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1.
JAMA ; 331(10): 840-849, 2024 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-38329440

RESUMO

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Feminino , Humanos , Idoso , Método Duplo-Cego , Trombectomia/efeitos adversos , Hemorragias Intracranianas , Metilprednisolona/efeitos adversos
2.
Exp Neurol ; 373: 114654, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38104887

RESUMO

We have previously demonstrated that treatment with cannabidiol (CBD) ameliorates mitochondrial dysfunction and attenuates neuronal injury in rats following cerebral ischemia. However, the role of CBD in the progression of ischemic stroke-induced inflammation and the molecules involved remain unclear. Here, we found that CBD suppressed the production of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), reduced the activation of microglia, ameliorated mitochondrial deficits, and decreased the phosphorylation of nuclear factor κ-B (NF-κB) in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cyclin-dependent kinase regulatory subunit 1B (CKS1B) expression was decreased in BV-2 cells following OGD/R and this reduction was blocked by treatment with CBD. Knockdown of CKS1B increased the activation of microglia and enhanced the production of IL-1ß and TNF-α in BV-2 cells treated with CBD. Moreover, CKS1B knockdown exacerbated mitochondrial deficits and increased NF-κB phosphorylation. CBD treatment also ameliorated brain injury, reduced neuroinflammation, and enhanced the protein levels of mitochondrial transcription factor A and CKS1B in rats following middle cerebral artery occlusion/reperfusion. These data identify CKS1B as a novel regulator of neuroinflammation; and reveals its involvement in the anti-inflammatory effects of CBD. Interventions targeting CKS1B expression are potentially promising for treating in ischemic stroke.


Assuntos
Isquemia Encefálica , Canabidiol , AVC Isquêmico , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Microglia/metabolismo , Doenças Neuroinflamatórias , NF-kappa B/metabolismo , Oxigênio/farmacologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Acta Pharmacol Sin ; 44(3): 499-512, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36229600

RESUMO

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 µM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD's protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin's binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.


Assuntos
Isquemia Encefálica , Canabidiol , GTP Fosfo-Hidrolases , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Masculino , Ratos , Apoptose , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Canabidiol/farmacologia , Glucose/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Oxigênio/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Ubiquitina-Proteína Ligases/metabolismo , GTP Fosfo-Hidrolases/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo
4.
Brain Behav Immun ; 104: 155-170, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35688339

RESUMO

Currently, there is increasing attention on the regulatory effects of cannabidiol (CBD) on the inflammatory response and the immune system. However, the mechanisms have not yet been completely revealed. Mitofusin 2 (Mfn2) is a mitochondrial fusion protein involved in the inflammatory response. Here, we investigated whether Mfn2 confers the anti-inflammatory effects of CBD. We found that treatment with CBD decreased the levels of tumor necrosis factor α, interleukin 6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and ionized calcium-binding adaptor molecule-1 (Iba1) in lipopolysaccharide (LPS)-challenged microglia. CBD also significantly suppressed the increase in reactive oxygen species (ROS) and the decline of mitochondrial membrane potential in BV-2 cells subjected to LPS. Interestingly, CBD treatment increased the expression of Mfn2, while knockdown of Mfn2 blocked the effect of CBD. By contrast, overexpression of Mfn2 reversed the increase in the levels of iNOS, COX-2, and Iba1 induced by Mfn2 small interfering RNA. In mice challenged with LPS, we found that CBD ameliorated the anxiety responses and cognitive deficits, increased the level of Mfn2, and decreased the expression of Iba1. Since neuro-inflammation and microglial activation are the common events that are observed in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, we treated EAE mice with CBD. Mice that received CBD showed amelioration of clinical signs, reduced inflammatory response, and increased myelin basic protein level. Most importantly, the adeno-associated virus delivery of short hairpin RNA against Mfn2 reversed the protective effects of CBD. Altogether, these results indicate that Mfn2 is an essential immunomodulator conferring the anti-inflammatory effects of CBD. Our results also shed new light on the mechanisms underlying the protective effects of CBD against inflammatory diseases including multiple sclerosis.

