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1.
Exp Cell Res ; 440(1): 114127, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38857839

RESUMO

CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.


Assuntos
Apoptose , Heme Oxigenase-1 , AVC Isquêmico , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Neurônios/metabolismo , Neurônios/patologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Ratos , Masculino , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Transdução de Sinais , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Heme Oxigenase (Desciclizante)
2.
Dement Geriatr Cogn Disord ; 50(3): 224-230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34404042

RESUMO

BACKGROUND: Functional gene polymorphisms of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) may contribute to the onset and development of Alzheimer's disease (AD), but the relationships between these polymorphisms and predisposition of AD remain controversial. OBJECTIVES: This meta-analysis was conducted to more robustly assess relationships between TNF-α/IL-6/IL-8/IL-18 polymorphisms and predisposition of AD by pooling the findings of relevant studies. METHODS: A comprehensive literature searching was performed in PubMed, Embase, Web of Science, Wanfang, and CNKI databases, and 63 studies were found to be eligible for quantitative analyses. RESULTS: The pooled meta-analysis results showed that genotypic frequencies of TNF-α rs1800629, IL-6 rs1800795, IL-8 rs4073, and IL-18 rs187238 polymorphisms among AD cases and controls of Asian ethnicity differed significantly. But, we did not observe such genotypic frequencies differences in Caucasians. CONCLUSIONS: This meta-analysis suggests that TNF-α rs1800629, IL-6 rs1800795, IL-8 rs4073, and IL-18 rs187238 polymorphisms may affect predisposition of AD in Asians, but not in Caucasians.


Assuntos
Doença de Alzheimer , Citocinas , Predisposição Genética para Doença , Doença de Alzheimer/genética , Povo Asiático , Citocinas/genética , Genótipo , Humanos , Interleucina-18/genética , Interleucina-6/genética , Interleucina-8/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , População Branca
3.
Stroke ; 50(4): 1021-1025, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30862257

RESUMO

Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Membro 2 da Família 12 de Carreador de Soluto , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/patologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Teste de Desempenho do Rota-Rod , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Acidente Vascular Cerebral/patologia , Resultado do Tratamento
4.
Mol Pharmacol ; 92(3): 265-277, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28424220

RESUMO

G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells. RTK array analysis revealed that the GABABR-specific agonist baclofen selectively induced the transactivation of EGFR in PC-3 cells. EGFR transactivation resulted in the activation of ERK1/2 by a mechanism that is dependent on Gi/o protein and that requires matrix metalloproteinase-mediated proligand shedding. Positive allosteric modulators (PAMs) of GABABR, such as CGP7930, rac-BHFF, and GS39783, can function as PAM agonists to induce EGFR transactivation and subsequent ERK1/2 activation. Moreover, both baclofen and CGP7930 promoted cell migration and invasion through EGFR signaling. In summary, our observations demonstrated that GABABR transactivated EGFR in a ligand-dependent mechanism to promote prostate cancer cell migration and invasion, thus providing new insights into developing a novel strategy for prostate cancer treatment by targeting neurotransmitter signaling.


Assuntos
Receptores ErbB/genética , Neoplasias da Próstata/patologia , Ativação Transcricional , Regulação Alostérica , Linhagem Celular Tumoral , Movimento Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Humanos , Masculino , Invasividade Neoplásica , Receptores de GABA-B/fisiologia
5.
Med Sci Monit ; 22: 3229-37, 2016 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-27618395

