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1.
Org Lett ; 26(27): 5856-5861, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38950381

RESUMO

Here, we present a silver-catalyzed decarboxylative nitrooxylation via a radical-based approach. The substrate scope of this reaction prototype extends to nonactivated primary and secondary carboxylic acids. This protocol provides a practical method for the synthesis of an unprecedented family of organic nitrates and exhibits wide functional group compatibility. Preliminary mechanistic studies reveal that a high-valent silver(II) nitrate complex is a versatile NO3 resource pool, allowing for facile C-O bond formation.

2.
Org Lett ; 26(20): 4257-4261, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38738813

RESUMO

Herein, we present a decarboxylative nucleophilic fluorination of carboxylic acids with a silver catalyst. This strategy enables the synthesis of a myriad of diverse and valuable fluorinated motifs under mild conditions, demonstrating good functional-group tolerance and utility in late-stage functionalization. In contrast to traditional electrophilic fluorination, this nucleophilic method utilizes a more readily available nucleophilic fluorinating reagent, providing substantial advantages in terms of cost efficiency, broad substrate scope, and functional-group compatibility.

3.
Front Mol Neurosci ; 16: 1290556, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38076208

RESUMO

Background: Vascular smooth muscle cell (VSMC) dysfunction is one of the crucial pathologic processes in the development of intracranial aneurysm (IA). Secreted protein acidic and rich in cysteine (SPARC), a multifunctional glycoprotein, is overexpressed in many tumor, but its underlying mechanism in vascular disease has not been elucidated. The aim of this study is to evaluate the potential function of SPARC in IA generation and regulation of mitochondrial function in VSMC. Methods: Human brain vascular smooth muscle cells were treated with recombinant SPARC to detect apoptosis-related markers. The downstream targets affecting mitochondrial dysfunction after SPARC treatment were explored by transcriptome sequencing and bioinformatics analysis, and verified using by immunohistochemistry and western blot. Further in vitro experiments verified the role of downstream targets in regulating VSMC mitochondrial function. Results: Secreted protein acidic and rich in cysteine (SPARC) expression was associated with the risk of IA rupture. SPARC induces mitochondrial pathway apoptosis in human brain VSMC. We screened 40 differentially expressed genes related to mitochondrial function after SPARC treatment. Hexokinase 2 (HK2) was identified as a downstream target of mitochondrial pathway apoptosis in VSMC induced by SPARC. In addition, immunohistochemical results confirmed that the difference between SPARC and HK2 expression is located mainly in the smooth muscle layer of IA. Overexpression of HK2 reversed the SPARC-induced increase in apoptosis and mitochondrial damage in VSMC. Conclusion: Secreted protein acidic and rich in cysteine (SPARC) regulated mitochondrial function in VSMC and induced apoptosis through HK2, which plays an important role in the formation and rupture of IA. Targeting SPARC may be a novel strategy to delay the development of intracranial aneurysms.

4.
Front Neurol ; 14: 1282486, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38090273

RESUMO

Background and purpose: Diabetes mellitus (DM) is a well-established cardiovascular risk factor for atherosclerotic disease; however, its effect on the risk of rupture of intracranial aneurysms remains controversial. Herein, we aimed to perform a case-control study to investigate the relationship between DM and aneurysmal subarachnoid hemorrhage (aSAH). Methods: We retrospectively reviewed the data of patients with ruptured or unruptured aneurysms who were treated between 2013 and 2023. Univariate and multivariate analyses were performed. Propensity score matching (PSM) analysis was conducted to evaluate the relationship between DM and risk of aSAH. Results: A total of 4,787 patients with 5,768 intracranial aneurysms were included. Among them, 2,957 (61.8%) were females, 1765 (36.9%) had ruptured aneurysms, and 531 (11.1%) presented with DM. Female sex, current drinking, and hypercholesterolemia were associated with a higher risk of aSAH, whereas old age, former smoking, and DM were associated with a lower risk of aSAH in multivariate analysis (p < 0.05). The incidence of DM (13.4%, 406/3022) in the unruptured group was higher than that in the ruptured group (7.1%, 125/1765) (odds ratio, 0.55; 95% confidence interval, 0.444-0.680) (p < 0.001). After propensity score matching, 530 patients with DM were successfully matched, and DM was still associated with a lower risk of aSAH (odds ratio, 0.24; 95% confidence interval, 0.185-0.313) (p < 0.001). Conclusion: Patients with aSAH have a lower incidence of DM, however, this case-cohort study could not establish a causal relationship. A prospective and large study with long-term follow-up is warranted to establish a causal relationship.