5.
Eur J Pharmacol ; 926: 175027, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35569548

RESUMO

The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 µM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Inibidores da Fosfodiesterase 4 , Traumatismo por Reperfusão , Aminopiridinas , Animais , Benzamidas , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto Cerebral/complicações , Ciclopropanos , Células Endoteliais , Humanos , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Ratos , Receptor Notch1/metabolismo , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Fatores de Transcrição HES-1/metabolismo
6.
Biomed Pharmacother ; 121: 109550, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704617

RESUMO

The aging process is accompanied by changes in the gut microbiota and metabolites. This study aimed to reveal the relationship between gut microbiota and the metabolome at different ages, as well as the anti-aging effect of FTZ, which is an effective clinical prescription for the treatment of hyperlipidemia and diabetes. METHODS: In the present study, mice were randomly divided into different age and FTZ treatment groups. The aging-relevant behavioral phenotype the levels of blood glucose, cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, high density lipoprotein-cholesterol and cytokine TNF-α,IL-6, IL-8 in the serum were measured. Changes of serum metabolties were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-Q-TOF/MS). Gut microbiota were identified using 16S rDNA sequencing. RESULTS: Our results indicated that with age, the aging-relevant behavioral phenotype appeared, glucose and lipid metabolism disordered, secretion levels of cytokine TNF-α, IL-6 and IL-8 increased.The Firmicutes/Bacteroidetes ratio changed with age, first increasing and then decreasing, and the microbial diversity and the community richness of the aging mice were improved by FTZ. The abundance of opportunistic bacteria decreased (Lactobacillus murinus, Erysipelatoclostridium), while the levels of protective bacteria such as Butyricimonas, Clostridium and Akkermansia increased. Metabolic analysis identified 24 potential biomarkers and 10 key pathways involving arachidonic acid metabolism, phospholipid metabolism, fatty acid metabolism, taurine and hypotaurine metabolism. Correlation analysis between the gut microbiota and biomarkers suggested that the relative abundance of protective bacteria was negatively correlated with the levels of leukotriene E4, 20-HETE and arachidonic acid, which was different from protective bacteria. CONCLUSION: Shifts of gut microbiota and metabolomic profiles were observed in the mice during the normal aging process, and treatment with FTZ moderately corrected the aging, which may be mediated via interference with arachidonic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, taurine and hypotaurine metabolism and gut microbiota in mice.


Assuntos
Envelhecimento/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Bactérias/efeitos dos fármacos , Biomarcadores/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL
7.
Front Pharmacol ; 10: 926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555127

RESUMO

The aim of this study was to investigate the metabolic trajectory of liver aging, the effect of FTZ against liver aging in aging mice, and its mechanism using ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Methods: A total of 80 C57BL/6J Narl mice were randomly divided into five groups: 3-month-old group, 9-month-old group, 14-month-old group, 20-month-old group, and FTZ treatment group (20 months old). The mice in the treatment group received a therapeutic dose of oral FTZ extract (1.0 g/kg, on raw material weight basis) once daily during the experiment. The other groups received the corresponding volume of oral normal saline solution. Liver samples of all five groups were collected after 12 weeks, and UPLC-Q-TOF/MS was used to analyze metabolic changes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to analyze the resulting data. Additionally, cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver were determined. Results: The levels of TC, TG, AST, and ALT were increased, and liver tissue structure was damaged. The secretion levels of TNF-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver also increased with aging. FTZ administration reduced the symptoms of liver aging. The OPLS-DA score plot illustrated the effect of FTZ against liver aging, with N-acetyl-leukotriene E4, 20-hydroxy-leukotriene E4, leukotriene E4, and arachidonic acid among the key biomarkers. The pivotal pathways revealed by pathway analysis included arachidonic acid metabolism and biosynthesis of unsaturated fatty acids. The mechanism by which FTZ reduces the symptoms of liver aging in mice might be related to disorders of the abovementioned pathways. Conclusion: A metabolomic approach based on UPLC-Q-TOF/MS and multivariate statistical analysis was successfully applied to investigate the metabolic trajectory of liver aging. FTZ has a protective effect against liver aging, which may be mediated via interference with the metabolism of arachidonic acid, biosynthesis of unsaturated fatty acids, and downregulation of pro-inflammatory factors in the liver in mice in vivo.

8.
Zhongguo Zhong Yao Za Zhi ; 43(17): 3466-3470, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30347913

RESUMO

Rhizoma et Radix Notopterygii is a rare and endangered Chinese medicine. In the collection of Notopterygium franchetii fruits, we collected a sample of N. forrestii , which is a spurious breed. Fruits of N. franchetii and N. forrestii are very similar in morphology and can be easily confused. Until now the morphological identification of the fruits of Notopterygium has not been reported. To provide a scientific basis for the identification of N. franchetii and N. forrestii fruits, the morphology and microscopic identification were studied in this paper. In this study, stereomicroscope and paraffin sections were used to compare the morphological characteristics and microscopic characteristics of these two fruits. Our results showed that these two fruits were different in size, surface texture and the number of vertical edges on the back. These traits can be used as diagnostic characteristic of these two fruits. The difference between the number of tubing and the endosperm cell contents can be used as microscopic identification features. The above discriminative characteristics can distinguish the two fruits and provide scientific basis for the identification and germplasm evaluation of Notopterygium fruits.


