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INTRODUCTION: Identifying controllable risk factors for large-artery atherosclerosis (LAA) stroke is crucial due to its significant role as a leading cause of ischemic stroke. We aimed to validate the correlation of serum vitamin B12 with LAA stroke. METHODS: Inpatients with LAA stroke and healthy controls were retrospectively collected for a case-control study from January 2020 to May 2022. Serum vitamin B12 concentration and other blood indicators, demographic, lifestyle factors and comorbidities were investigated. Logistic regression analysis was used to identify the correlation of serum vitamin B12 concentrations with LAA stroke, meanwhile adjusted for confounding factors. RESULTS: Patients with LAA stroke had significantly lower serum vitamin B12 concentrations in comparison to those of controls. In the fully adjusted model, vitamin B12 (per 1 interquartile range increase, odds ratio [OR] = 0.84, 95 % confidence interval [CI]: 0.77-0.91), vitamin B12 < 200 pg/mL (OR=7.70, 95 %CI: 2.19-27.03) and vitamin B12 < 300 pg/mL (OR=4.19, 95 %CI: 1.82-9.66) were independently factors for LAA stroke. Furthermore, the optimal cut-off values for vitamin B12 to predict LAA stroke were 305.25 pg/mL (area under the curve [AUC] = 0.71) when unadjusted and 308.25 pg/mL when adjusted for age and sex (AUC=0.68). Lower vitamin B12 concentrations were significantly associated with male sex, smoking, older age, higher neutrophil count, higher creatinine, lower folate and higher total homocysteine. CONCLUSION: Results indicate that low concentration of serum vitamin B12 may be a strong predictor for the risk of LAA stroke.
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Aterosclerosis , Accidente Cerebrovascular , Vitamina B 12 , Humanos , Vitamina B 12/sangre , Masculino , Femenino , Estudios de Casos y Controles , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular/sangre , Aterosclerosis/sangre , Factores de Riesgo , Estudios Retrospectivos , Biomarcadores/sangreRESUMEN
Background and Purpose: Ischemic stroke is a leading cause of mortality and disability globally, necessitating accurate prediction of intra-hospital mortality (IHM) for improved patient care. This study aimed to develop a practical nomogram for personalized IHM risk prediction in ischemic stroke patients. Methods: A retrospective study of 422 ischemic stroke patients (April 2020 - December 2021) from Chongqing Medical University's First Affiliated Hospital was conducted, with patients divided into training (n=295) and validation (n=127) groups. Data on demographics, comorbidities, stroke risk factors, and lab results were collected. Stroke severity was assessed using NIHSS, and stroke types were classified by TOAST criteria. Least absolute shrinkage and selection operator (LASSO) regression was employed for predictor selection and nomogram construction, with evaluation through ROC curves, calibration curves, and decision curve analysis. Results: LASSO regression and multivariate logistic regression identified four independent IHM predictors: age, admission NIHSS score, chronic obstructive pulmonary disease (COPD) diagnosis, and white blood cell count (WBC). A highly accurate nomogram based on these variables exhibited excellent predictive performance, with AUCs of 0.958 (training) and 0.962 (validation), sensitivities of 93.2% and 95.7%, and specificities of 93.1% and 90.9%, respectively. Calibration curves and decision curve analysis validated its clinical applicability. Conclusion: Age, admission NIHSS score, COPD history, and WBC were identified as independent IHM predictors in ischemic stroke patients. The developed nomogram demonstrated high predictive accuracy and practical utility for mortality risk estimation. External validation and prospective studies are warranted for further confirmation of its clinical efficacy.