5.
Biol Res ; 56(1): 50, 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37752552

RESUMO

BACKGROUND: Intracranial aneurysm (IA) is the most common cerebrovascular disease, and subarachnoid hemorrhage caused by its rupture can seriously impede nerve function. Pyroptosis is an inflammatory mode of cell death whose underlying mechanisms involving the occurrence and rupture of IAs remain unclear. In this study, using bioinformatics analysis, we identified the potential pyroptosis-related genes (PRGs) and performed their inflammatory response mechanisms in IAs. METHODS: The mRNA expression matrix of the IA tissue was obtained from the Gene Expression Omnibus database, and 51 PRGs were obtained from previous articles collected from PubMed. The differentially expressed PRGs (DEPRGs) were performed using R software. Subsequently, we performed enrichment analysis, constructed a protein-protein interaction network, performed weighted gene coexpression network analysis (WGCNA) and external validation using another dataset, and identified a correlation between hub genes and immune cell infiltration. Finally, the expression and tissue distribution of these hub genes in IA tissues were detected using Western blotting and immunohistochemical (IHC) staining. RESULTS: In total, 12 DEPRGs associated with IA were identified in our analysis, which included 11 up-regulated and one down-regulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the DEPRGs were mostly enriched in the NOD-like receptor signaling pathway, interleukin-1 beta production, and the inflammasome complex. Three hub genes, NLRP3, IL1B and IL18, were identified using Cytoscape software and the WGCNA correlation module, and external validation revealed statistically significant differences between the expression of these hub genes in the ruptured and unruptured aneurysm groups (p < 0.05). Furthermore, all AUC values were > 0.75. Immune cell infiltration analysis suggested that the hub genes are related to CD8 T cell, macrophages and mast cells. Finally, IHC staining revealed that the protein levels of these hub genes were higher in ruptured and unruptured IA tissues than in normal tissues (p < 0.05). CONCLUSION: The results of bioinformatics analysis showed that pyroptosis is closely related to the formation and rupture of IA, and identified three potential hub genes involved in the pyroptosis and infiltration ofcells. Our findings may improve the understanding of the mechanisms underlying pyroptosis in IA.


Assuntos
Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/genética , Piroptose/genética , Morte Celular , Biologia Computacional , Inflamação/genética
6.
Front Neurol ; 14: 1202565, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37483445

RESUMO

Background: Vertebral artery stenosis and occlusion (VASO) is a high-risk factor for posterior circulation stroke. Post-stent restenosis and drug tolerance have facilitated the exploration of microsurgical vascular reconstruction. This study aims to evaluate the safety and efficacy of microsurgical reconstruction of the proximal VA. Methods: Twenty-nine patients (25 men, aged 63.2 years) who had symptoms of posterior circulation ischemia underwent microsurgical revascularization for proximal VASO were retrospectively included in this study. Procedural complications and clinical and angiographic outcomes were reviewed. Results: Twelve, three, and five patients underwent VA endarterectomy, artery transposition, or both, respectively; seven patients underwent vertebral endarterectomy plus stent implantation; and two patients failed surgery because of the difficult exposure of the VA and the occurrence of vascular dissection. The perioperative period-related complications included seven cases of Horner's syndrome, five cases of hoarseness, and one case of chylothorax. No cases of perioperative stroke or death were reported. The mean follow-up period was 28.4 (8-62 months). Most patients improved clinically; however, the vertebrobasilar ischemia symptoms did not decrease significantly in two patients during the follow-up. Moreover, follow-up imaging was performed in all the patients, and no signs of anastomotic stenosis were reported. Conclusion: Microsurgical reconstruction is an alternative option that can effectively treat refractory proximal VASO disease and in-stent stenosis, with a high rate of postoperative vascular recirculation. Prospective cohort studies with larger sample sizes must be conducted to validate the above conclusions.

