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Cerebral ischemia reperfusion injury is a severe neurological impairment that occurs after blood flow reconstruction in stroke, and microglia cell pyroptosis is one of its important mechanisms. Electroacupuncture has been shown to be effective in mitigating and alleviating cerebral ischemia reperfusion injury by inhibiting neuroinflammation, reducing cellular pyroptosis, and improving neurological function. In this experiment, we divided the rats into three groups, including the sham operation (Sham) group, the middle cerebral artery occlusion/reperfusion (MCAO/R) group, and the pre-electroacupuncture (EAC) group. Pre-electroacupuncture group was stimulated with electroacupuncture of a certain intensity on the Baihui (GV 20) and Dazhui (GV 14) of the rat once a day from the 7th day to the 1st day before the MCAO/R operation. The extent of cerebral infarction was detected by TTC staining. A modified Zea-Longa five-point scale scoring system was used to determine neurologic function in MCAO rats. The number of neurons and morphological changes were accessed by Nissl staining and HE staining. The cellular damage was detected by TUNEL staining. In addition, the expression levels of RhoA, pyrin, GSDMD, Caspase1, cleaved-Caspase1, Iba-1, CD206, and ROCK2 were examined by western blotting and immunofluorescence. The results found that pre-electroacupuncture significantly attenuated neurological impairment and cerebral infarction compared to the post-MCAO/R rats. In addition, pre-electroacupuncture therapy promoted polarization of microglia to the neuroprotective (M2) phenotype. In addition, pre-electroacupuncture inhibited microglia pyroptosis by inhibiting RhoA/pyrin/GSDMD signaling pathway, thereby reducing neuronal injury and increasing neuronal survival in the MCAO/R rats. Taken together, these results demonstrated that pre-acupuncture could attenuate cerebral ischemia-reperfusion injury by inhibiting microglial pyroptosis. Therefore, pre-electroacupuncture might be a potential preventive strategy for ischemic stroke patients.
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BACKGROUND: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. METHODS: Aß1-42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aß deposition respectively. RESULTS: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. CONCLUSION: Tan IIA could promote Aß transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.
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Doença de Alzheimer , Células Endoteliais , Camundongos , Animais , Células Endoteliais/metabolismo , Sirtuína 1/metabolismo , Simulação de Acoplamento Molecular , Estresse do Retículo Endoplasmático , Doença de Alzheimer/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Vascular dementia (VaD) is the second cause of dementia after Alzheimer's disease. Ligustilide (LIG) is one of the main active ingredients of traditional Chinese medicines, such as Angelica. Studies have reported that LIG could protect against VaD. However, the mechanism is still confused. In this study, we employed a bilateral common carotid artery occlusion rat model to study. LIG (20 or 40 mg/kg/day) and Nimodipine (20 mg/kg) were orally administered to the VaD rats for four weeks. Morris water maze test showed that LIG effectively ameliorated learning and memory impairment in VaD rats. LIG obviously reduced neuronal oxidative stress damage and the level of homocysteine in the brain of VaD rats. Western blot results showed that pro-apoptotic protein Bax and cleaved caspase 3 increased and anti-apoptotic protein Bcl-2 decreased in the hippocampi of VaD rats. But after LIG treatment, these changes were reversed. Moreover, Nissl staining result showed that LIG could reduce neuronal degeneration in VaD rats. Furthermore, LIG enhanced the expressions of P-AMPK and Sirtuin1(SIRT1) in VaD rats. In conclusion, these studies indicated that LIG could ameliorate cognitive impairment in VaD rats, which might be related to AMPK/SIRT1 pathway activation.
