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1.
J Endovasc Ther ; : 15266028241245907, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38590278

RESUMO

BACKGROUND: Blunt traumatic aortic injury (BTAI) is a rare occurrence in adolescents, yet it is associated with a high mortality rate necessitating immediate treatment. Although endovascular repair has become the preferred treatment for such injuries in adults, its effectiveness in adolescents remains uncertain. CASE SUMMARY: Blunt traumatic aortic injury typically presents with concomitant injuries to other organs and carries a high perioperative mortality rate with operative repair (OR). In this report, we describe the treatment of 3 clinical cases of BTAI in adolescents using thoracic endovascular aortic repair (TEVAR). These cases contribute pertinent evidence supporting the efficacy of intravascular repair for BTAI. CONCLUSION: Operative repair (OR) remains the gold standard for treating BTAI in adolescents. Nevertheless, TEVAR therapy presents a viable alternative for patients with multiple injuries in whom anticoagulation is contraindicated. Further long-term observation is necessary to assess the lasting effects of TEVAR therapy. CLINICAL IMPACT: This study has provided insights into endovascular repair for adolescent BTAT, offering clinicians significant reference material for choosing treatment strategies for adolescent BTAT. The study aims to demonstrate the safety and effectiveness of endovascular repair treatments in a series of clinical cases involving adolescent BTAI.

2.
Small ; 19(30): e2302238, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37191328

RESUMO

Developing efficient and durable electrocatalysts for the oxygen evolution reaction (OER) in proton exchange membrane (PEM) electrolyzers represents a significant challenge. Herein, the cobalt-ruthenium oxide nano-heterostructures are successfully synthesized on carbon cloth (CoOx /RuOx -CC) for acidic OER through a simple and fast solution combustion strategy. The rapid oxidation process endows CoOx /RuOx -CC with abundant interfacial sites and defect structures, which enhances the number of active sites and the charge transfer at the electrolyte-catalyst interface, promoting the OER kinetics. Moreover, the electron supply effect of the CoOx support allows electrons to transfer from Co to Ru sites during the OER process, which is beneficial to alleviate the ion leaching and over-oxidation of Ru sites, improving the catalyst activity and stability. As a self-supported electrocatalyst, CoOx /RuOx -CC displays an ultralow overpotential of 180 mV at 10 mA cm-2 for OER. Notably, the PEM electrolyzer using CoOx /RuOx -CC as the anode can be operated at 100 mA cm-2 stably for 100 h. Mechanistic analysis shows that the strong catalyst-support interaction is beneficial to redistribute the electronic structure of RuO bond to weaken its covalency, thereby optimizing the binding energy of OER intermediates and lowering the reaction energy barrier.

3.
J Transl Med ; 20(1): 520, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348351

RESUMO

BACKGROUND: The tumour microenvironment and cirrhotic liver are excellent sources of cancer-associated fibroblasts (CAFs), which participate in carcinogenesis. Thus, it is important to clarify the crosstalk between CAFs and HCC cells and the related mechanism in regulating carcinogenesis. METHODS: Human hepatocellular carcinoma (HCC) tissues and matched adjacent normal tissues were obtained from HCC patients. Immunohistochemistry, Western blotting (WB) and RT-qPCR were performed to detect the expression of SCUBE1. The roles of SCUBE1 in inducing stemness features in HCC cells were explored and investigated in vitro and in vivo. Student's t tests or Mann-Whitney U tests were used to compare continuous variables, while chi-square tests or Fisher's exact tests were used to compare categorical variables between two groups. RESULTS: SCUBE1 was confirmed to be highly expressed in CAFs in HCC and had a strong connection with stemness and a poor prognosis. In addition, CAFs were found to secrete SCUBE1 to enhance the malignancy of HCC cells and increase the proportion of CD133-positive cells. Silencing SCUBE1 expression had the opposite effect. The Shh pathway was activated by SCUBE1 stimulation. Inhibition of cyclopamine partially reversed the stimulating effect of SCUBE1 both in vivo and in vitro. Moreover, based on the RT-qPCR, ELISA and WB results, a high SCUBE1 expression level was found in HCC tissue and serum. CONCLUSION: This study revealed that CAFs-derived SCUBE1 can enhance the malignancy and stemness of HCC cells through the Shh pathway. This study aims to provide new perspectives for future HCC studies and provide new strategies for HCC treatment.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Proteínas de Ligação ao Cálcio/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proteínas Hedgehog , Neoplasias Hepáticas/patologia , Microambiente Tumoral , Proteína GLI1 em Dedos de Zinco/genética , Células-Tronco Neoplásicas
4.
J Cell Mol Med ; 25(14): 6618-6633, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34085405