RESUMO

BACKGROUND Migraine is a chronic disease that interferes with life quality and work productivity. Valproate shows protective effects against migraine, yet the underlying mechanisms are unclear. This study aimed to evaluate the potential effect of valproate on migraine using a rat model of nitroglycerin-induced trigeminovascular activation, as well as to explore the underlying mechanism. MATERIAL AND METHODS Intraperitoneal injection of nitroglycerin was conducted to induce trigeminovascular activation in rats. To explore the protective effect of valproate, a low dose (100 mg/kg) or a high dose (200 mg/kg) of valproate was intraperitoneally injected into rats, and then the levels of 5-hydroxytryptamine and nitric oxide in the peripheral blood were examined. The mtDNA copy number and the protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α, mitochondrial transcription factor A, and peroxisome proliferator-activated receptor-γ in the spinal trigeminal nucleus were detected to evaluate the biogenesis of mitochondria. The mitochondrial energy metabolism was determined by the mitochondrial membrane potential and the levels of adenosine triphosphate, cytochrome C oxidase, and reactive oxygen species. RESULTS Valproate attenuated nitroglycerin-induced trigeminovascular activation in rats, with reduced scratching behavior and restored 5-hydroxytryptamine and nitric oxide levels. Moreover, the mitochondrial energy metabolism and the biogenesis of mitochondria were preserved by valproate in nitroglycerin-treated rats. CONCLUSIONS The protective effect of valproate against migraine may be achieved through the modulation of mitochondrial biogenesis and function. Our study provides evidence for the potential use of valproate in the treatment of migraine.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Nitroglicerina/farmacologia , Nervo Trigêmeo/efeitos dos fármacos , Nervo Trigêmeo/fisiopatologia , Ácido Valproico/farmacologia , Animais , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transtornos de Enxaqueca/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/efeitos dos fármacos
6.
J Headache Pain ; 17: 49, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27150105

RESUMO

BACKGROUND: As a complex nervous system disease, migraine causes severe healthy and social issues worldwide. Valproate (VPA) is a widely used treatment agent against seizures and bipolar disorder, and its function to alleviate damage due to migraine has also been verified in clinical investigations. However, the mechanism underlying the protective effect of VPA against migraine remains poorly revealed. In the current study, the major purpose was to uncover the mechanism which drove VPA to antagonize migraine. METHODS: Nitroglycerin (NTG) was employed to induce a migraine model in rats and the migraine animals were exposed to treatment of VPA of different doses. Thereafter, the levels of indicators related to oxidative stress were measured and used to evaluate the anti-oxidant potential of VPA. The expression of calcitonin gene-related peptide (CGRP) and c-Fos was also quantified with ELISA and immunohistochemistry, respectively. Western blotting and electrophoretic mobility shift assays (EMSA) were conducted to explore the effect of VPA treatment on NF-кB pathway. RESULTS: NTG induced the activation of oxidative stress and led to migraine in model animals, but pre-treatment with VPA attenuated the damage due to migraine attack in brain tissues. The level of lipid peroxidation was significantly reduced while the prodcution of anti-oxidant factors was restored. Furthermore, expressions of CGRP and c-Fos, which represented the neuronal activation, were also down-regulated by VPA. The results of western blotting and EMSA demonstrated that the above mentioned effect of VPA acted through the inhibition of NF-кB pathway. CONCLUSIONS: Although controversies on the effect of VPA on NF-кB pathway existed, our study revealed an alternative mechanism of VPA in protecting against migraine, which would promote the development of therapeutic strategies of migraine.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , NF-kappa B/antagonistas & inibidores , Núcleo Inferior Caudal do Nervo Trigêmeo/efeitos dos fármacos , Ácido Valproico/farmacologia , Animais , Western Blotting , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Nitroglicerina , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos
7.
Aging Dis ; 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38300642

