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Strokes are one of the leading causes of death and disability in the world. Previously we have found that conventional protein kinase Cγ (cPKCγ) plays neuroprotective role in ischemic strokes. Further, we found that cPKCγ knockdown increased the level of cleaved (cl)-Caspase-3. However, the precise mechanisms underlying cPKCγ-mediated neuronal death remain unclear. To this end, a model incorporating 1 h oxygen-glucose deprivation/24 h reoxygenation (1 h OGD/24 h R) was established in cortical neurons. We found that cPKCγ knockdown remarkably increased neuronal death after OGD. We also found that cPKCγ knockdown increased the level of cl-Caspase-3 through the upstream initiators Capsases-9 (not Caspase-8/12) in OGD-treated neurons. Overexpression of cPKCγ could decrease neuronal death and cl-Caspase-3 and -9 levels. Moreover, cPKCγ knockdown further reduced the phosphorylation levels of p38 MAPK, p90RSK, and Bad. In addition, the protein levels of Bcl-2 and Bcl-xl were decreased after cPKCγ knockdown, whereas that of Bax was increased. In conclusion, our results suggest that cPKCγ partly alleviates ischemic injury through activating the p38 MAPK-p90RSK-Bad pathway and inhibiting Caspase-9 initiated apoptosis. This may have potential as a therapeutic target for ischemic stroke.
Assuntos
Traumatismo por Reperfusão , Transdução de Sinais , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Glucose/metabolismo , Isquemia/metabolismo , Neurônios/metabolismo , Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Reperfusão , Traumatismo por Reperfusão/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/uso terapêutico , Animais , CamundongosRESUMO
Cytochrome P450 family 3 subfamily A (CYP3A), a major member of cytochrome P450 (CYP) family, is one of the most important drug metabolizing enzymes in human. CYP3A includes 4 gene subtypes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43), which is involved in 60% of drug metabolism in the human. It is not only widely distributed in normal tissues, but also significantly overexpressed in various tumor tissues. Recently, CYP3A has attracted great attention due to its involvement in the progression from chronic atrophic gastritis to gastric cancer, as well as the differential metabolism and resistance of chemotherapeutic drugs. Targeting CYP3A gene mediated-prodrug provides new ideas for the treatment of gastric cancer and is expected to become a new target for the diagnosis and treatment of gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Citocromo P-450 CYP3A/genéticaRESUMO
[This corrects the article DOI: 10.3389/fneur.2023.1211108.].
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An ischemic stroke occurs when the blood supply is obstructed to the vascular basin, causing the death of nerve cells and forming the ischemic core. Subsequently, the brain enters the stage of reconstruction and repair. The whole process includes cellular brain damage, inflammatory reaction, blood-brain barrier destruction, and nerve repair. During this process, the proportion and function of neurons, immune cells, glial cells, endothelial cells, and other cells change. Identifying potential differences in gene expression between cell types or heterogeneity between cells of the same type helps to understand the cellular changes that occur in the brain and the context of disease. The recent emergence of single-cell sequencing technology has promoted the exploration of single-cell diversity and the elucidation of the molecular mechanism of ischemic stroke, thus providing new ideas and directions for the diagnosis and clinical treatment of ischemic stroke.
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Background: Acute ischemic stroke (AIS) is the leading cause of morbidity and mortality among cerebrovascular diseases. While animal studies have suggested a correlation between cold-inducible RNA-binding protein (CIRP) serum levels and the severity and prognosis of cerebral infarction, there has been a lack of research exploring this association in humans with cerebral infarction. Materials and methods: A total of 148 patients diagnosed with AIS within 7 days from symptom onset were included in this study. Comprehensive information regarding the patients' basic demographics, medical history, clinical parameters, the severity of cerebral infarction, and serum CIRP levels was collected. Follow-up data were obtained through telephonic interviews or by reviewing clinical notes for 3 months after the patients were discharged to assess the functional outcomes of treatment. Results: The findings of this study demonstrated a significant increase in serum CIRP levels during the early stages of AIS, followed by a gradual decline after 3 days. Significant differences were observed in the serum CIRP levels between the 1-day group and the 4-7 day group (P < 0.0047), as well as between the 2-3 day group and the 4-7 day group (P < 0.0006). Moreover, a significant positive correlation was observed between the serum CIRP levels and the severity of cerebral infarction. Higher serum CIRP levels were associated with more severe National Institutes of Health Stroke Scale scores (P < 0.05) and larger cerebral infarction volumes (P < 0.05). Furthermore, patients with higher serum CIRP levels exhibited poorer modified Rankin scale scores (P < 0.05). These findings indicate that serum CIRP serves as an essential pro-inflammatory mediator and a valuable biomarker for assessing brain injury in patients with AIS. Conclusion: The findings of this study suggest an elevation in serum CIRP levels among patients with AIS. These levels are positively correlated with the severity of AIS and serve as indicators of a poor prognosis. Therefore, CIRP could serve as a target for early clinical intervention while managing AIS, and further research should explore serum CIRP levels as prognostic indicators in AIS.
