes which may even be life-threatening. Astragaloside-IV (AS-IV), a natural compound extracted from Astragalus (Astragalus membranaceus (Fisch.) Bunge., Leguminosae, Huangqi in Chinese), showed neuroprotective effects in the study of cerebral ischemia-reperfusion injury. In this study we investigate the effects of AS-IV on apoptosis induced by transient cerebral ischemia and reperfusion in rats, as well as the associated regulatory factors. METHODS: AS-IV was administrated to male Sprague-Dawley (SD) rats after transient cerebral ischemia and reperfusion surgery (12.5, 25, and 50 mg/kg, once per day, continued for 7 days after surgey). After seven days of continuous administration, neurological function, cerebral infarction volume, and pathological changes of brain tissue were detected. Fas, FasL, Caspase-8, Bax, and Bcl-2 mRNA levels were determined by real-time PCR. Caspase-8, Bid, Cytochrome C (Cyto C), cleaved Caspase-3 proteins were determined by western blot and immunohistochemistry was used to quantify Cyto C. RESULTS: AS-IV significantly attenuated the neurological deficit in rats with ischemica-reperfusion injury, and reduced cerebral infarction and neuronal apoptosis. AS-IV inhibited the mRNA upregulation of Fas, FasL, Caspase-8, and Bax/Bcl-2. Furthermore, the protein level of apoptosis cytokines Caspase-8, Bid, cleaved Caspase-3 and Cyto C were also inhibited after ischemia reperfusion, suggesting that AS-IV might alleviate ischemia reperfusion-induced apoptosis by inhibiting the activation of key factors in death receptor pathway and mitochondrial pathway.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis/drug effects , Brain Infarction/prevention & control , Brain/drug effects , Mitochondria/drug effects , Neuroprotective Agents/pharmacology , Receptors, Death Domain/metabolism , Reperfusion Injury/prevention & control , Saponins/pharmacology , Triterpenes/pharmacology , Animals , Apoptosis Regulatory Proteins/genetics , Brain/metabolism , Brain/pathology , Brain Infarction/genetics , Brain Infarction/metabolism , Brain Infarction/pathology , Disease Models, Animal , Male , Mitochondria/metabolism , Mitochondria/pathology , Rats, Sprague-Dawley , Receptors, Death Domain/genetics , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction
13.
Medicina (Kaunas) ; 55(4)2019 04 11.
Article in English | MEDLINE | ID: mdl-30979054

ABSTRACT

Numerous studies examined the association between factors FV, FVII, FXII, and FXIII-A gene polymorphisms and ischemic stroke, but conclusive evidence is yet to be obtained. Thus, this meta-analysis aimed to investigate the novel association of FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms with ischemic stroke risk. A systematic review was performed on articles retrieved before June 2018. Relevant data were extracted from eligible studies and meta-analyzed using RevMan version 5.3. The strength of association between studied polymorphisms and ischemic stroke risk was calculated as odds ratios and 95% confidence intervals, by applying both fixed- and random-effect models. A total of 25 studies involving 6100 ischemic stroke patients and 9249 healthy controls were incorporated in the final meta-analysis model. Specifically, rs1800595, rs5742910, rs1801020, rs5982, and rs3024477 consisted of 673, 3668, 922, 433, and 404 cases, as well as 995, 4331, 1285, 1321, and 1317 controls, respectively. The pooled analysis indicated that there was no significant association of FV rs1800595, FVII rs5742910, FXII rs1801020, FXIII-A rs5982, and FXIII-A rs3024477 polymorphisms with ischemic stroke risk, under any genetic models (dominant, recessive, over-dominant, and allelic). The present meta-analysis concluded that FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms are not associated with ischemic stroke risk.