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Mortalidad Hospitalaria , Accidente Cerebrovascular Isquémico , Nomogramas , Humanos , Masculino , Femenino , Accidente Cerebrovascular Isquémico/mortalidad , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Curva ROC , Medición de Riesgo/métodos , Modelos Logísticos , Índice de Severidad de la Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Factores de Edad , Recuento de Leucocitos , Anciano de 80 o más Años , China/epidemiologíaRESUMEN
Background and purpose: Clinically, the ability to identify individuals at risk of ischemic stroke remains limited. This study aimed to develop a nomogram model for predicting the risk of acute ischemic stroke. Methods: In this study, we conducted a retrospective analysis on patients who visited the Department of Neurology, collecting important information including clinical records, demographic characteristics, and complete hematological tests. Participants were randomly divided into training and internal validation sets in a 7:3 ratio. Based on their diagnosis, patients were categorized as having or not having ischemic stroke (ischemic and non-ischemic stroke groups). Subsequently, in the training set, key predictive variables were identified through multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression methods, and a nomogram model was constructed accordingly. The model was then evaluated on the internal validation set and an independent external validation set through area under the receiver operating characteristic curve (AUC-ROC) analysis, a Hosmer-Lemeshow goodness-of-fit test, and decision curve analysis (DCA) to verify its predictive efficacy and clinical applicability. Results: Eight predictors were identified: age, smoking status, hypertension, diabetes, atrial fibrillation, stroke history, white blood cell count, and vitamin B12 levels. Based on these factors, a nomogram with high predictive accuracy was constructed. The model demonstrated good predictive performance, with an AUC-ROC of 0.760 (95% confidence interval [CI]: 0.736-0.784). The AUC-ROC values for internal and external validation were 0.768 (95% CI: 0.732-0.804) and 0.732 (95% CI: 0.688-0.777), respectively, proving the model's capability to predict the risk of ischemic stroke effectively. Calibration and DCA confirmed its clinical value. Conclusions: We constructed a nomogram based on eight variables, effectively quantifying the risk of ischemic stroke.
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PURPOSE: This study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke. MATERIALS AND METHODS: This retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke. RESULTS: Serum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098-4.770), SVD (aOR = 4.471, 95% CI = 1.110-4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733-5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954-6.449), CEI (aOR = 2.809, 95% CI = 1.073-4.991), SVD (aOR = 5.376, 95% CI = 1.708-6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535-7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008-5.148), CEI (aOR = 2.212, 95% CI = 1.247-5.946), SVD (aOR = 2.957, 95% CI = 1.324-6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586-4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR. CONCLUSIONS: Vitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.
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Ácido Fólico , Homocisteína , Accidente Cerebrovascular Isquémico , Vitamina B 12 , Humanos , Vitamina B 12/sangre , Ácido Fólico/sangre , Homocisteína/sangre , Estudios Retrospectivos , Femenino , Masculino , Estudios de Casos y Controles , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/epidemiología , Anciano , Factores de Riesgo , Curva ROC , Accidente Cerebrovascular/sangreRESUMEN
BACKGROUND: Studies have found that BH3 interacting domain death agonist (BID) is closely related to the occurrence and development of many kinds of tumors. However, little attention has been paid to the situation of BID in clear cell renal cell carcinoma (ccRCC). So, our aim was to explore the effect of BID in ccRCC. METHODS: Survival analysis, ROC curve, correlation analysis and Cox regression analysis were executed to analyze the prognostic value and clinical correlation of BID in ccRCC. The risk prognosis model was constructed in the training cohort and further validated in the internal testing cohort, ICGC cohort, and GEO cohort. Transcriptome sequencing and immunohistochemical staining of clinical specimens were used to validate the results of bioinformatics analysis. The GSEA, ESTIMATE algorithm, CIBERSORT algorithm, ssGSEA, TIDE score, correlation and difference analysis were used to analyze the effects of BID on immune infiltration in tumor microenvironment (TME). RESULTS: BID was highly expressed in ccRCC tissues, which was verified by transcriptome sequencing and immunohistochemical staining of clinical specimens. Patients with high expression of BID had a worse prognosis. BID is an independent prognostic factor for ccRCC. The prognostic model based on BID can accurately predict the prognosis of patients in different cohorts. In addition, the expression levels of BID was closely related to immunomodulatory molecules such as PD-1, LAG3, and CTLA4. Enrichment analysis indicated that BID was significantly enriched in immune-related responses and cancer-related pathways. The change of BID expression mediates different characteristics of immune infiltration in TME. CONCLUSIONS: BID is highly expressed in ccRCC, which is a reliable biomarker of ccRCC prognosis. It is closely related to TME, and may be a potential target for immunotherapy in patients with ccRCC.
