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1.
Bioorg Med Chem Lett ; 98: 129576, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38061401

RESUMO

Alzheimer's disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aß species, amyloid-ß 42 (Aß42) aggregates are proposed to be more neurotoxic than that of Aß40, and oligomeric Aß42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aß42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aß42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aß42 aggregation over that of Aß40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aß species in AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Animais , Camundongos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Corantes , Fragmentos de Peptídeos , Imidazóis/química , Imidazóis/farmacologia
2.
BMC Vet Res ; 20(1): 252, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851737

RESUMO

BACKGROUND: The insulin/insulin-like signalling (IIS) pathway is common in mammals and invertebrates, and the IIS pathway is unknown in Fasciola gigantica. In the present study, the IIS pathway was reconstructed in F. gigantica. We defined the components involved in the IIS pathway and investigated the transcription profiles of these genes for all developmental stages of F. gigantica. In addition, the presence of these components in excretory and secretory products (ESPs) was predicted via signal peptide annotation. RESULTS: The core components of the IIS pathway were detected in F. gigantica. Among these proteins, one ligand (FgILP) and one insulin-like molecule binding protein (FgIGFBP) were analysed. Interestingly, three receptors (FgIR-1/FgIR-2/FgIR-3) were detected, and a novel receptor, FgIR-3, was screened, suggesting novel functions. Fg14-3-3ζ, Fgirs, and Fgpp2a exhibited increased transcription in 42-day-old juveniles and 70-day-old juveniles, while Fgilp, Fgigfb, Fgsgk-1, Fgakt-1, Fgir-3, Fgpten, and Fgaap-1 exhibited increased transcription in metacercariae. FgILP, FgIGFBP, FgIR-2, FgIR-3, and two transcription factors (FgHSF-1 and FgSKN-1) were predicted to be present in FgESPs, indicating their exogenous roles. CONCLUSIONS: This study helps to elucidate the signal transduction pathway of IIS in F. gigantica, which will aid in understanding the interaction between flukes and hosts, as well as in understanding fluke developmental regulation, and will also lay a foundation for further characterisation of the IIS pathways of trematodes.


Assuntos
Fasciola , Proteínas de Helminto , Insulina , Transdução de Sinais , Animais , Fasciola/genética , Fasciola/metabolismo , Insulina/metabolismo , Proteínas de Helminto/metabolismo , Proteínas de Helminto/genética
3.
J Org Chem ; 86(24): 17696-17709, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34818024

RESUMO

Diimine (HN═NH) is a strong reducing agent, but the efficiency of diimine oxidized from hydrazine hydrate or its derivatives is still not good enough. Herein, we report an in situ neocuproine-copper complex formation method. The redox potential of this complex enable it can serve as an ideal redox catalyst in the synthesis of diimine by oxidation of hydrazine hydrate, and we successfully applied this technique in the reduction of alkynes. This reduction method displays a broad functional group tolerance and substrate adaptability as well as the advantages of safety and high efficiency. Especially, nitro, benzyl, boc, and sulfur containing alkynes can be reduced to the corresponding alkanes directly, which provides a useful complementary method to traditional catalytic hydrogenation. Besides, we applied this method in the preparation of the Alzheimer's disease drug CT-1812 and studied the mechanism.


Assuntos
Alcinos , Cobre , Hidrazinas , Hidrogenação , Fenantrolinas
4.
Bioorg Med Chem Lett ; 54: 128444, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34763082

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Many studies have shown a significant increase in the marker signal of the receptor for advanced glycation end-products (RAGE) with the malignant progression of tumor growth, metastasis and recurrence of breast cancer, including TNBC of primary tumors and lymph node metastases. Azeliragon is a RAGE inhibitor and it has been shown to actively inhibit the TNBC cell line, SUM149 (IC50 = 5.292 ± 0.310 µM). In order to develop a new anti-TNBC agent, we designed, synthesized and screened 26 Azeliragon triazole analogues to determine their anti-TNBC activities in vitro. The most active compound was KC-10 with an IC50 value of 0.220 ± 0.034 µM.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Neoplasias de Mama Triplo Negativas/patologia
5.
Bioorg Med Chem ; 28(7): 115358, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081628

RESUMO

PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in highthroughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD < 10 nM), which well met the requirement of binding activity for the PET probe. These DBC compounds were firstly reported as α-syn ligands herein and the preliminary obtained structure has been further modified into F-labeled ones. Among them, a high-affinity tracer (5-41) with 1.03 nM (KD) has been acquired, indicating its potential as a new lead compound for developing PET radiotracer.