RESUMO

The blood-brain barrier (BBB) plays a critical role in maintaining ion and fluid homeostasis, essential for brain metabolism and neuronal function. Regulation of nutrient, water, and ion transport across the BBB is tightly controlled by specialized ion transporters and channels located within its unique cellular components. These dynamic transport processes not only influence the BBB's structure but also impact vital signaling mechanisms, essential for its optimal function. Disruption in ion, pH, and fluid balance at the BBB is associated with brain pathology and has been implicated in various neurological conditions, including stroke, epilepsy, trauma, and neurodegenerative diseases such as Alzheimer's disease (AD). However, knowledge gaps exist regarding the impact of ion transport dysregulation on BBB function in neurodegenerative dementias. Several factors contribute to this gap: the complex nature of these conditions, historical research focus on neuronal mechanisms and technical challenges in studying the ion transport mechanisms in in vivo models and the lack of efficient in vitro BBB dementia models. This review provides an overview of current research on the roles of ion transporters and channels at the BBB and poses specific research questions: 1) How are the expression and activity of key ion transporters altered in AD and vascular dementia (VaD); 2) Do these changes contribute to BBB dysfunction and disease progression; and 3) Can restoring ion transport function mitigate BBB dysfunction and improve clinical outcomes. Addressing these gaps will provide a greater insight into the vascular pathology of neurodegenerative disorders.

8.
Free Radic Biol Med ; 217: 116-125, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548187

RESUMO

PURPOSE: Ferroptosis has recently been recognized as a mechanism of cerebral ischemia-reperfusion (I/R) injury, attributed to blood-brain barrier (BBB) disruption. Edaravone dexboneol (Eda.B) is a novel neuroprotective agent widely employed in ischemic stroke, which is composed of edaravone (Eda) and dexborneol. This study aimed to investigate the protective effects of Eda.B on the BBB in cerebral I/R and explore its potential mechanisms. METHODS: Transient middle cerebral artery occlusion (tMCAO) Sprague-Dawley-rats model was used. Rats were randomly assigned to sham-operated group (sham, n = 20), model group (tMCAO, n = 20), Eda.B group (Eda.B, n = 20), Eda group (Eda, n = 20) and dexborneol group (dexborneol, n = 20), and Eda.B + Zinc protoporphyria group (Eda.B + ZnPP, n = 5). Infarct area, cellular apoptosis and neurofunctional recovery were accessed through TTC staining, TUNEL staining, and modified Garcia scoring system, respectively. BBB integrity was evaluated via Evans blue staining. Nuclear factor E2 related factor 2 (Nrf-2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling were qualified by Western blot. Transmission electron microscopy (TEM) revealed alterations in ipsilateral brain tissue among groups. Glutathione (GSH) and malondialdehyde (MDA) levels, and Fe2+ tissue content determination were detected. RESULTS: Eda.B effectively improved neurological deficits, diminished infarct area and cellular apoptosis, as well as ameliorated BBB integrity in tMCAO rats. Further, Eda.B significantly inhibited ferroptosis, as evidenced by ameliorated pathological features of mitochondria, down-regulated of MDA and Fe2+ levels and up-regulated GSH content. Mechanistically, Eda.B attenuated BBB disruption via Nrf-2-mediated ferroptosis, promoting nuclear translocation of Nrf-2, increasing HO-1, GPX4 expression, alleviating the loss of zonula occludens 1 (ZO-1) and occludin as well as decreasing 4-hydroxynonenal (4-HNE) level. CONCLUSIONS: This study revealed for the first time that Eda.B safeguarded the BBB from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/GPX4 axis, providing a novel insight into the neuroprotective effect of Eda.B in cerebral I/R.


Assuntos
Isquemia Encefálica , Ferroptose , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Ratos , Animais , Barreira Hematoencefálica , Heme Oxigenase-1/metabolismo , Edaravone/farmacologia , Ratos Sprague-Dawley , Isquemia Encefálica/patologia , Fármacos Neuroprotetores/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Reperfusão , Traumatismo por Reperfusão/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
9.
Neurol Sci ; 34(9): 1605-11, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23423463