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BACKGROUND: To examine serum vitamin B12 concentrations in relation to the risk of ischemic stroke among hospitalized patients in the Department of Neurology. METHODS: We performed a cross-sectional study involving 2,212 inpatients discharged from the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University, from January 2020 to January 2022. The results of laboratory assays such as serum vitamin B12, homocysteine, and folate levels were measured. Logistic regression analysis was used to investigate the association between serum vitamin B12 concentrations and ischemic stroke, with adjustment for a number of relevant demographic and lifestyle factors and comorbidities. RESULTS: A total of 961 (43.4%) patients had an ischemic stroke. In the fully adjusted model, logistic regression analysis suggested a positive association between serum vitamin B12 levels<150 pg/mL (aOR: 1.42; 95% CI 1.02-1.97; p = 0.035), serum vitamin B12 150-300 pg/mL (aOR: 1.37; 95% CI 1.11-1.68; p = 0.003) and the prevalence of ischemic stroke. Furthermore, an inverse association was observed between serum vitamin B12 levels ≥ 900 pg/mL (aOR: 0.38; 95% CI: 0.19-0.77; p =0.007) and the prevalence of ischemic stroke. Moreover, the cut-off value of vitamin B12 concentration was 316.4 pg/mL and the discrimination power of the score evaluated by AUC-ROC was 0.71 (95%CI 0.68-0.73, p<0.001) in the vitamin B12 and ischemic stroke. CONCLUSION: Findings suggest that low vitamin B12 levels may predict the risk of ischemic stroke, early and timely supplementation of vitamin B12 can improve the short-term prognosis of ischemic stroke patients.
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Accidente Cerebrovascular Isquémico , Humanos , Estudios Transversales , Vitamina B 12 , Ácido Fólico , Vitaminas , HomocisteínaRESUMEN
To conduct the association between vitamin B12 and mental health in children and adolescents. Five databases were searched for observational studies in any language reporting on mental health and vitamin B12 levels or intake in children and adolescents from inception to March 18, 2022. Two authors independently extracted data and assessed study quality. Qualitative and quantitative analysis of data were performed. The review was registered in the PROSPERO database (CRD42022345476). Fifty six studies containing 37,932 participants were identified in the review. Vitamin B12 levels were lower in participants with autism spectrum disorders (ASD) (standardized mean difference [SMD], -1.61; 95% confidence interval [95% CI], -2.44 to -0.79; p ï¼ 0.001), attention deficit hyperactivity disorders (SMD, -0.39; 95% CI, -0.78 to -0.00; p = 0.049) compared with control group. Vitamin B12 intake were lower in participants with ASDs (SMD, -0.86; 95% CI, -1.48 to -0.24; p = 0.006) compared with control group, but showed no difference between depression group (SMD, -0.06; 95% CI, -0.15 to 0.03; p = 0.17) and the control group. Higher vitamin B12 intake were associated with lower risk of depression (odds ratio [OR], 0.79; 95% CI, 0.63-0.98; p = 0.034) and behavioral problems (OR, 0.83; 95% CI, 0.69-0.99; p = 0.04). The vast majority of included studies supported potential positive influence of vitamin B12 on mental health, and vitamin B12 deficiency may be a reversible cause for some mental health disorders in children and adolescents.