Assuntos
Cinamatos/química , Cinamatos/farmacologia , Desenho de Fármacos , Tomografia por Emissão de Pósitrons , alfa-Sinucleína/química , Encéfalo , Humanos , Ligantes , Estrutura Molecular , Ensaio Radioligante
6.
Bioorg Med Chem ; 26(12): 3308-3320, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29739714

RESUMO

We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33 nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/-p53-/- mouse medulloblastoma allograft model also indicated encouraging results.


Assuntos
Antineoplásicos/síntese química , Proteínas Hedgehog/metabolismo , Piridazinas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Modelos Animais de Doenças , Desenho de Fármacos , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Simulação de Acoplamento Molecular , Piridazinas/metabolismo , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened/química , Receptor Smoothened/metabolismo , Relação Estrutura-Atividade , Transplante Homólogo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
7.
Small ; 12(40): 5633-5645, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27571928

RESUMO

Energy metabolism abnormity is one of the most significant hallmarks of cancer. As a result, large amino acid transporter 1 (LAT1) is remarkably overexpressed in both blood-brain-barrier and glioma tumor cells, leading a rapid and sufficient substrate transportation. 3CDIT and 4CDIT are originally synthesized by modifying the existing most potent LAT1 substrate. 3CDIT is selected as its higher glioma-targeting ability. Since the microenvironment variation in tumor cells is another important feature of cancer, a great disparity in adenosine-5'-triphosphate (ATP) and glutathione (GSH) levels between extracellular and intracellular milieu can provide good possibilities for dual-responsive drug release in tumor cells. Doxorubicin (DOX) is successfully intercalated into the ATP aptamer DNA scaffolds, compressed by GSH-responsive polymer pOEI, and modified with 3CDIT to obtain 3CDIT-targeting pOEI/DOX/ATP aptamer nanoparticles (NPs). Enhanced NP accumulation and rapid GSH & ATP dual-responsive DOX release in glioma are demonstrated both in vitro and in vivo. More efficient therapeutic effects are shown with 3CDIT-targeting pOEI/DOX/ATP aptamer NPs than free DOX and no systemic toxicity is observed. Therefore, glioma-targeting delivery and GSH & ATP dual-responsive release guarantee an adequate DOX accumulation within tumor cells and ensure a safe and efficient chemotherapy for glioma.


Assuntos
Aminoácidos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Glioma/metabolismo , Microambiente Tumoral , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Glioma/patologia , Glutationa/metabolismo , Humanos , Espaço Intracelular/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Camundongos Nus , Nanopartículas/química , Microambiente Tumoral/efeitos dos fármacos
8.
Bioorg Med Chem Lett ; 26(13): 3048-3051, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27180012

RESUMO

We report herein the design and synthesis of a series of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Gli-luciferase assay demonstrated that changing piperazine ring of Anta XV to different four, five or six-membered heterocyclic building blocks afforded significant influences on Hh pathway inhibition. In particular, compound 10e with piperidin-4-amine moiety was found to possess 12-fold higher Hh inhibitory activities comparing to the lead compound in vitro. In vivo efficacy of 10e in a ptch(+/-)p53(-/-) mouse medulloblastoma allograft model also indicated encouraging results.


Assuntos
Proteínas Hedgehog/metabolismo , Ftalazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Camundongos , Células NIH 3T3 , Ftalazinas/síntese química , Ftalazinas/farmacocinética , Piperazinas/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade
9.
Molecules ; 21(8)2016 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-27527142

RESUMO

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [(18)F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [(11)C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [(11)C]-TKF can be made by reaction precursor with [(11)C]MeOTf or (11)CH3I, but [(11)C]MeOTf will give us higher labeling yields and specific activity. [(11)C]-TKF presented better brain uptake in normal mouse than [(18)F]-THK523 (3.23% ± 1.25% ID·g(-1) vs. 2.62% ± 0.39% ID·g(-1) at 2 min post-injection). The acute toxicity studies of [(11)C]-TKF were unremarkable.