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Disfunção Cognitiva , Demência Vascular , 4-Butirolactona/análogos & derivados , Proteínas Quinases Ativadas por AMP , Animais , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Modelos Animais de Doenças , Aprendizagem em Labirinto , Ratos , Sirtuína 1RESUMO
Alzheimer's disease (AD) is a most common neurodegenerative disease. Sodium Tanshinone IIA Sulfonate (STS) has been reported to ameliorate AD pathology. However, the underlying mechanism is still unclear. In this study, AD transgenic mouse model (APP/PS1) was used to explore the potential mechanism of STS against AD. Morris water maze and Y-maze tests showed that administration of STS improved learning and memory abilities of APP/PS1 mice. STS reduced the levels of reactive oxygen species and malondialdehyde, while improved the activity of superoxide dismutase in both hippocampus and cortex in APP/PS1 mice. STS inhibited the activity of acetylcholinesterase, while improved the activity of choline acetyltransferase in APP/PS1 mice. In addition, STS elevated the protein expressions of neurotrophic factors and synapse-related proteins in both the hippocampus and cortex in APP/PS1 mice. At last, STS improved the protein expressions of glucose transporter 1 (GLUT1) and low-density lipoprotein receptor-related protein 1 (LRP1). These results indicated that the potential mechanism of STS on AD might be related to Aß transportation function via GLUT1/LRP1 pathway. HIGHLIGHTS: STS improves cognitive impairment of APP/PS1 mice. STS ameliorates the oxidative stress damage and improves the cholinergic system. STS protects against neuronal dysfunction and enhances the synaptic plasticity. STS mediates the Aß transportation of BMECs.
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Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Transportador de Glucose Tipo 1 , Camundongos , Camundongos Transgênicos , FenantrenosRESUMO
Purpose: Gait variability analysis has been clinically adopted to characterize the presentation of various neurological diseases. However, literature and practice lack a comprehensive murine model assessment of the gait deficits that result from transient focal ischemic stroke. Further, correlations between gait parameters and the gene expression profiles associated with brain ischemia have yet to be identified. This study quantitatively assesses gait deficits through a murine model of transient focal cerebral ischemia on day 7 to determine associations between gait deficits and ischemia-related gene expressions.Methods: A total of 182 dynamic and static gait parameters from the transient middle cerebral artery occlusion (MCAO) murine model for simulating human transient focal ischemic stroke on day 7 were measured using the CatWalk system. Pearson's correlation analysis and genes associated with ischemia were identified from the existing literature to aid the investigation of the relationship between gait variability and gene expression profiles.Results: Thirty-nine gait parameters and the mRNA expression levels of four of the eight ischemia-associated genes exhibited more significant change in the MCAO models (p < 0.005) on day 7. Twenty-six gait parameters exhibited strong correlations with four ischemia-associated genes.Conclusion: This examination of gait variability and the strong correlation to the gene expression profiles associated with transient focal brain ischemia on day 7 provides a quantitative and reliable assessment of the MCAO model's motor performance. This research provides valuable insights into the study of disease progression and offers novel therapeutic interventions in the murine modeling of ischemic stroke.
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Marcha/genética , Marcha/fisiologia , Expressão Gênica/genética , Expressão Gênica/fisiologia , Ataque Isquêmico Transitório/genética , Acidente Vascular Cerebral/genética , Animais , Correlação de Dados , Infarto da Artéria Cerebral Média , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Camundongos , Córtex Motor/metabolismo , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologiaRESUMO
With the advancement of the aging process, cerebrovascular disease has become China's first cause of death. Injection of Breviscapine is a type of traditional Chinese medicine injections published in the Chinese Pharmacopoeia of 2015 Edition and the National Basic Medical Insurance, Industrial Injury Insurance and Maternity Insurance Drug Catalogue, and used to treat ischemic cerebrovascular disease in clinic. In order to further improve clinicians' understanding of the drug and guidance of its rational clinical use, we gave full consideration of clinical research evidences and expert experience, followed the procedures developed based on expert consensus of Chinese Academy of Traditional Chinese Medicine, and then offered recommendations for clinical problems summarized by clinical first-line investigations and evidence-based clinical problems according to internationally accepted evidence grading and recommendation standards, i.e. Grade. As for clinical problems without evidence, we reached through nominal group method, and formed consensus recommendations. Safety issues of Injection of Breviscapine, such as indication, syndrome, dosage, course of treatment, precautions, suggestions and contraindications, were defined to improve clinical efficacy, promote rational drug use and reduce drug risks. This consensus needs to be revised in the future based on emerging clinical issues and evidence-based updates in practical applications.