7.
J Neurointerv Surg ; 15(12): 1194-1200, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36639233

RESUMO

BACKGROUND: Basilar artery trunk aneurysms (BTAs) are rare intracranial aneurysms. We aim to investigate the procedural complications and clinical and angiographic outcomes of BTAs treated with reconstructive endovascular treatment (EVT). METHODS: We retrospectively reviewed the data of 111 patients with BTAs who underwent reconstructive EVT during 2013-2022. The factors associated with procedural complications and clinical and angiographic outcomes were analyzed. RESULTS: The study included 81 men and 30 women (median age 60 years). Overall, 26 (23.4%) cases presented with subarachnoid hemorrhage and 85 (76.6%) presented with unruptured aneurysms. Periprocedural ischemic and hemorrhagic complications occurred in 29 (26.1%) and 4 (3.6%) cases, respectively. The rate of favorable clinical outcomes was 83.8% (92/111) and the mortality rate was 14.4% (16/111). Angiographic follow-up data were available for 77/95 (81.1%) survivors; 57 (74.0%) and 20 (26%) aneurysms exhibited complete and incomplete obliteration, respectively. Old age, high Hunt and Hess grades (IV-V), hemorrhagic complications, and increased aneurysm size were independent risk factors for unfavorable clinical outcomes (p<0.05). Increased aneurysm size and incomplete aneurysm occlusion on immediate angiography were independent risk factors for incomplete occlusion during follow-up (p<0.05). CONCLUSION: Reconstructive EVTs are a feasible and effective treatment for BTAs but are associated with a high risk of ischemic and hemorrhagic complications and a high mortality rate. Larger aneurysms may predict unfavorable clinical outcomes and aneurysm recurrence during follow-up. Hemorrhagic complications may predict unfavorable clinical outcomes, whereas immediate complete aneurysm occlusion may predict total occlusion during follow-up.


Assuntos
Aneurisma Roto , Embolização Terapêutica , Procedimentos Endovasculares , Aneurisma Intracraniano , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Aneurisma Intracraniano/complicações , Estudos Retrospectivos , Artéria Basilar , Angiografia Cerebral , Resultado do Tratamento , Procedimentos Endovasculares/efeitos adversos , Aneurisma Roto/terapia
8.
Org Lett ; 25(1): 47-52, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36563335

RESUMO

Herein, we demonstrate an efficient method for the decarboxylative hydroxylation of carboxylic acids with silver(I) as the catalyst and cerium ammonium nitrate as the oxidant and its utility in chemoselective late-stage functionalization of natural products and drug molecules. The chemoselectivity of this protocol arises from a benzylic nitrate intermediate that retards further oxidation and is hydrolyzed to the final benzylic alcohol product. Mechanistic investigation reveals that the facile oxidation of silver carboxylate affords silver(II) species as an intermediate oxidant responsible for decarboxylation.


Assuntos
Álcool Benzílico , Prata , Hidroxilação , Estrutura Molecular , Ácidos Carboxílicos , Oxidantes
9.
Infect Genet Evol ; 97: 105159, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34839024

RESUMO

Based on previous reports,toll-like receptors (TLRs) are recognition molecules common in various aquatic animals and play a vital role in innate immunity. In this study, a novel TLR CgToll-3 with leucine-rich repeats (LRRs) and a TIR (Toll-interleukin 1-resistance) domain was cloned in Crassostrea gigas. CgToll-3 with sixteen potential extracellular N-linked glycosylation sites and shares the closest phylogenic relationship with molluscan TLRs. Alignment of LRRs and TIR domains indicated that CgToll-3 was highly conserved compared to other LRRs of mollusks which could respond against Vibrio or other bacterial molecules, and contained three conserved functionally important motifs (Box 1, Box 2, and Box 3). The Hex Molecular Docking result showed that CgToll-3 could interact with CgMyd88 via the TIR domain. Subcellular Co-localization and BiFC Assay confirmed this interaction, and they could induce NF-κB activation. CgToll-3 was moderately expressed in the digestive gland, and its expression level was significantly up-regulated after Vibrio alginolyticus challenge. Taken together, CgToll-3 might be involved in the innate immune response to V. alginolyticus for C. gigas through a MyD88-dependent TLR mediated signaling pathway.


Assuntos
Crassostrea/imunologia , Imunidade Inata/genética , Receptores Toll-Like/genética , Vibrio alginolyticus/fisiologia , Animais , Crassostrea/genética , Receptores Toll-Like/imunologia
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