RESUMO

Cerebral ischemic stroke is one of the most prevalent diseases in senior individuals. Its therapeutical strategies include anticoagulation, thrombolysis and cell protection. Tissue-type plasminogen activator (t-PA) that interacts with thrombin for the lysis of thrombosis is widely used to treat stroke patients in early stage. The mechanism of action of t-PA is not clear. Here, we report a novel role of t-PA in protecting blood-brain barrier and its potential mechanisms. In a model of the blood-brain barrier with human umbilical vascular epithelium cells, we found that t-PA in low concentrations prevented the impairment of the blood-brain barrier as a result of oxygen and glucose deprivation. This protection was fulfilled by strengthening the junctions among vascular endothelia and by upregulating the productions of vascular endothelium growth factor and of zonula occludens-1. Therefore, t-PA may strengthen the junctions of vascular endothelia in the blood-brain barrier to improve the microenvironment of brain cells and, in turn, the outcome of stroke patients.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fibrinolíticos/farmacologia , Junções Íntimas/efeitos dos fármacos , Ativador de Plasminogênio Tecidual/farmacologia , Barreira Hematoencefálica/patologia , Humanos , Acidente Vascular Cerebral/patologia , Junções Íntimas/patologia , Cordão Umbilical
10.
Neuroscience ; 514: 14-24, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36720302

RESUMO

Cullin 3 (CUL3), a member of Cullin-RING ubiquitin ligase family, regulates multiple intracellular pathways. CUL3 expression in peripheral immune cells is highly associated with the development of stroke, while little is known about the mechanism of how CUL3 participates in cerebral ischemia/reperfusion (I/R) injury. In this study, we showed that CUL3 was obviously upregulated in brain tissues of male rats received middle cerebral artery occlusion (MCAO) and reperfusion and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neurons. We firstly confirmed that CUL3 interacted with WNK3, a protein that has been proved to be associated with brain damage after ischemic stroke. CUL3 knockdown inhibited the ubiquitination of WNK3 and accelerated the phosphorylation of OSR1 in OGD/R-stimulated neurons. CUL3 silencing did not further aggravate cerebral I/R injury and played a neuroprotective role in vitro and in vivo. CUL3 knockdown attenuated the impairment of cell viability caused by OGD/R. CUL3 silencing reduced TUNEL-positive cells, down-regulated pro-apoptotic factor (Bax and Cleaved caspase 3) levels and increased the anti-apoptotic factor (Bcl-2) level in vitro and in vivo, suggesting that CUL3 repression alleviated neuronal apoptosis. Interestingly, rescue experiments revealed that WNK3 downregulation did not block the neuroprotection of CUL3 inhibition. These findings suggested that CUL3-mediated cerebral I/R injury might be not achieved through WNK3 signaling but other pathways. Furthermore, CUL3 inhibition suppressed ubiquitin-mediated degradation of Nrf2 and activated Nrf2 signaling by increasing the nuclear translocation of Nrf2 and expression levels of HO-1 and NQO-1. Taken together, CUL3 exacerbates cerebral I/R injury potentially due to its negative regulation of Nrf2 activation.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Masculino , Ratos , Apoptose , Isquemia Encefálica/metabolismo , Proteínas Culina , Glucose , Infarto da Artéria Cerebral Média/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas Quinases/metabolismo , Traumatismo por Reperfusão/metabolismo , Ubiquitinas/metabolismo
11.
Brain Res Bull ; 194: 23-34, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36681251

RESUMO

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress occur in ischemic stroke. The disruption of these two organelles can directly lead to cell death through various signaling pathways. Thus, investigation of the associated molecular mechanisms in cerebral ischemia is a prerequisite for stroke treatment. Pleckstrin homology-like domain family A member 1 (PHLDA1) is a multifunctional protein that can modulate mitochondrial function and ER stress in cardiomyocyte and cancer cells. This work studied the role of PHLDA1 in cerebral ischemic/reperfusion (I/R) injury and explored the underlying mechanisms associated with mitochondrial functions and ER stress. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated neurons were used as I/R models in vivo and in vitro, respectively. PHLDA1 was upregulated in ischemic penumbra of MCAO/R-induced mice and OGD/R-exposed neurons. In vitro, PHLDA1 knockdown protected neurons from OGD/R-induced apoptosis. In vivo, PHLDA1 silencing facilitated functional recovery and reduced cerebral infarct volume. Mechanistically, PHLDA1 knockdown promoted PPARγ nuclear translocation, which may mediate the effects on reversion of mitochondrial functions and alleviation of ER stress. In summary, PHLDA1 knockdown alleviates neuronal ischemic injuries in mice. PPARγ activation and mitochondrial dysfunction and endoplasmic reticulum stress attenuation are involved in the underlying mechanisms.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Camundongos , Apoptose , Isquemia Encefálica/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Infarto da Artéria Cerebral Média/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , PPAR gama/metabolismo , Traumatismo por Reperfusão/metabolismo
12.
Biochem Biophys Res Commun ; 419(4): 627-31, 2012 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-22369942