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Ischemic stroke is the most prevalent form of stroke and has a high incidence in older adults, characterized by high morbidity, mortality, disability, and recurrence rate. Vitamin B12 deficiency is prevalent in the elderly and has been reported to be associated with ischemic stroke. The mechanisms maybe include the disorder of methylation metabolism, accumulation of toxic metabolites, immune dysfunction, affecting gut microbial composition and gut-brain immune homeostasis, and toxic stress responses to the brain. Vitamin B12 deficiency may lead to cerebral artery atherosclerosis, change myelination, influence the metabolism and transmission between nerve tissue, and ultimately causes the occurrence and development of ischemic stroke. This paper reviews the correlation between vitamin B12 deficiency and ischemic stroke, looking forward to improving clinicians' understanding and providing new therapeutic directions for ischemic stroke.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Deficiencia de Vitamina B 12 , Humanos , Anciano , Vitamina B 12 , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , VitaminasRESUMEN
In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury (within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4 (IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.
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Purpose: To evaluate the prevalence of abnormal vitamin B12, folate, total homocysteine (tHcy), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) levels, to analyze the relationship between these parameters and the severity of anxiety or depressive symptoms, and to explore the possible factors associated with abnormal levels of these parameters in adolescents with anxiety or depressive symptoms. Methods: Adolescent (aged 12-18 years) outpatients with anxiety or depressive symptoms were recruited. The patient health questionnaire-9 and generalized anxiety disorder scale-7 were used to measure the severity of depression and anxiety. Serum vitamin B12, folate, tHcy, IL-6, TNF-α, and CRP levels were determined. Results: 128 subjects were recruited. The prevalence of vitamin B12 and folate deficiency, tHcy, TNF-α, IL-6, and CRP elevation was 8.6%, 10.2%, 25.8%, 14.8%, 21.9%, and 10.2%, respectively, in adolescents with anxiety or depressive symptoms. Lower vitamin B12 levels were correlated with a higher risk of severe anxiety and depressive symptoms. The severity of some symptoms of anxiety or depression were weakly correlated with vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were not associated with inflammatory mediators. Vitamin B12 deficiency was associated with older age and higher tHcy levels. Folate deficiency was associated with elevated tHcy. Elevated tHcy was associated with lower vitamin B12 and folate levels. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking. Conclusion: Lower vitamin B12 levels were correlated with a higher risk of severe anxiety or depressive symptoms. Weak correlations were observed between the severity of some symptoms of anxiety or depression and vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were related to each other. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking.
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Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.
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Objectives: This study aimed to develop a score including novel putative predictors for predicting the risk of sICH and outcomes after thrombolytic therapy with intravenous (IV) recombinant tissue-type plasminogen activator (r-tPA) in acute ischemic stroke patients. Methods: All patients with acute ischemic stroke treated with IV r-tPA at three university-based hospitals in Chongqing, China, from 2014 to 2019 were retrospectively studied. Potential risk factors associated with sICH (NINDS criteria) were determined with multivariate logistic regression, and we developed our score according to the magnitude of logistic regression coefficients. The score was validated in another independent cohort. Area under the receiver operating characteristic curve (AUC-ROC) was used to assess the performance of the score. Calibration was evaluated using the Hosmer-Lemeshow goodness-of-fit method. Results: The SON2A2 score (0 to 8 points) consisted of history of smoking (no = 1, yes = 0, ß = 0.81), onset-to-needle time (≥3.5 = 1,<3.5=0, ß = 0.74), NIH Stroke Scale on admission (>10 = 2, ≤10 = 0, ß = 1.22), neutrophil percentage (≥80.0% = 1, <80% = 0, ß = 0.81), ASPECT score (≤11 = 2, >11 = 0, ß = 1.30), and age (>65 years = 1, ≤65 years = 0, ß = 0.89). The SON2A2 score was strongly associated with sICH (OR 1.98; 95%CI 1.675-2.34) and poor outcomes (OR 1.89; 95%CI 1.68-2.13). AUC-ROC in the derivation cohort was 0.82 (95%CI 0.77-0.86). Similar results were obtained in the validation cohort. The Hosmer-Lemeshow test revealed that predicted and observed event rates in derivation and validation cohorts were very close. Conclusion: The SON2A2 score is a simple, efficient, quick, and easy-to-perform scale for predicting the risk of sICH and outcome after intravenous r-tPA thrombolysis within 4.5 h in patients with ischemic stroke, and risk assessment using this test has the potential for early and personalized management of this disease in high-risk patients.