Assuntos
Encéfalo/diagnóstico por imagem , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Proteínas tau/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Distribuição Tecidual
10.
Zhonghua Xin Xue Guan Bing Za Zhi ; 43(3): 212-8, 2015 Mar.
Artigo em Zh | MEDLINE | ID: mdl-26269339

RESUMO

OBJECTIVE: To investigate the effects and related mechanisms of 2-methylthio-adenosine-5'-triphosphate (2-MeSATP), an important extracellular agonist that activates receptors for purine nucleotides (P2XR), on ventricular arrhythmias in rabbits with chronic heart failure (CHF). METHODS: The male New Zealand rabbits were divide into control (n=12), CHF (n=12) and CHF+2-MeSATP groups (2-MeSATP, n=12). CHF was induced by isoproterenol injection (0.3 mg·kg⁻¹·d⁻¹ for 3 weeks) and rabbits were observed 6 months later. The main cardioelectrophysiological parameters and ventricular arrhythmias were tested by recording monophasic action potential (MAP) with burst-pacing (BCL) in rabbits in vivo. The transient outward potassium current (Ito) was recorded via whole-cell patch clamp technique and the fluorescence intensity of intracellular free Ca²âº was detected with Flup-3/AM loading by the laser scanning confocal microscope in enzymatically dissociated single rabbet ventricular myocytes. RESULTS: CHF rabbits developed severely clinical CHF signs and symptoms, reduced left ventricular ejection fraction and fractional shortening as well as enlarged end-diastolic dimension. Compared with CHF group, APA and MaxdV/dt were significantly increased, while APD20, APD50 and APD90 were significantly reduced in 2-MeSATP group (all P<0.01). Moreover, 2-MeSATP could obviously shorten BCL induced ventricular arrhythmias, and decrease deducibility and persistence time of ventricular arrhythmias with burst-pacing in 2-MeSATP group in vivo (all P<0.05). With voltage clamp model, 2-MeSATP could significantly increase the current density of Ito in different command potential in CHF ventricular myocytes (all P<0.01). When holding potential was set at -50 mV and command potential was set at +50 mV, the current densities of Ito increase was more significant in 2-MeSATP group than that in CHF group ((11.79 ± 4.51) pA/pF vs. (7.94 ± 3.53) pA/pF, P<0.01). 2-MeSATP could completely change the I-V curve upward without changing the I-V curve direction in CHF ventricular myocytes. The fluorescence intensities of intracellular free Ca²âº increase was more significant in 2-MeSATP group compared to CHF group ((1 291.98 ± 123.31) µmol/L vs. (793.59 ± 114.65) µmol/L, P<0.01). CONCLUSION: 2-MeSATP as a potent agonist acting on P2XR could significantly shorten APD, increase heart rate and improve cardiac performance as well as decrease the susceptibility of ventricular arrhythmias in this rabbit CHF model. Our results suggest that Ito increase and sarcoplasmic reticulum uptake Ca²âº enhancement as well as dynamic balance of intracellular Ca²âº cycling sustenance might linked to the beneficial effects of 2-MeSATP in this CHF model.


Assuntos
Insuficiência Cardíaca , Potenciais de Ação , Trifosfato de Adenosina/análogos & derivados , Animais , Síndrome de Brugada , Doença do Sistema de Condução Cardíaco , Doença Crônica , Ventrículos do Coração , Isoproterenol , Masculino , Miócitos Cardíacos , Técnicas de Patch-Clamp , Potássio , Coelhos , Tionucleotídeos
11.
Transplant Proc ; 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38806312

RESUMO

An uncommon and dangerous disease with a fatality rate of more than 95% is caused by the amoeba known as Balamuthia mandrillaris. Here, we discuss the treatment of a patient who underwent a renal transplant and contracted the amoeba B. mandrillaris. The patient had a sudden onset of high fever on the 13th day after renal transplantation; on the morning of the 16th postoperative day, the patient's condition worsened and he was transferred to the ICU for treatment; on the 17th postoperative day, the patient was given mechanical ventilation; and on the 20th postoperative day, he underwent a lumbar large-pool puncture, combined with intrathecal injection of the administered medication. In order to prevent further deterioration of the patient's condition, the main aspects of care for this patient included close monitoring of changes in the patient's condition and early detection of risk factors; prompt emergency care for the patient's seizures; close monitoring of the efficacy and side effects of the patient's medication; and precise medication administration; improved hemodynamic monitoring while administering CRRT to the patient, as well as performing exercises on the patient's limb and respiratory functions. On the 32nd postoperative day, a tracheotomy is performed following thorough monitoring and care. The ventilator was turned off on postoperative day 34, and a venturi mask was installed for tracheotomy-cannula-based oxygen administration. On surgical day 40, the intrathecal injections halted and the lumbar pool drainage tube was removed. On postoperative day 46, the patient was stabilized and transferred from the intensive care unit to the organ transplant unit for extra care. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source.