RESUMO

Acid-base imbalance leads to pathological cognition and behaviors in the clinical practices. In the comparison with acidosis, the cellular mechanisms underlying alkalosis-induced brain dysfunction remain unclear. By using electrophysiological approach, we investigated the influences of high extracellular pH environment on cortical GABAergic neurons in terms of their responsiveness to synaptic inputs and their ability to produce action potentials. Artificial cerebral spinal fluid in high pH impairs excitatory synaptic transmission and spike initiation in cortical GABAergic neurons. The alkalosis-induced dysfunction of GABAergic neurons is associated with the decrease of receptor responsiveness and the increases of spike refractory periods and threshold potentials. Our studies reveal that alkalosis impairs cortical GABAergic neurons and subsequently deteriorate brain functions. The molecular targets for alkalosis action include glutamate receptor-channels and voltage-gated sodium channels on GABAergic neurons.


Assuntos
Alcalose/fisiopatologia , Encefalopatias Metabólicas/fisiopatologia , Córtex Cerebral/fisiopatologia , Neurônios GABAérgicos/fisiologia , Potenciais de Ação , Animais , Células Cultivadas , Camundongos
13.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 34(2): 183-9, 2012 Apr.
Artigo em Zh | MEDLINE | ID: mdl-22776607

RESUMO

B-type natriuretic peptide (BNP) is a plasma marker of left ventricular dysfunction and cardiac volume overload. Currently it is mainly used in the cardiovascular field. BNP is an intrinsic regulator of the embryonic stem cell proliferation, and the reduction in BNP can increase the apoptosis rate. The epitope of N terminal pro-brain natriuretic peptide-BNP is most stable. BNP1-32 has the strongest biological activity but with lower plasma level in heart failure patients. The plasma BNP level plays an important role in the diagnosis, prognosis, hospital admission and mortality of heart failure, and can be used as a monitoring indicator in the treatment of heart failure. The deficiency of corin enzyme in patients with heart failure can cause the increase of cracking pro-BNP. BNP can also provide diagnostic and prognostic information for other populations and diseases. Genetic studies on BNP and its receptors also provide important information. Nesiritide, neutral endopeptidase inhibitors, and vasopeptidase inhibitors of the natriuretic peptide synthesis have been used for the treatment of cardiovascular disorders. However, more reliable and accurate approaches for detecting BNP and N terminal pro-brain natriuretic peptide-BNP require further investigations.


Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/tratamento farmacológico , Peptídeo Natriurético Encefálico/fisiologia , Doenças Cardiovasculares/sangue , Humanos , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/uso terapêutico
14.
Neuroscience ; 487: 66-77, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35093445