Subject(s)
Brain Infarction/genetics , Polymorphism, Genetic , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Factor V/genetics , Factor VII/genetics , Factor XII/genetics , Factor XIIIa/genetics , Female , Humans , Male , Middle Aged , Risk , Young Adult
14.
Cerebrovasc Dis ; 47(3-4): 105-111, 2019.
Article in English | MEDLINE | ID: mdl-30947170

ABSTRACT

BACKGROUND: Homozygosity of this p.R4810K founder variant of RNF213moyamoya disease (MMD) susceptibility gene is known to influence the severity of the clinical disease phenotype at disease onset. However, the association between this genotype and long-term clinical manifestations has remained unclear. OBJECTIVES: The principal goal of this study was to investigate whether and how the p.R4810K variant of RNF213influences the long-term phenotype in Japanese patients with MMD. METHOD: This retrospective cohort study included 94 Japanese patients with MMD who underwent direct or combined bypass for revascularization with the p.R4810K genotype determined in our hospital. The following phenotypic parameters were analyzed at disease onset and over a long-term period: age and initial presentation at onset, recurrent stroke after initial revascularization, and final modified Rankin Scale. RESULTS: The p.R4810K genotype was significantly associated with the phenotype at onset, especially in younger patients. Over a median follow-up period of 100 months, recurrent stroke occurred in 6 out of 94 patients: none out of 5 patients with the homozygous variant, 5 out of 64 with the heterozygous variant, and 1 out of 25 in the wild-type group. There were no significant differences among the genotypes. In particular, recurrent cerebral hemorrhage occurred in 5 patients, all possessing the heterozygous variant. The log-rank test showed no difference between the genotypes in the stroke-free survival rate. Furthermore, the p.R4810K genotype was not associated with a poor functional condition. CONCLUSIONS: The p.R4810K founder variant of RNF213 affects the phenotype at disease onset. However, the optimal revascularization may be effective, regardless of the genotype, even for the homozygous variant, which has been thought to be the most pathogenic. This genotype may not strongly influence the long-term clinical manifestations or poor prognosis in MMD.


Subject(s)
Adenosine Triphosphatases/genetics , Brain Infarction/genetics , Cerebral Hemorrhage/genetics , Genetic Variation , Ischemic Attack, Transient/genetics , Moyamoya Disease/genetics , Ubiquitin-Protein Ligases/genetics , Adolescent , Adult , Brain Infarction/diagnosis , Brain Infarction/surgery , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/surgery , Cerebral Intraventricular Hemorrhage/diagnosis , Cerebral Intraventricular Hemorrhage/genetics , Cerebral Intraventricular Hemorrhage/surgery , Cerebral Revascularization , Child , Child, Preschool , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Infant , Ischemic Attack, Transient/diagnosis , Ischemic Attack, Transient/surgery , Middle Aged , Moyamoya Disease/diagnosis , Moyamoya Disease/therapy , Phenotype , Progression-Free Survival , Recurrence , Retrospective Studies , Risk Factors , Time Factors , Tokyo , Young Adult
15.
Neonatology ; 115(4): 355-362, 2019.
Article in English | MEDLINE | ID: mdl-30909283

ABSTRACT

BACKGROUND: Following birth asphyxia there is a robust inflammatory response. NLRP3 is a receptor of the innate immune system. Upon activation, NLRP3 forms an inflammasome together with ASC and procaspase-1 to mediate release of IL-1ß and IL-18. NLRP3 has previously been shown to be upregulated following neonatal hypoxic-ischemic (HI) brain injury in mice, but with no early effect on brain injury. OBJECTIVE: We aimed to evaluate if deficiency of NLRP3 or ASC protects against neonatal HI brain damage 7 days after hypoxia-ischemia. METHODS: C57BL/6J, NLRP3-/-, and ASC-/- mice were subjected to unilateral common carotid artery ligation followed by hypoxia at P9. Brain infarction, apoptosis, and microglial response were evaluated, as well as total RNA sequencing and examination of plasma levels of systemic proinflammatory cytokines. RESULTS: NLRP3-/- mice showed significantly increased brain infarction volumes compared to wild-type (Wt) mice, while ASC-/- mice showed reduced brain infarction volumes after neonatal hypoxia-ischemia. The amount of activated microglia was increased in NLRP3-/- mice, while decreased in ASC-/- mice compared to Wt mice. Total RNA sequencing showed an impaired inflammatory transcriptional response in the hippocampus of NLRP3-/- mice. Plasma levels of IL-1ß and IL-18 were not affected, but TNF was lower in NLRP3-/- and ASC-/- mice compared to Wt mice. CONCLUSION: ASC deficiency is neuroprotective in neonatal HI brain damage in mice, while NLRP3 deficiency increases brain damage.