12.
Chem Sci ; 15(4): 1431-1440, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38274081

RESUMO

Imine reductases (IREDs) are important biocatalysts in the asymmetric synthesis of chiral amines. However, a detailed understanding of the stereocontrol mechanism of IRED remains incomplete, making the design of IRED for producing the desired amine enantiomers challenging. In this study, we investigated the stereoselective catalytic mechanism and designed an (R)-stereoselective IRED from Paenibacillus mucilaginosus (PmIR) using pharmaceutically relevant 2-aryl-substituted pyrrolines as substrates. A putative mechanism for controlling stereoselectivity was proposed based on the crucial role of electrostatic interactions in controlling iminium cation orientation and employed to achieve complete inversion of stereoselectivity in PmIR using computational design. The variant PmIR-Re (Q138M/P140M/Y187E/Q190A/D250M/R251N) exhibited opposite (S)-stereoselectivity, with >96% enantiomeric excess (ee) towards tested 2-aryl-substituted pyrrolines. Computational tools were employed to identify stabilizing mutations at the interface between the two subunits. The variant PmIR-6P (P140A/Q190S/R251N/Q217E/A257R/T277M) showed a nearly 5-fold increase in activity and a 12 °C increase in melting temperature. The PmIR-6P successfully produced (R)-2-(2,5-difluorophenyl)-pyrrolidine, a key chiral pharmaceutical intermediate, at a concentration of 400 mM with an ee exceeding 99%. This study provides insight into the stereocontrol elements of IREDs and demonstrates the potential of computational design for tailored stereoselectivity and thermal stability.

13.
J Mater Chem B ; 12(8): 2054-2069, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38305698

RESUMO

Microporous organic polymers (MOPs) and metal oxide hybrid composites are considered valuable coating materials because of their versatility derived from the synergistic combination of MOPs' inherent dispersibility and the distinctive properties of metal oxides. In this study, we present the synthesis of sea-urchin-like MOPs hybridised with silver oxide nanoparticles (Ag2O NPs) to fabricate antibacterial composites suitable for potential antibacterial coating applications. Ag2O NP-decorated urchin-like MOPs (Ag2O@UMOPs) were synthesised by employing a combination of two methods: a one-pot Lewis acid-base interaction-mediated self-assembly and a straightforward impregnation process. The as-prepared Ag2O@UMOPs demonstrated high antibacterial efficacy against both E. coli (G-) and S. aureus (G+). The antibacterial mechanism of Ag2O@UMOPs mainly involved the synergistic effects of accumulation of Ag2O@UMOPs, the release of Ag+ ions, and the generation of reactive oxygen species. The exceptional processability and biosafety of Ag2O@UMOPs make them ideal organic coating materials for convenient application on various substrates. These remarkable features of Ag2O@UMOPs provide an effective platform for potential antibacterial applications in biological sciences.


Assuntos
Escherichia coli , Compostos de Prata , Staphylococcus aureus , Óxidos/química , Antibacterianos/farmacologia , Antibacterianos/química
14.
Front Med (Lausanne) ; 10: 1258037, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37822466

RESUMO

Background: There is a significant controversy surrounding the impact of the geriatric nutritional risk index (GNRI) on mortality among elderly septic patients. This retrospective cohort study aimed to investigate the association between GNRI at admission and 28 days mortality in elderly septic patients. Methods: We retrospectively analyzed data collected from the MIMIC IV database between 2009 and 2019, which included 2,834 septic patients aged 65 years and above. The exposure variable was the GNRI, determined according to albumin levels, height, and weight. The primary outcome was 28 days mortality. We employed multivariable Cox regression analyses and Kaplan-Meier survival curves to examine the association between GNRI and 28 days mortality. We used restricted cubic splines to determine if there was a non-linear relationship between 28 days mortality and GNRI in elderly patients with sepsis and to examine the presence of a threshold saturation effect. In addition, interaction tests were conducted to identify subgroups that exhibited significant differences. Results: A total of 2,834 elderly patients with sepsis participated in the study. Following adjustment, multivariable Cox regression analyses demonstrated that the GNRI was related to 28 days mortality (HR = 0.97, p < 0.001, 95% CI: 0.97-0.98). An L-shaped connection between GNRI and 28 days mortality was discovered via restricted cubic spline analysis, with an inflection point of 98.1. On the left side of the inflection point, GNRI levels were significantly negatively linked with 28 days mortality (HR = 0.967, 95% CI: 0.959-0.974; p < 0.001), and on the right side, there was no significant correlation (HR = 1.043, 95% CI: 0.984-1.106; p = 0.1549). Conclusion: In this analysis of data from a large cohort of elderly septic patients, GNRI scores on admission were correlated with a 28 days risk of death from sepsis in the elderly suggesting that GNRI scores could serve as a valuable indicator for evaluating mortality rates among elderly septic patients in the intensive care unit (ICU).