RESUMO

Cerebral ischemia/reperfusion injury is the main cause of neurological deficit following stroke. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is increasingly recognized as a critical determinant in immunological regulation and cell apoptosis, but its role in neuroinflammation during cerebral ischemia/reperfusion injury remains to be elucidated. In this study, middle cerebral artery occlusion/reperfusion (MCAO/R) in C57BL/6 mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in BV-2 cells were used as models in vivo and in vitro, respectively. MACO/R mice and OGD/R cells were treated with scramble or PHLDA1 small interfering RNAs (siRNAs) to achieve the goal of PHLDA1 knockdown. The results showed that the expression of PHLDA1 was significantly increased in MCAO/R mice and OGD/R cells compared to their normal controls, respectively. Mice treated with PHLDA1 siRNA exhibited a lower degree of infarct volume and brain water content compared to the NC siRNA-treated mice. Notably, PHLDA1 knockdown switched the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype by decreasing the expression of M1 markers (i.e., CD16, TNF-α, IL-6 and IFN-γ, and iNOS) and elevating the expression of M2 markers (i.e., CD206, IL-4, IL-10, and Arg-1). Moreover, PHLDA1 knockdown suppressed the NLRP3 inflammasome activation by reducing NLRP3, ASC, cleaved caspase 1 and cleaved IL-1ß expression. In summary, these results suggest that PHLDA1 blockade effectively alleviates the ischemia/reperfusion-induced cerebral injury by switching microglial M1/M2 polarization and inhibiting NLRP3 inflammasome activation. Targeting PHLDA1 could be considered as a novel strategy in the treatment against post-ischemic brain injury.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Interferente Pequeno/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
15.
Theranostics ; 11(3): 1295-1309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391535

RESUMO

Background: Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is one of the contributing factors for failed immunotherapies. Therefore, there is an urgent need to better understand TME and to identify novel modulators of TME for more effective GBM therapies. We hypothesized that H+ extrusion protein Na/H exchanger 1 (NHE1) plays a role in dysregulation of glucose metabolism and immunosuppression of GBM. We investigated the efficacy of blockade of NHE1 activity in combination with temozolomide (TMZ) therapy in increasing anti-tumor immunity. Methods: Mouse syngeneic intracranial glioma model was used to test four treatment regimens: DMSO (Vehicle-control), TMZ, NHE1 specific inhibitor HOE642, or TMZ+HOE642 (T+H) combination. Ex vivo1H/19Fluorine magnetic resonance imaging (MRI) with cell tracking agent Vsense was performed to monitor the infiltration of glioma-associated microglia/myeloid cells (GAMs). Glucose metabolism and transcriptome profiles were analyzed by Seahorse analyzer and bulk RNA-sequencing. The impact of selective Nhe1 deletion in GAMs on sensitivity to anti-PD-1 therapy was evaluated in transgenic NHE1 knockout (KO) mice. Results: Among the tested treatment regimens, the T+H combination therapy significantly stimulated the infiltration of GAMs and T-cells; up-regulated Th1 activation, and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes, increased glucose uptake and mitochondrial mass, and decreased aerobic glycolysis in GAMs. Selective deletion of Nhe1 in Cx3cr1+Nhe1 KO mice increased anti-tumor immunity and sensitivity to TMZ plus anti-PD-1 combinatorial therapy. Conclusions: NHE1 plays a role in developing glioma immunosuppressive TME in part by dysregulating glucose metabolism of GAMs and emerges as a therapeutic target for improving glioma immunity.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Glioma/tratamento farmacológico , Glioma/imunologia , Células Mieloides/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glioma/metabolismo , Glucose/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Temozolomida/farmacologia , Células Th1/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
16.
iScience ; 24(11): 103311, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34778730

RESUMO

Neurotransmitter receptors are involved in cancer progression. Among them, the heterodimeric GABAB receptor, activated by the main inhibitory neurotransmitter GABA, is composed of the transmembrane GABAB1 and GABAB2 subunits. The oncogenic role of the isoform GABAB1e (GB1e) containing only the extracellular domain of GABAB1 remains unclear. We revealed that GB1e is largely expressed in human breast cancer (BrCa) cell lines as well as in BrCa tissues where it is upregulated. Moreover, GB1e promoted the malignancy of BrCa cells both in vitro and in vivo. We propose that GB1e favors EGFR signaling by interacting with PTPN12 to disrupt the interaction between EGFR and PTPN12, and phosphorylation of Y230 and Y404 on GB1e is required in this process. Our data highlight that the GABBR1 gene through the expression of the GB1e isoform might play an important oncogenic role in BrCa and that GB1e is of interest for the treatment of some cancers.