Subject(s)
Brain Infarction/pathology , Brain/pathology , CARD Signaling Adaptor Proteins/genetics , Hypoxia-Ischemia, Brain/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Tumor Necrosis Factors/blood , Animals , Animals, Newborn , Apoptosis , Brain Infarction/genetics , Down-Regulation , Hypoxia-Ischemia, Brain/genetics , Interleukin-18/blood , Interleukin-1beta/blood , Mice , Mice, Inbred C57BL , Mice, Knockout , Microglia/pathology , Sequence Analysis, RNA , Up-Regulation
16.
J Alzheimers Dis ; 68(1): 357-365, 2019.
Article in English | MEDLINE | ID: mdl-30775993

ABSTRACT

Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer's disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998-2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoproteinɛ4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.


Subject(s)
Alleles , Brain Infarction/genetics , Dementia/genetics , Genetic Predisposition to Disease , Hippocampus/diagnostic imaging , Methionine Sulfoxide Reductases/genetics , Polymorphism, Single Nucleotide , Aged , Brain Infarction/diagnostic imaging , Brain Infarction/epidemiology , Dementia/diagnostic imaging , Dementia/epidemiology , Female , Humans , Incidence , Magnetic Resonance Imaging , Male , Middle Aged
18.
Int J Mol Med ; 43(3): 1356-1372, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30664169

ABSTRACT

Inflammatory response has an important role in the outcome of cerebral ischemia reperfusion injury (CIR). Biliverdin (BV) administration can relieve CIR in rats, but the mechanism remains unknown. The aim of the present study was to explore the expressional network of microRNA (miRNA)­mRNA in CIR rats following BV administration. A rat middle cerebral artery occlusion model with BV treatment was established. After neurobehavior was evaluated by neurological severity scores (NSS), miRNA and mRNA expressional profiles were analyzed by microarray technology from the cerebral cortex subjected to ischemia and BV administration. Then, bioinformatics prediction was used to screen the correlation between miRNA and mRNA, and 20 candidate miRNAs and 33 candidate mRNAs were verified by reverse transcription­quantitative polymerase chain reaction. Furthermore, the regulation relationship between ETS proto­oncogene 1 (Ets1) and miRNA204­5p was examined by luciferase assay. A total of 86 miRNAs were differentially expressed in the BV group compared with the other groups. A total of 10 miRNAs and 26 candidate genes were identified as a core 'microRNA­mRNA' regulatory network that was linked with the functional improvement of BV administration in CIR rats. Lastly, the luciferase assay results confirmed that miRNA204­5p directly targeted Ets1. The present findings suggest that BV administration may regulate multiple miRNAs and mRNAs to improve neurobehavior in CIR rats, by influencing cell proliferation, apoptosis, maintaining ATP homeostasis, and angiogenesis.


Subject(s)
Biliverdine/pharmacology , Brain Ischemia/genetics , Gene Expression Regulation , MicroRNAs/genetics , RNA, Messenger/genetics , Reperfusion Injury/genetics , Animals , Brain Infarction/genetics , Brain Infarction/metabolism , Brain Infarction/pathology , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Computational Biology/methods , Disease Models, Animal , Gene Expression Profiling , Gene Ontology , Gene Regulatory Networks , Genes, Reporter , Male , RNA Interference , Rats , Reperfusion Injury/drug therapy , Reperfusion Injury/pathology , Reproducibility of Results , Transcriptome
19.
Acta Pharmacol Sin ; 40(6): 762-768, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30487649

ABSTRACT

Pregnane X receptor (PXR) is a member of nuclear receptor subfamily 1 (NR1I2) that is a transcriptional regulator of several metabolic enzymes involved in clopidogrel metabolism. In this study we identified and evaluated the contributions of single nucleotide polymorphisms (SNPs) in NR1I2 and cytochrome P450 (CYP) 2C19 alleles to clopidogrel resistance (CR) and long-term clinical outcomes in acute ischemic stroke (IS) patients. A total of 634 patients with acute IS were recruited, who received antiplatelet medication (clopidogrel or aspirin) every day and completed a 1-year follow-up. The selected SNPs were genotyped, and platelet function was measured. Modified Rankin Scale (mRS) scores and main adverse cardiovascular and cerebrovascular events (MACCE) were noted to assess the prognosis. We showed that SNPs NR1I2 rs13059232 and CYP2C19 alleles (2*/3*) were related to CR. SNP NR1I2 (rs13059232) was identified as an independent risk factor for the long-term clinical outcomes in the clopidogrel cohorts (P < 0.001), but similar results were not observed in a matched aspirin cohort (P > 0.05). Our results suggest that NR1I2 variant (rs13059232) could serve as biomarker for clopidogrel therapy and individualized antiplatelet medications in the treatment of acute IS patients.