15.
Anal Methods ; 15(6): 703-708, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36691870

RESUMO

A ratiometric and pH-sensitive fluorescent dye named IDE was applied to the detection of argine and lysine from common amino acids and exploited to monitor the Lys and Arg levels in living cells and zebrafish larvae successfully. IDE will be a useful fluorescence indicator of pH changes by Lys and Arg.


Assuntos
Corantes Fluorescentes , Peixe-Zebra , Humanos , Animais , Corantes Fluorescentes/química , Peixe-Zebra/metabolismo , Células HeLa , Lisina/metabolismo , Espectrometria de Fluorescência/métodos
16.
Adv Sci (Weinh) ; 8(8): 2004044, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33898188

RESUMO

Hypoxia is considered as a key microenvironmental feature of solid tumors. Luminescent transition metal complexes particularly those based on iridium and ruthenium have shown remarkable potentials for constructing sensitive oxygen-sensing probes due to their unique oxygen quenching pathway. However, the low aqueous solubility of these complexes largely retards their sensing applications in biological media. Moreover, it remains difficult so far to use the existing complexes typically possessing only one luminescent domain to quantitatively detect the intratumoral hypoxia degree. Herein, an Ir(III) complex showing red emissions is designed and synthesized, and innovatively encapsulated within a hydrophobic pocket of Cyanine7-modified cyclodextrin. The Ir(III) complex enables the oxygen detection, while the cyclodextrin is used not only for improving the water solubility and suppressing the luminescence quenching effect of the surrounding aqueous media, but also for carrying Cyanine7 to establish a ratiometric oxygen fluorescence probe. 2D nuclear magnetic resonance is carried out to confirm the host-guest structure. The oxygen-responsive ability of the resulting ratiometric probe is evaluated through in vitro cell and multicellular experiments. Further animal studies about tumor oxygen level mapping demonstrate that the probe can be successfully used for quantitatively visualizing tumor hypoxia in vivo.


Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/fisiopatologia , Ciclodextrinas , Irídio , Espectroscopia de Ressonância Magnética/métodos , Hipóxia Tumoral/fisiologia , Animais , Modelos Animais de Doenças , Corantes Fluorescentes , Humanos , Luminescência , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
17.
ACS Sens ; 4(11): 3084-3087, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31674767

RESUMO

Recently, we published a paper on the detection of superoxide (O2•-) with a water-soluble fluorescent probe (ACS Sens. 2018, 3, 59-64), and Francesco Tampieri et al. provided comments on our publication, mostly on the detection medium (deionized water) we used. Herein we present our responses to the addressed questions to explain that although KO2 decomposes in aqueous environment, the results we obtained did not affect the general trend, since evidence from the literature afforded the correlation between KO2 in aqueous media as a surrogate of superoxide and enzymatically produced O2•- for the probes wherein the deprotection pathway operated. Moreover, fluorescence imaging on cells and zebrafish embryos under PMA stimulation confirmed the effectiveness of our probe to detect superoxide using KO2 as a convenient source. The detailed studies from Francesco Tampieri and coauthors are scientifically meaningful for the reliable evaluation of fluorescent probes using KO2 as a surrogate of superoxide.