17.
Oxid Med Cell Longev ; 2019: 2140427, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281568

RESUMO

BACKGROUND: Neurotoxicity induced by the amyloid-ß (Aß) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Based on accumulating evidence in AD research, both endoplasmic reticulum stress (ER stress) and alterations in the microRNA (miRNA) network contribute to the pathogenesis of the disease, making them potential therapeutic targets for AD. The present study was performed to investigate whether miR-34a and the inositol-requiring enzyme 1 (IRE1) are involved in the regulation of Aß-induced cytotoxicity. METHODS: Human neuroblastoma SH-SY5Y cells were treated with Aß1-40. Cell viability was assessed by the MTT assay. The integrity of the plasma membrane was assessed by LDH release. The expression levels of XBP1s, IRE1α, p-IRE1α, and Caspase-2 were detected by Western blot analysis. Spliced-XBP1 mRNA and miR-34a were detected by reverse transcription- (RT-) PCR and quantitative real-time PCR, respectively. Caspase-2 activity was measured using the Caspase-2 cellular activity assay kit. The IRE1 inhibitor (STF-083010) was used to determine the role of IRE1α on miR-34a expression. SH-SY5Y cells were transfected with miR-34a mimics to assess the role of miR-34a on the activation of Caspase-2 and the viability of Aß-exposed SH-SY5Y cells. RESULTS: We showed that Aß caused concentration- and duration-dependent death of SH-SY5Y cells. The expression levels of XBP1s, p-IRE1α, and Caspase-2 were increased, along with a corresponding decrease in the miR-34a levels in Aß-exposed SH-SY5Y cells. The IRE1 inhibitor (STF-083010) upregulated the expression of miR-34a and suppressed the activation of Caspase-2, effectively alleviating the Aß-induced death of SH-SY5Y cells. Transfection studies show that miR-34a mimics inhibit the expression of Caspase-2 and restore the viability of Aß-exposed SH-SY5Y cells. CONCLUSION: Aß peptide induced downregulation of miR-34a through the activation of IRE1α, which may induce cytotoxicity by targeting Caspase-2. Upregulation of miR-34a by inhibition of IRE1α has protective effects against Aß-induced injury in SH-SY5Y cells.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Caspase 2/metabolismo , Cisteína Endopeptidases/metabolismo , Endorribonucleases/antagonistas & inibidores , MicroRNAs/metabolismo , Fragmentos de Peptídeos/toxicidade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Caspase 2/biossíntese , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/biossíntese , Endorribonucleases/metabolismo , Humanos , MicroRNAs/administração & dosagem , MicroRNAs/biossíntese , MicroRNAs/genética , Neuroblastoma , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Transfecção , Regulação para Cima
18.
Aging Dis ; 10(3): 626-636, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31165006

RESUMO

In recent years, cation-chloride cotransporters (CCCs) have drawn attention in the medical neuroscience research. CCCs include the family of Na+-coupled Cl- importers (NCC, NKCC1, and NKCC2), K+-coupled Cl- exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC interacting protein (CIP1). For decades, CCCs have been the targets of several commonly used diuretic drugs, including hydrochlorothiazide, furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause congenital renal tubular disorders and lead to renal salt-losing hypotension, secondary hyperreninemia, and hypokalemic metabolic alkalosis. New studies reveal that CCCs along with their regulatory WNK (Kinase with no lysine (K)), and SPAK (Ste20-related proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1) are essential for regulating cell volume and maintaining ionic homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl- exporter KCC2 has an effect on synaptic inhibition, which may be involved in developing pain, epilepsy, and possibly some neuropsychiatric disorders. Interference with KCC3 leads to peripheral nervous system neuropathy as well as axon and nerve fiber swelling and psychosis. The WNK-SPAK/OSR1-CCCs complex emerges as therapeutic targets for multiple neurological diseases. This review will highlight these new findings.