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Medicamentos de Ervas Chinesas , China , Consenso , Feminino , Flavonoides , Humanos , Medicina Tradicional Chinesa , GravidezRESUMO
The mechanism of papillary thyroid cancer (PTC) has shown numerous recurrently mutated genes, but the discovery of abnormal expression of novel tumor suppressor genes has been slow. The aim of our study is to explore the biological functions of SDPR in thyroid cancer. We reanalyzed the RNA-Seq data of PTC from The Cancer Genome Atlas (TCGA) database and found that serum deprivation response (SDPR) was significantly downregulated in PTC. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was performed to assess the expression of SDPR. Both loss- and gain-of-function experiments, and flow cytometry were performed to investigate the functions. SDPR was significantly downregulated in PTC. Reduced expression of SDPR was associated with larger tumor size, more serious lymph node metastasis, and advanced American Joint Committee on Cancer (AJCC) stage. Patients with lower SDPR expression had a shorter recurrence-free survival. SDPR expression and AJCC stage were independent predictors of poor recurrence-free survival (RFS). Moreover, cell proliferation, colony formation, and migration were inhibited after SDPR overexpression, whereas knockdown of SDPR exerted an oncogenic effect. SDPR induction also initiated the mesenchymal-epithelial transition, alongside suppressing AKT signaling and cyclin family expression. Apart from DNA methylation, LOC105373813, may also co-regulate SDPR expression by forming a stable hybrid with SDPR messenger RNA. Our study indicated that SDPR may function as a potential prognostic marker in PTC.
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Biomarcadores Tumorais/genética , Metilação de DNA/genética , Proteínas de Ligação a Fosfato/genética , Câncer Papilífero da Tireoide/genética , Proliferação de Células/genética , Feminino , Mutação com Ganho de Função/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , RNA-Seq , Câncer Papilífero da Tireoide/patologiaRESUMO
Pregnane X receptor (PXR) is a member of nuclear receptor subfamily 1 (NR1I2) that is a transcriptional regulator of several metabolic enzymes involved in clopidogrel metabolism. In this study we identified and evaluated the contributions of single nucleotide polymorphisms (SNPs) in NR1I2 and cytochrome P450 (CYP) 2C19 alleles to clopidogrel resistance (CR) and long-term clinical outcomes in acute ischemic stroke (IS) patients. A total of 634 patients with acute IS were recruited, who received antiplatelet medication (clopidogrel or aspirin) every day and completed a 1-year follow-up. The selected SNPs were genotyped, and platelet function was measured. Modified Rankin Scale (mRS) scores and main adverse cardiovascular and cerebrovascular events (MACCE) were noted to assess the prognosis. We showed that SNPs NR1I2 rs13059232 and CYP2C19 alleles (2*/3*) were related to CR. SNP NR1I2 (rs13059232) was identified as an independent risk factor for the long-term clinical outcomes in the clopidogrel cohorts (P < 0.001), but similar results were not observed in a matched aspirin cohort (P > 0.05). Our results suggest that NR1I2 variant (rs13059232) could serve as biomarker for clopidogrel therapy and individualized antiplatelet medications in the treatment of acute IS patients.
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Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/genética , Clopidogrel/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X/genética , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Infarto Encefálico/diagnóstico , Estudos de Coortes , Citocromo P-450 CYP2C19/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/genética , Prognóstico , Fatores de RiscoRESUMO
AIM: Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. METHODS: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit. RESULTS: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638). CONCLUSION: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.
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1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Receptores de Superfície Celular/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Acidente Vascular Cerebral/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Povo Asiático , Isquemia Encefálica/sangue , Isquemia Encefálica/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Tromboxano B2/biossíntese , Tromboxano B2/sangue , Falha de TratamentoRESUMO
AIM: There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke. METHODS: A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4(*)1G (rs2242480), CYP2C19(*)2 (rs4244285) and P2RY12 (rs2046934) were genotyped. RESULTS: The CR rate in this population was 36%. The CYP2C19(*)2 variant was a risk factor for CR ((*)2/(*)2+wt/(*)2 vs wt/wt, OR: 2.366, 95% CI: 1.180-4.741, P=0.014), whereas the CYP3A4(*)1G variant had a protective effect on CR ((*)1/(*)1 vs (*)1G/(*)1G+(*)1/(*)1G, OR: 2.360, 95% CI: 1.247-4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286-0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs TT, OR: 0.407, 95% CI: 0.191-0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022). CONCLUSION: The individuals with both the CYP2C19(*)2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4(*)1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.