Assuntos
Corantes Fluorescentes , Superóxidos , Animais , Lisossomos , Mitocôndrias , Água , Peixe-Zebra
18.
Medicine (Baltimore) ; 98(26): e15960, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261502

RESUMO

New-onset atrial fibrillation (NOAF) remains common arrhythmia in acute myocardial infarction (AMI), and is closely associated with increased subsequent cardiovascular mortality. Our meta-analysis aims to summarize more clinical risk factors for NOAF.Comprehensive systematic search of MEDLINE, EMBASE, and the Cochrane Library were carried out to find relevant studies inception to December 2017. Pooled mean difference (MD) and 95% confidence interval (CI) were calculated to evaluate the value of clinical risk factors in the prediction of NOAF after AMI.Eleven studies containing 9570 patients were included in the meta-analysis. Overall, older age and increased heart rate (HR) levels had a significant positive association with NOAF in patients with AMI. The MD in age between the patients with, and those without NOAF, was 8.22 units (95% confidence interval [CI]: 7.44-9.01), test for overall effect z score = 20.51 (P < .00001, I = 0%). Moreover, the MD in a subgroup analysis for HR levels between the patients with, and those without NOAF was 4.34 units (95% Cl: 2.56-6.11), test for overall effect z score = 4.78 (P < .00001, I = 31%).In patient with AMI, our meta-analysis demonstrated that older age and increased HR levels on admission are related to greater risk of NOAF.


Assuntos
Fibrilação Atrial/epidemiologia , Infarto do Miocárdio/epidemiologia , Humanos , Fatores de Risco
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 213: 416-422, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738350

RESUMO

Novel cyanine-based fluorescent probes for the detection of H2S were developed. The probes developed are stable under physiological conditions. The water soluble fluorescent probe 2 displayed ultrafast and specific response to H2S displaying NIR fluorescence of 115-fold turn-on with the detection limit of 11 nM without assistance of organic solvent or surfactant. Cell imaging experiments indicated that probe 2 was cell-permeable and was able to detect H2S sensitively in lysosomes. Moreover, our probe was able to detect H2S intrinsically produced H2S through enzymatic/non-enzymatic biosynthetic pathway from Cys/GSH. Moreover, we applied probe 2 to detect H2S in living mice and demonstrated the fast metabolism of H2S. Thus, probe 2 shows great promise as a reporter for H2S.


Assuntos
Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Animais , Sobrevivência Celular , Colorimetria , Corantes Fluorescentes/síntese química , Fluorometria , Células HeLa , Células Hep G2 , Humanos , Imageamento Tridimensional , Camundongos , Espectrometria de Fluorescência , Fatores de Tempo
20.
Mol Med Rep ; 20(1): 709-718, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180563

RESUMO

Anti­apoptotic and anti­inflammatory treatments are imperative for skeletal muscle regeneration following injury. Baicalin is well known and has previously been investigated for its role in the treatment of injury and inflammatory diseases. Therefore, the present study aimed to investigate the effects of baicalin in inhibiting apoptosis of C2C12 myoblasts and preventing skeletal muscle injury. A cell counting kit­8 (CCK­8) assay and Annexin V/PI staining were initially performed to measure cell viability and apoptosis under conditions of H2O2 exposure with or without baicalin. Subsequently, oxidative activity, mitochondrial function, mitochondrial apoptogenic factors and caspase proteins were analyzed to examine the mechanism underlying the effect of baicalin on inhibiting apoptosis in C2C12 myoblasts. Furthermore, BALB/C mice with skeletal muscle injuries were established, and the potential application of baicalin for anti­apoptotic and anti­inflammatory effects was examined via small animal ß­2­[18F]­fluoro­2­deoxy­D­glucose (18F­FDG) positron emission tomography (PET) imaging and pathological examination. The CCK­8 assay and Annexin V/PI staining revealed cell death in the C2C12 myoblasts induced by H2O2, which was apoptotic, and this was effectively reversed by treatment with baicalin. H2O2 increased the reactive oxygen species and malondialdehyde levels in C2C12 myoblasts, which was caused by mitochondrial dysfunction, decreased expression of cytochrome c and apoptosis­inducing factor from cytosolic and mitochondrial fractions, and activated expression of caspase­3 and caspase­9; however, treatment with baicalin reversed these effects. In addition, small animal PET imaging revealed that treatment with baicalin decreased the accumulation of FDG by ~65.9% in the injured skeletal muscle induced by H2O2. These pathological results also confirmed the protective effect of baicalin on injured skeletal muscle. Taken together, the results of the present study indicated that baicalin effectively inhibited the apoptosis of C2C12 myoblasts and protected skeletal muscle from injury, which may have potential therapeutic benefits for patients in a clinical setting.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Flavonoides/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Mioblastos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Feminino , Flavonoides/química , Flavonoides/farmacologia , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Scutellaria baicalensis/química
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