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OBJECTIVE: This study aimed to determine the characteristics and risk factors of adult new-onset seizure patients with tuberculous meningitis (TBM) during long-term follow-up. METHODS: Patients with TBM who were seen between June 2012 and January 2018 were retrospectively reviewed and categorized into two groups based on the presence or absence of new-onset seizures. Seizure characteristics, functional outcomes and risk factors were assessed. RESULTS: A total of 223 patients with TBM were enrolled, including 20.6% (46/223) with seizures. In all, 39.1% (18/46) of the patients with new-onset seizures and 14.1% (25/177) of the patients without seizures died (p < 0.001). Seizures were classified as single (n = 14/46, 30.4%), repetitive (n = 25/46, 54.3%), or status epilepticus (n = 7/46, 15.2%). We found that non-single seizures (repetitive seizures and status epilepticus) were associated with mortality (P = 0.002, P = 0.022), while single seizures were not (P = 0.834). The independent risk factors associated with non-single seizures were cortical involvement (p = 0.007) and epileptiform discharges (p = 0.001). CONCLUSIONS: Non-single seizures were associated with poor functional outcomes and should be noted by the clinic. Cortical involvement and epileptiform discharges are independent risk factors for non-single seizures.
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Convulsiones/etiología , Tuberculosis Meníngea/complicaciones , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND/AIMS: Neurite outgrowth and synaptogenesis are critical steps for functional recovery after stroke. Resveratrol promotes neurite outgrowth and synaptogenesis, but the underlying mechanism is not well understood, although the Sonic hedgehog (Shh) signaling pathway may be involved. Given that resveratrol activates sirtuin (Sirt)1, the present study examined whether this is mediated by Shh signaling. METHODS: Primary cortical neuron cultures were pretreated with drugs before oxygen-glucose deprivation/reoxygenation (OGD/R). Cell viability and apoptosis were evaluated with Cell Counting Kit 8 and by terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Neurite outgrowth and synaptogenesis were assessed by immunocytochemistry and western blotting, which was also used to examine the expression of Sirt1 and Shh signaling proteins. RESULTS: Resveratrol and the Smoothened (Smo) agonist purmophamine, which activates Shh signaling, increased viability, reduced apoptosis, and stimulated neurite outgrowth after OGD/R injury. Moreover, the expression of growth-associated protein(GAP)-43, synaptophysin, Shh, Patched (Ptc)-1, Smo, glioma-associated oncogene homolog (Gli)-1, and Sirt1 were upregulated under these conditions. These effects were reversed by treatment with the Smo inhibitor cyclopamine, whereas the Sirt1 inhibitor sirtinol reduced the levels of Shh, Ptc-1, Smo, and Gli-1. CONCLUSIONS: Resveratrol reduces neuronal injury following OGD/R injury and enhances neurite outgrowth and synaptogenesis by activating Shh signaling, which in turn induces Sirt1.