19.
Basic Clin Pharmacol Toxicol ; 122(3): 310-316, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28990289

RESUMO

Migraine is a common disease with a high morbidity. Valproate (VP) is used as an anti-epilepsy drug in clinic. This study aimed to investigate the role of VP in nitroglycerin (NTG)-induced migraine using a mouse model. NTG was employed by intraperitoneal injection to induce a migraine model in mice. The NTG administration caused mouse head discomforts, decreased tolerance to cold or hot stimulation and increased content of nitric oxide, calcitonin gene-related peptide and neuropeptide Y in serum, which were ameliorated by intraperitoneal injection of VP. The levels of two inflammatory factors, interleukin (IL)-1ß and inducible nitric oxide synthase, in dura mater were increased by NTG treatment, while the increase was attenuated by application of VP. In addition, the phosphorylation levels of protein kinase C (PKC) α, γ, δ and ε were increased by NTG and decreased by VP. However, their total expression at the transcriptional and translational levels did not change significantly. Two substrates of PKC, cAMP-response element binding protein 1 and signal transducer and activator of transcription 1 were also phosphorylated by NTG application, and the phosphorylation level was attenuated by VP, consistent with the change of PKC informs. Together, we demonstrated that VP prevented damage due to migraine by inhibiting PKC signalling in NTG-injected mice, which may provide a basis for investigating the clinical treatment of migraine.


Assuntos
Dura-Máter/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Transtornos de Enxaqueca/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Proteína Quinase C/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Animais , Dura-Máter/enzimologia , Dura-Máter/metabolismo , Inibidores Enzimáticos/administração & dosagem , Injeções Intraperitoneais , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico/agonistas , Óxido Nítrico/sangue , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/toxicidade , Nitroglicerina/administração & dosagem , Nitroglicerina/toxicidade , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Distribuição Aleatória , Ácido Valproico/administração & dosagem
20.
Zhonghua Yi Xue Za Zhi ; 87(13): 889-93, 2007 Apr 03.
Artigo em Zh | MEDLINE | ID: mdl-17650398

RESUMO

OBJECTIVE: Inpatients of 15 general hospitals were investigated in order to understand the incidence of depression and anxiety state and the patients'quality of life in the Department of Neurology. METHODS: We used Hospital Anxiety and Depression scale (HADS), 17-item Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAMA) and 36-item Short Form Health Survey (SF-36) as tools to evaluate inpatients' emotional state and health related quality of life within 48 hours after admitted and before discharge, respectively. RESULTS: 610 inpatients were finished admitted evaluation, patients showed clinical depressive symptoms and anxiety symptoms were 123 (20.2%) and 161 (26.4%) respectively, in which including 96 showed the both. 405 inpatients finished discharge evaluation, patients showed clinical depression symptoms and anxiety symptoms were 68 (16.8%) and 93 (23%) respectively, in which including 52 showed the both. Regression analysis indicated that health related quality of life was associated with gender, anxiety and depression state. Only 59 (20.8%) patients received drug treatment during they admitted. There were statistic significance decrease of the HAMA and HAMD total scores between treatment group and non-treatment group when discharged; Vitality, role of emotional and mental health were significantly increased at the time of discharge. CONCLUSION: High rate of depression and anxiety state occurred in the department of Neurology. These abnormal emotions affected the quality of life of patients. If a physician treated somatic diseases only, the depressive and anxiety disturbances could not be remission. Thus, more attention should be paid to give adequate treatment if a patient concomitant presented the emotional disturbances in the general hospital.


Assuntos
Ansiedade/psicologia , Depressão/psicologia , Pacientes Internados/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infarto Encefálico/psicologia , Hemorragia Cerebral/psicologia , China , Feminino , Hospitais Gerais/estatística & dados numéricos , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Neurologia , Qualidade de Vida
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