Subject(s)
Brain Infarction/drug therapy , Brain Infarction/genetics , Clopidogrel/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Polymorphism, Single Nucleotide , Pregnane X Receptor/genetics , Acute Disease , Aged , Aged, 80 and over , Aspirin/therapeutic use , Brain Infarction/diagnosis , Cohort Studies , Cytochrome P-450 CYP2C19/genetics , Female , Humans , Male , Middle Aged , Platelet Aggregation/genetics , Prognosis , Risk Factors
20.
Autophagy ; 14(7): 1164-1184, 2018.
Article in English | MEDLINE | ID: mdl-29938598

ABSTRACT

Circular RNAs (circRNAs) are highly expressed in the central nervous system and are involved in the regulation of physiological and pathophysiological processes. However, the potential role of circRNAs in stroke remains largely unknown. Here, using a circRNA microarray, we showed that circular RNA Hectd1 (circHectd1) levels were significantly increased in ischemic brain tissues in transient middle cerebral artery occlusion (tMCAO) mouse stroke models and further validated this finding in plasma samples from acute ischemic stroke (AIS) patients. Knockdown of circHectd1 expression significantly decreased infarct areas, attenuated neuronal deficits, and ameliorated astrocyte activation in tMCAO mice. Mechanistically, circHECTD1 functions as an endogenous MIR142 (microRNA 142) sponge to inhibit MIR142 activity, resulting in the inhibition of TIPARP (TCDD inducible poly[ADP-ribose] polymerase) expression with subsequent inhibition of astrocyte activation via macroautophagy/autophagy. Taken together, the results of our study indicate that circHECTD1 and its coupling mechanism are involved in cerebral ischemia, thus providing translational evidence that circHECTD1 can serve as a novel biomarker of and therapeutic target for stroke. ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; AIS: acute ischemic stroke; AS: primary mouse astrocytes; BECN1: beclin 1, autophagy related; BMI: body mass index; circHECTD1: circRNA HECTD1; circRNAs: circular RNAs; CBF: cerebral blood flow; Con: control; DAPI: 4',6-diamidino-2-phenylindole; ECA: external carotid artery; FISH: fluorescence in situ hybridization; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; Gdna: genomic DNA; GFAP: glial fibrillary acidic protein; GO: gene ontology; HDL: high-density lipoprotein; IOD: integrated optical density; LDL: low-density lipoprotein; LPA: lipoprotein(a); MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MIR142: microRNA 142; mNSS: modified neurological severity scores; MRI: magnetic resonance imaging; NIHSS: National Institute of Health Stoke Scale; OGD-R: oxygen glucose deprivation-reperfusion; PCR: polymerase chain reaction; PFA: paraformaldehyde; SQSTM1: sequestosome 1; TIPARP: TCDD inducible poly(ADP-ribose) polymerase; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; UTR: untranslated region; WT: wild type.


Subject(s)
Astrocytes/metabolism , Autophagy , Brain Ischemia/pathology , MicroRNAs/metabolism , Poly(ADP-ribose) Polymerases/metabolism , RNA/metabolism , Stroke/pathology , Aged , Animals , Base Sequence , Brain Infarction/genetics , Brain Infarction/pathology , Brain Ischemia/complications , Brain Ischemia/genetics , Female , Humans , Infarction, Middle Cerebral Artery/pathology , Male , Mice, Inbred C57BL , MicroRNAs/genetics , Nucleoside Transport Proteins , Poly(ADP-ribose) Polymerases/genetics , RNA/genetics , RNA, Circular , Stroke/complications , Stroke/genetics , Up-Regulation/genetics
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