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Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Resistência a Medicamentos/genética , Receptores Purinérgicos P2Y12/genética , Receptores de Esteroides/genética , Ticlopidina/análogos & derivados , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Clopidogrel , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/genética , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X , Fatores de Proteção , Fatores de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Ticlopidina/farmacologia , Ticlopidina/uso terapêuticoRESUMO
BACKGROUND: The purpose of this study was to evaluate the clinicopathologic and ultrasonographic (US) characteristics and establish an effective scoring system for predicting central lymph node metastasis (CLNM) in papillary thyroid microcarcinoma (PTMC). METHODS: A total of 498 patients with PTMC who underwent total thyroidectomy or lobectomy with therapeutic central lymph node dissection (CLND) were enrolled. Univariate and multivariate analyses were performed to find the independent predictors for CLNM based on clinicopathological and US characteristics. Using the standardized regression coefficient, a 10-point score system was constructed in line with these independent predictors. Then, the scoring system was evaluated for the diagnostic value in predicting CLNM. RESULTS: Tumor location (the lower polo), tumor size (>5 mm), extrathyroidal extension, margin (no well-defined), display of enlarged lymph node, and contact of >25% with the adjacent capsule were independent predictors for CLNM. Verifying the scoring system, a cutoff value of 5 points was found to be the best prediction for CLNM, the sensitivity and specificity were 64.7 and 80.5%, respectively, and the positive and negative predictive values were 77.3 and 69.0%, respectively. CONCLUSIONS: The points≤5 could be considered as a low risk for CLNM, and the points>5 could be identified as a high risk for CLNM. More advanced diagnostic approaches and prophylactic CLND are needed for patients with the points>5.
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Carcinoma Papilar/patologia , Linfonodos/patologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Carcinoma Papilar/cirurgia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Glândula Tireoide/cirurgia , Carga TumoralRESUMO
BACKGROUND: Gene expression profiling of breast cancers identifies distinct molecular subtypes that affect prognosis. The aim of this study was to determine whether features of tumors especially the risks of lymph node (LN) metastases differ among molecular subtypes. METHODS: Subtypes were classified by immunohistochemical surrogates as luminal A, luminalHer2-, luminalHer2+, TNBC, and HER-2+. Data were obtained from an established, registered database of patients with invasive breast cancer treated at our hospital between July 2012 and October 2014. A total of 929 tumors were classifiable into molecular subtypes. RESULTS: The distribution of subtypes was luminal A (24.2%), luminalHer2- (27.8%), luminalHer2+ (9.1%), TNBC (21.3%), and HER-2+ (17.5%). Marked differences in age, tumor size, extent of lymph node involvement, and grade were observed among subtypes. On univariate analysis, the LN positivity varied across subtypes with 33.6% in luminal A, 40.3% in luminalHer2-, 37.3% in luminalHer2+, 37.6% in TNBC, and 47.4 % in HER-2+ (p=0.201). There was no significant difference in LN positivity among subtypes. On multivariable analysis, grade and tumor size were independent predictors of LN positivity. CONCLUSIONS: Predictors of LN metastases include higher grade and larger tumor size. Even though breast cancer subtype is not a statistically significant predictor of LN positivity, this information may still be useful in selecting the appropriate therapy in clinical practice.
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Biomarcadores Tumorais/análise , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Humanos , Linfonodos/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
In Alzheimer's disease (AD), amyloid-beta (Aß) plays a crucial role in pathogenesis. Clearing Aß from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aß. Molecular docking result showed that Tan IIA might block AD by upregulating Aß-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aß-degrading enzymes.