Assuntos
Apiaceae/classificação , Frutas/anatomia & histologia , Plantas Medicinais/classificação , Microscopia
9.
Front Pharmacol ; 9: 1483, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30670964

RESUMO

Fufang Zhenzhu Tiaozhi (FTZ), as an effective traditional Chinese medicine, has been prescribed for more than 20 years. It has proven clinical efficacy as a prescription for patients with dyslipidemia, glucocorticoid- and high-fat-induced osteoporosis, but its effect on osteoporosis induced by aging is still unclear. The aim of this study was to investigate the anti-osteoporosis effect of FTZ in aging mice and revealed its biochemical action mechanism using metabolomics. Model of primary osteoporosis induced by aging was established. The mice in treatment group received a therapeutic dose of oral FTZ extract once daily during the experiment. The model and control groups received the corresponding volume of oral normal saline solution. Plasma samples of all three groups were collected after 12 weeks. Clinical biochemical parameters and biomechanics were determined in the osteoporosis model induced by normal aging to evaluate anti-osteoporosis effect of FTZ. Ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was used to analyze metabolic changes. The changes of histomorphometric and biomechanic parameters of femurs, as well as osteoblast and osteoclast activity indicated that FTZ administration reduced the risk of osteoporosis. Partial least squares discriminant analysis (PLS-DA) score plot revealed a clear separation trend between model and controls. Moreover, PLS-DA score plot indicated the anti-osteoporosis effect of FTZ with sphingosine 1-phosphate, LPA (16:0) and arachidonic acid (AA) among key biomarkers. The pivotal pathways revealed by pathway analysis including sphingolipid metabolism, glycerophospholipid metabolism, and AA metabolism. The mechanism by which FTZ reduces the risk of primary age-related osteoporosis in mice might be related to disorders of the above-mentioned pathways. FTZ has a protective effect against osteoporosis induced by aging, which may be mediated via interference with sphingolipid, glycerophospholipid, and AA metabolisms in mice.

10.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 9): m1065-6, 2009 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21577423

RESUMO

In the title complex, [Nd(C(5)H(3)N(2)O(2))(C(2)O(4))(H(2)O)(2)](n), the Nd(III) atom is ten-coordinated by one N atom and three O atoms from two pyrazine-2-carboxyl-ate ligands, four O atoms from two oxalate ligands and two water mol-ecules in a distorted bicapped square-anti-prismatic geometry. The two crystallographically independent oxalate ligands, each lying on an inversion center, act as bridging ligands, linking Nd atoms into an extended zigzag chain. Neighboring chains are linked by the pyrazine-2-carboxyl-ate ligands into a two-dimensional layerlike network in the (10) plane. The layers are further connected by O-H⋯O and O-H⋯N hydrogen bonds, forming a three-dimensional supra-molecular network.

11.
Mol Vis ; 14: 2304-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19093007

RESUMO

PURPOSE: To describe the clinical features of and identify a novel mutation in Bardet-Biedl syndrome 7 gene (BBS7) in a Chinese family. METHODS: Nineteen individuals at risk for inheriting Bardet-Biedl syndrome (BBS) in a Chinese family participated in the study. Physical examination was performed and blood was drawn for DNA extraction. Linkage analysis was conducted for all known BBS loci, and mutation screening of BBS7 gene and BBS12 gene was performed. RESULTS: A Chinese family with inherited BBS was identified. After performing linkage analysis on all 13 known loci, we found the disease phenotype of a Chinese family with BBS linked to a locus where BBS7 and BBS12 genes locate. CONCLUSIONS: This study describes a novel mutation in BBS7 causing BBS in a Chinese family. This is the first report that a mutation in a BBS gene causes BBS in a Chinese population. These results expand the spectrum of human disease associated with mutations of BBS7 since the initial three mutations in BBS7 were first identified in 2003.


Assuntos
Povo Asiático/genética , Síndrome de Bardet-Biedl/genética , Mutação/genética , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Sequência de Bases , China , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Família , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Retina/patologia
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