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Antioxidantes/farmacología , Glucosa/metabolismo , Proteínas Hedgehog/metabolismo , Proyección Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oxígeno/metabolismo , Estilbenos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-Dawley , Resveratrol , Transducción de Señal/efectos de los fármacosRESUMEN
Carnitine/organic cation transporter 2 (OCTN2) is localized at the basolateral membrane of epididymal epithelial cells, and mainly serves to reabsorb carnitine as an essential factor for sperm maturation; however, its functional features in epididymal epithelial cells have remained unclear. We isolated primary epididymal epithelial cells from rat epididymides and verified their phenotype by detecting the presence of cytokeratin-19 (CK-19, an epithelial cell marker) and the absence vimentin (an interstitial cell marker). We found that cultured epididymal epithelial cells isolated from rat epididymides expressed high levels of CK-19 but barely expressed vimentin. Gain-of-function assays, which included the CCK-8 assay and EdU flow cytometry assay, indicated that overexpression of OCTN2 significantly promoted epididymal epithelial cell growth and proliferation. Moreover, forced expression of OCTN2 inhibited the cell apoptosis process, and at the same time increased expression of the pro-apoptosis factor BAX, and decreased expression of the anti-apoptosis factors BCL-2 and Survivin. Furthermore, we also found that OCTN2 overexpression dramatically increased the levels of biomarkers associated with spermatogenesis, including azoospermia-like (DAZL), phosphoglycerate kinase 2 (PGK2), and protamine 2 (PRM2). These results demonstrate that OCTN2 plays a positive role in epididymal epithelial cells, and might be useful in the clinical treatment of male infertility by serving as a key regulatory factor.
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Carnitina/metabolismo , Epidídimo/citología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Animales , Apoptosis , Biomarcadores/metabolismo , Proliferación Celular , Separación Celular , Células Cultivadas , Masculino , Ratas Sprague-Dawley , EspermatogénesisRESUMEN
Resveratrol has neuroprotective effects for ischemic cerebral stroke. However, its neuroprotective mechanism for stroke is less well understood. Beneficial actions of the activated Sonic hedgehog (Shh) signaling pathway in stroke, such as improving neurological function, promoting neurogenesis, anti-oxidative, anti-apoptotic, and pro-angiogenic effects, have been noted, but relatively little is known about the role of Shh signaling in resveratrol-reduced cerebral ischemic injury after stroke. The present study tests whether the Shh pathway mediates resveratrol to decrease cerebral ischemic injury and improve neurological function after stroke. We observed that resveratrol pretreatment significantly improved neurological function, decreased infarct volume, enhanced vitality, and reduced apoptosis of neurons in vivo and vitro after stroke. Meanwhile, expression levels of Shh, Ptc-1, Smo, and Gli-1 mRNAs were significantly upregulated and Gli-1 was relocated to the nucleus. Intriguingly, in vivo and in vitro inhibition of the Shh signaling pathway with cyclopamine, a Smo inhibitor, completely reversed the above effects of resveratrol. These results suggest that decreased cerebral ischemic injury and improved neurological function by resveratrol may be mediated by the Shh signaling pathway.
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Isquemia Encefálica/metabolismo , Proteínas Hedgehog/biosíntesis , Fármacos Neuroprotectores/administración & dosificación , Recuperación de la Función/fisiología , Estilbenos/administración & dosificación , Accidente Cerebrovascular/metabolismo , Animales , Animales Recién Nacidos , Antioxidantes/administración & dosificación , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Resveratrol , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: There is interest in drugs and rehabilitation methods to enhance neurogenesis and improve neurological function after brain injury or degeneration. Resveratrol may enhance hippocampal neurogenesis and improve hippocampal atrophy in chronic fatigue mice and prenatally stressed rats. However, its effect and mechanism of neurogenesis after stroke is less well understood. Sonic hedgehog (Shh) signaling is crucial for neurogenesis in the embryonic and adult brain, but relatively little is known about the role of Shh signaling in resveratrol-enhanced neurogenesis after stroke. METHODS: Neural stem cells (NSCs) before oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were