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Non-cardioembolic ischemic stroke (IS) is the predominant subtype of IS. This study aimed to construct a nomogram for recurrence risks in patients with non-cardioembolic IS in order to maximize clinical benefits. From April 2015 to December 2019, data from consecutive patients who were diagnosed with non-cardioembolic IS were collected from Lanzhou University Second Hospital. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize variable selection. Multivariable Cox regression analyses were used to identify the independent risk factors. A nomogram model was constructed using the "rms" package in R software via multifactor Cox regression. The accuracy of the model was evaluated using the receiver operating characteristic (ROC), calibration curve, and decision curve analyses (DCA). A total of 729 non-cardioembolic IS patients were enrolled, including 498 (68.3%) male patients and 231 (31.7%) female patients. Among them, there were 137 patients (18.8%) with recurrence. The patients were randomly divided into training and testing sets. The Kaplan-Meier survival analysis of the training and testing sets consistently revealed that the recurrence rates in the high-risk group were significantly higher than those in the low-risk group (p < 0.01). Moreover, the receiver operating characteristic curve analysis of the risk score demonstrated that the area under the curve was 0.778 and 0.760 in the training and testing sets, respectively. The nomogram comprised independent risk factors, including age, diabetes, platelet-lymphocyte ratio, leukoencephalopathy, neutrophil, monocytes, total protein, platelet, albumin, indirect bilirubin, and high-density lipoprotein. The C-index of the nomogram was 0.752 (95% CI: 0.705~0.799) in the training set and 0.749 (95% CI: 0.663~0.835) in the testing set. The nomogram model can be used as an effective tool for carrying out individualized recurrence predictions for non-cardioembolic IS.
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Ischemic stroke is the leading cause of mortality and disability in aging populations. Dysregulation of microRNA is associated with the pathophysiology of ischemic brain injury. Previously, we found that miR-338-3p was prominently downregulated in OGD-treated neurons, which indicates that miR-338-3P potentially plays an important role in ischemic injury. Furthermore, we performed a bioinformatic analysis and found that conventional protein kinase cγ (cPKCγ), an important autophagy regulator, is a potential target of miR-338-3p, and it is upregulated in neurons after ischemic injury. Therefore, we speculated that miR-338-3P may play a role in neuronal autophagy associated with ischemic brain injury by regulating cPKCγ levels. In the present study, oxygen glucose deprivation was used to test this hypothesis. Our results show that miR-338-3p expression is prominently downregulated after OGD. Additionally, miR-338-3p knockdown attenuated ischemic injury and simultaneously reduced the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, which contributes to neuronal survival after ischemia. Moreover, the cPKCγ protein level increased, and miR-338-3p recognized the 3'-untranslated region of the cPKCγ messenger RNA (mRNA) and negatively regulated the cPKCγ protein level by promoting the degradation of its mRNA. In addition, Lv-cPKCγ blocked the pri-miR-338-3p-induced decrease of the Akt and mammalian target of rapamycin (mTOR) phosphorylation levels, as well as the accompanying increase of the LC3-II/LC3-I ratio, thereby alleviating ischemic injury. This suggests that miR-338-3p downregulation following ischemic injury alleviates neuronal injury by targeting cPKCγ, thereby activating the Akt/mTOR signaling cascade and decreasing downstream autophagy. These results provide a potential therapeutic target for ischemic stroke.
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MicroRNAs , Proteínas Proto-Oncogênicas c-akt , Autofagia , Regulação para Baixo , Glucose/metabolismo , Humanos , Isquemia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Ferroptosis is an iron-dependent pathway of regulated cell death. But the exact mechanism of ferroptosis in ischemic stroke remains unclear. We hypothesize that conventional protein kinase cγ (cPKCγ) can attenuate neuronal death by regulating ferroptosis. In this study, primary cultured cortical neurons were used to establish 1 h oxygen-glucose deprivation (OGD) and reoxygenation (R) 0-12 h (i.e., 1 h OGD/R 0-12 h) as in vitro models of cell ischemia. After 1 h OGD/R 0-12 h, cyclooxygenase 2 (COX2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels increased, and glutathione peroxidase 4 (GPx4) levels decreased significantly. Concurrently, GPx4 activity decreases, and iron levels increased. The inhibition of ferroptosis by Liproxstatin-1 ameliorated OGD-induced neuronal injury. Liproxstatin-1 administration prominently induced GPx4 expression and suppressed COX2 expression. Additionally, Liproxstatin-1 administration substantially reduced iron accumulation and rescued GPx4 activity, accompanying by prominent changes in lipid peroxidation indicators. cPKCγ knockdown significantly aggravated neuronal death, and increased GPx4 depletion and COX2 and ACSL4 levels, thus dramatically increasing iron accumulation and GPx4 inactivation. Changes in lipid peroxidation indicators were also significantly increased. Ferroptosis is closely associated with OGD-induced ischemic injury, and cPKCγ can attenuate ischemic injury after OGD via ferroptosis suppression.
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Ferroptose , Ciclo-Oxigenase 2/metabolismo , Glucose/metabolismo , Humanos , Ferro/metabolismo , Isquemia/metabolismo , Neurônios/metabolismo , OxigênioRESUMO
BACKGROUND: Hypertension is one of the most common chronic diseases and an increasingly public-health challenge worldwide. Previous meta-analyses evaluated the effects of azilsartan medoxomil compared to placebo or other antihypertensive drugs in patients with hypertension. However, it is still unclear which dose of azilsartan is optimal. This study will perform a network meta-analysis to assess the efficacy and safety of different doses of azilsartan medoxomil in patients with hypertension. METHODS: PubMed, EMBASE.com, the Cochrane library, Scopus, and Web of Science were searched from inception to May 2019. Randomized controlled trials reporting efficacy and safety of different doses of azilsartan medoxomil on hypertension will be included if they compared 1 dose of azilsartan medoxomil with another dose of azilsartan medoxomil or with a placebo. Risk of bias of the included trials will be evaluated according to the Cochrane Handbook 5.1.0. NMA will be performed in a Bayesian hierarchical framework using WinBUGS 14. RESULTS: The results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will summarize all the available data to provide reliable evidence of the value of different doses of azilsartan medoxomil for the treatment of hypertension. PROSPERO REGISTRATION NUMBER: CRD42019136882.