RESUMO

Ferroptosis is a newly identified cell death mechanism and potential biomarker for hepatocellular carcinoma (HCC) therapy; however, its clinical relevance and underlying mechanism remain unclear. In this study, transcriptome and methylome data from 374 HCC cases were investigated for 41 ferroptosis-related genes to identify ferroptosis activity-associated subtypes. These subtypes were further investigated for associations with clinical and pathological variables, gene mutation landscapes, deregulated pathways and tumour microenvironmental immunity. A gene expression signature and predictive model were developed and validated using an additional 232 HCC cases from another independent cohort. Two distinct ferroptosis phenotypes (Ferroptosis-H and Ferroptosis-L) were identified according to ferroptosis gene expression and methylation in the patients with HCC. Patients with the Ferroptosis-H had worse overall and disease-specific survival, and the molecular subtypes were significantly associated with different clinical characteristics, mRNA expression patterns, tumour mutation profiles and microenvironmental immune status. Furthermore, a 15-gene ferroptosis-related prognostic model (FPM) for HCC was developed and validated which demonstrated accurate risk stratification ability. A nomogram included the FPM risk score, ECOG PS and hepatitis B status was developed for eventual clinical translation. Our results suggest that HCC subtypes defined by ferroptosis gene expression and methylation may be used to stratify patients for clinical decision-making.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Ferroptose/genética , Neoplasias Hepáticas/genética , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Fenótipo , Prognóstico , Fatores de Risco , Transcriptoma/genética , Microambiente Tumoral/genética
5.
BMC Cancer ; 21(1): 1211, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772375

RESUMO

PURPOSE: Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD. METHODS: The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan-Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network. RESULTS: A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints-PD-L1, CD47, CD276, and PVR-was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis. CONCLUSION: We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.


Assuntos
Adenocarcinoma , Processamento Alternativo , Neoplasias Pancreáticas , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Idoso , Algoritmos , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos , Antígeno CD47/metabolismo , Linfócitos T CD8-Positivos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Feminino , Humanos , Proteínas de Checkpoint Imunológico/genética , Imunidade Celular , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Nomogramas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Processamento de RNA/metabolismo , Receptores Virais/metabolismo , Linfócitos T Reguladores , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
6.
Angew Chem Int Ed Engl ; 60(41): 22276-22282, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34427019

RESUMO

Designing definite metal-support interfacial bond is an effective strategy for optimizing the intrinsic activity of noble metals, but rather challenging. Herein, a series of quantum-sized metal nanoparticles (NPs) anchored on nickel metal-organic framework nanohybrids (M@Ni-MOF, M=Ru, Ir, Pd) are rationally developed through a spontaneous redox strategy. The metal-oxygen bonds between the NPs and Ni-MOF guarantee structural stability and sufficient exposure of the surface active sites. More importantly, such precise interfacial feature can effectively modulate the electronic structure of hybrids through the charge transfer of the formed Ni-O-M bridge and then improves the reaction kinetics. As a result, the representative Ru@Ni-MOF exhibits excellent hydrogen evolution reaction (HER) activity at all pH values, even superior to commercial Pt/C and recent noble-metal catalysts. Theoretical calculations deepen the mechanism understanding of the superior HER performance of Ru@Ni-MOF through the optimized adsorption free energies of water and hydrogen due to the interfacial-bond-induced electron redistribution.

7.
Pharmacol Res ; 159: 105035, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32562818

RESUMO

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) are considered as anti-diabetic targets based on their role in improving insulin secretion and resistance. Based on their synergetic mechanisms, we have previously identified the first-in-class dual FFA1/PPARδ agonist ZLY032. After long-term treatment, ZLY032 significantly improved glucolipid metabolism and alleviated fatty liver in ob/ob mice and methionine choline-deficient diet-fed db/db mice, mainly by regulating triglyceride metabolism, fatty acid ß-oxidation, lipid synthesis, inflammation, oxidative stress and mitochondrial function. Notably, ZLY032 exhibited greater advantages on lipid metabolism, insulin sensitivity and pancreatic ß-cell function than TAK-875, the most advanced candidate of FFA1 agonists. Moreover, ZLY032 prevented CCl4-induced liver fibrosis by reducing the expressions of genes involved in inflammation and fibrosis development. These results suggest that the dual FFA1/PPARδ agonists such as ZLY032 may be useful for the treatment of metabolic disorders.