pretreated with resveratrol with or without cyclopamine. Survival and proliferation of NSCs was assessed by the CCK8 assay and BrdU immunocytochemical staining. The expressions and activity of signaling proteins and mRNAs were detected by immunocytochemistry, Western blotting, and RT-PCR analysis. RESULTS: Resveratrol significantly increased NSCs survival and proliferation in a concentration-dependent manner after OGD/R injury in vitro. At the same time, the expression of Patched-1, Smoothened (Smo), and Gli-1 proteins and mRNAs was upregulated, and Gli-1 entered the nucleus, which was inhibited by cyclopamine, a Smo inhibitor. CONCLUSION: Shh signaling mediates resveratrol to increase NSCs proliferation after OGD/R injury in vitro.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Proliferación Celular/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Glucosa/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Nestina/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Oxígeno/metabolismo , Receptores Patched , Receptor Patched-1 , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Resveratrol , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Smoothened , Alcaloides de Veratrum/farmacología , Proteína con Dedos de Zinc GLI1RESUMEN
Cervical cancer remains a major problem in women's health worldwide. In this research, a novel biodegradable d-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) (TPGS-b-(PCL-ran-PGA)) nanoparticle (NP) was developed as a co-delivery system of docetaxel and endostatin for the synergistic treatment of cervical cancer. Docetaxel-loaded TPGS-b-(PCL-ran-PGA) NPs were prepared and further modified by polyethyleneimine for coating plasmid pShuttle2-endostatin. All NPs were characterized in size, surface charge, morphology, and in vitro release of docetaxel and pDNA. The uptake of coumarin 6-loaded TPGS-b-(PCL-ran-PGA)/PEI-pDsRED by HeLa cells was observed via fluorescent microscopy and confocal laser scanning microscopy. Endostatin expression in HeLa cells transfected by TPGS-b-(PCL-ran-PGA)/PEI-pShuttle2-endostatin NPs was detected using Western blot analysis, and the cell viability of different NP-treated HeLa cells was determined by MTT assay. The HeLa cells from the tumor model, nude mice, were treated with various NPs including docetaxel-loaded-TPGS-b-(PCL-ran-PGA)/PEI-endostatin NPs, and their survival time, tumor volume and body weight were monitored during regimen process. The tumor tissue histopathology was analyzed using hematoxylin and eosin staining, and microvessel density in tumor tissue was evaluated immunohistochemically. The results showed that the TPGS-b-(PCL-ran-PGA)/PEI NPs can efficiently and simultaneously deliver both coumarin-6 and plasmids into HeLa cells, and the expression of endostatin was verified via Western blot analysis. Compared with control groups, the TPGS-b-(PCL-ran-PGA)/PEI-pShuttle2-endostatin NPs significantly decreased the cell viability of HeLa cells (p < 0.01), inhibited the growth of tumors, and even eradicated the tumors. The underlying mechanism is attributed to synergistic anti-tumor effects by the combined use of docetaxel, endostatin, and TPGS released from NPs. The TPGS-b-(PCL-ran-PGA) NPs could function as multifunctional carrier for chemotherapeutic drugs and genetic material delivery, and offer considerable potential as an ideal candidate for in vivo cancer therapy.
RESUMEN
The purpose of this research was to develop formulation of docetaxel-loaded biodegradable TPGS-b-(PCL-ran-PGA) nanoparticles for breast cancer chemotherapy. A novel diblock copolymer, d-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) [TPGS-b-(PCL-ran-PGA)], was synthesized from ε-caprolactone, glycolide and d-α-tocopheryl polyethylene glycol 1000 succinate by ring-opening polymerization using stannous octoate as catalyst. The obtained copolymers were characterized by (1)H NMR, GPC and TGA. The docetaxel-loaded TPGS-b-(PCL-ran-PGA) nanoparticles were prepared and characterized. The data showed that the fluorescence TPGS-b-(PCL-ran-PGA) nanoparticles could be internalized by MCF-7 cells. The TPGS-b-(PCL-ran-PGA) nanoparticles achieved significantly higher level of cytotoxicity than commercial Taxotere®. MCF-7 xenograft tumor model on SCID mice showed that docetaxel formulated in the TPGS-b-(PCL-ran-PGA) nanoparticles could effectively inhibit the growth of tumor over a longer period of time than Taxotere® at the same dose. In conclusion, the TPGS-b-(PCL-ran-PGA) copolymer could be acted as a novel and potential biologically active polymeric material for nanoformulation in breast cancer chemotherapy.