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Doença de Alzheimer , Disfunção Cognitiva , Salvia miltiorrhiza , Camundongos , Animais , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de DoençasRESUMO
BACKGROUND: The prevalence of dementia around the world is increasing, and these patients are more likely to have cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorders over their lifetime. Previous studies have proven that melatonin could improve memory loss, but its specific mechanism is still confused. METHODS: In this study, we used in vivo and in vitro models to examine the neuroprotective effect of melatonin on scopolamine (SCOP)-induced cognitive dysfunction. The behavioral tests were performed. 18F-FDG PET imaging was used to assess the metabolism of the brain. Protein expressions were determined through kit detection, Western blot, and immunofluorescence. Nissl staining was conducted to reflect neurodegeneration. MTT assay and RNAi transfection were applied to perform the in vitro experiments. RESULTS: We found that melatonin could ameliorate SCOP-induced cognitive dysfunction and relieve anxious-like behaviors or HT22 cell damage. 18F-FDG PET-CT results showed that melatonin could improve cerebral glucose uptake in SCOP-treated mice. Melatonin restored the cholinergic function, increased the expressions of neurotrophic factors, and ameliorated oxidative stress in the brain of SCOP-treated mice. In addition, melatonin upregulated the expression of silent information regulator 1 (SIRT1), which further relieved endoplasmic reticulum (ER) stress by decreasing the expression of phosphorylate inositol-requiring enzyme (p-IRE1α) and its downstream, X-box binding protein 1 (XBP1). CONCLUSIONS: These results indicated that melatonin could ameliorate SCOP-induced cognitive dysfunction through the SIRT1/IRE1α/XBP1 pathway. SIRT1 might be the critical target of melatonin in the treatment of dementia.
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Disfunção Cognitiva , Melatonina , Escopolamina , Transdução de Sinais , Sirtuína 1 , Proteína 1 de Ligação a X-Box , Melatonina/farmacologia , Melatonina/uso terapêutico , Animais , Sirtuína 1/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Camundongos , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.
Assuntos
Apoptose , Disfunção Cognitiva , Demência Vascular , Medicamentos de Ervas Chinesas , Estresse do Retículo Endoplasmático , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Apoptose/efeitos dos fármacos , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.
Assuntos
Disfunção Cognitiva , Metformina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Sirtuína 1 , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Sirtuína 1/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Camundongos , Masculino , Transdução de Sinais/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.
Assuntos
Disfunção Cognitiva , Evodia , Camundongos , Animais , Inflamassomos , Evodia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Escopolamina/toxicidade , Etanol/toxicidade , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismoRESUMO
Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.
Assuntos
Nitrilas , Pirazóis , Pirimidinas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Dinâmica Mitocondrial , Piroptose , Caspase 9/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , ApoptoseRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: A growing number of people suffer from Alzheimer's disease (AD), but there is currently no effective treatment yet. Taohong Siwu Decoction (TSD) has been proved to take strong neuropharmacological activity on dementia, but the effect and mechanism of TSD against AD are still elusive. AIM OF STUDY: To investigate whether TSD could be effective in ameliorating cognitive deficits through SIRT6/ER stress pathway. MATERIALS AND METHODS: Herein, the APP/PS1 mice, an AD model, and HT-22 cell lines were utilized. Different dosages of TSD (4.25, 8.50 and 17.00 g/kg/d) were administered to the mice for 10 weeks by gavage. Following the behavioral tests, oxidative stress levels were measured using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. Nissl staining and Western blot analyses were used to detect the neuronal function. Then, immunofluorescence and Western blot analysis were applied to evaluate silent information regulator 6 (SIRT6) and ER Stress related protein levels in APP/PS1 mice and HT-22 cells. RESULTS: Behavioral tests revealed that APP/PS1 mice administered with TSD orally took more time in the target quadrant, crossed more times in the target quadrant, had a higher recognition coefficient, and spent more time in the central region. In addition, TSD could ameliorate oxidative stress and inhibit neuronal apoptosis in APP/PS1 mice. Furthermore, TSD could up-regulate the SIRT6 protein expression and inhibit ER sensing proteins expressions, such as p-PERK and ATF6, in APP/PS1 mice and Aß1-42-treated HT22 cells. CONCLUSION: According to the abovementioned findings, TSD could alleviate cognitive dysfunction in AD by modulating the SIRT6/ER stress pathway.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Medicamentos de Ervas Chinesas , Sirtuínas , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 µM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-ß peptides (Aß) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aß toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.