Assuntos
Glicemia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzofuranos/farmacologia , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Sulfonas/farmacologia
8.
Pharmacol Res ; 153: 104679, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014571

RESUMO

In the effort to identify anti-diabetic drug, we discovered a novel free fatty acid receptor 1 (FFA1) agonist CPU025, which is structurally different from previously reported FFA1 agonists. The present study revealed CPU025 is a potent FFA1 agonist (EC50 = 38.7 nM) with moderate agonistic activity on PPARδ (EC50 = 625.6 nM), and promotes insulin secretion at a glucose-dependent manner. Modeling study also illuminated CPU025 forms interaction with key residues closely related to the agonistic effects of FFA1 and PPARδ. Long-term treatment of CPU025 exerted better glycemic control and lipid profile than TAK-875, the most advanced FFA1 partial agonist in this field. Moreover, CPU025 improved ß-cell function and alleviated fatty liver in ob/ob mice. Further study suggested CPU025 could alleviate fatty liver through regulating the expression of genes involved in fatty acid ß-oxidation, lipoprotein lipolysis, lipid synthesis, oxidative stress and mitochondrial function. These results indicate that long-term treatment of CPU025 improves glucose and lipid metabolism, and may be useful for the treatment of diabetes mellitus and fatty liver.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Fígado Gorduroso/prevenção & controle , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Experimental/metabolismo , Fígado Gorduroso/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/química , Secreção de Insulina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Camundongos Obesos , Simulação de Acoplamento Molecular , Receptores Ativados por Proliferador de Peroxissomo/metabolismo
9.
Bioorg Chem ; 101: 103963, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32480174

RESUMO

Dual PPARα/δ agonists have been considered as potential therapeutics for the treatment of type 2 diabetes mellitus. After comprehensive structure-activity relationship study based on GFT505, a novel dual PPARα/δ agonist compound 6 was identified with highly activities on PPARα/δ and higher selectivity against PPARγ than that of GFT505. The modeling study revealed that compound 6 binds well to the binding pockets of PPARα and PPARδ, which formed multiple hydrogen bonds with key residues related to the activation of PPARα and PPARδ. Moreover, oral glucose tolerance test exhibited that compound 6 exerts dose-dependent anti-diabetic effects in ob/ob mice and reveals similar potency to that of GFT505, the most advanced candidate in this field. These findings suggested that compound 6 is a promising candidate for further researches, and the extended chemical space might help us to explore better PPARα/δ agonist.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , PPAR alfa/agonistas , PPAR delta/agonistas , Humanos
10.
Ann Vasc Surg ; 62: 497.e1-497.e5, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31449949

RESUMO

Celiac axis (CA) aneurysm is a rare vascular condition, consisting of only 3.6-4% of visceral artery aneurysms but is frequently life threatening and can result in death. A celiomesenteric trunk (CMT) is an anatomic anomaly in which the celiac and superior mesenteric arteries arise from a common trunk. This structure accounts for only 1% of visceral artery variation, and a celiac artery aneurysm at a CMT is exceptionally rare. Here, we report the case of a 62-year-old woman with a celiac artery aneurysm at a CMT. Endovascular repair was completed using a bare metal stent-assisted coil. Satisfactory results were observed at the 10-month follow-up. To our knowledge, this is the first case reported of bare metal stent-assisted coil repair of a CA aneurysm at a CMT.


Assuntos
Aneurisma/terapia , Angioplastia com Balão , Artéria Celíaca , Embolização Terapêutica , Artéria Mesentérica Superior , Aneurisma/diagnóstico por imagem , Aneurisma/fisiopatologia , Angioplastia com Balão/instrumentação , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/fisiopatologia , Embolização Terapêutica/instrumentação , Feminino , Humanos , Artéria Mesentérica Superior/diagnóstico por imagem , Artéria Mesentérica Superior/fisiopatologia , Pessoa de Meia-Idade , Circulação Esplâncnica , Stents , Resultado do Tratamento
11.
Chem Soc Rev ; 48(11): 2967-3014, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31089607

RESUMO

Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood-brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.


Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/terapia , Portadores de Fármacos/metabolismo , Glioblastoma/terapia , Nanopartículas/metabolismo , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Nanotecnologia/métodos
12.
Angew Chem Int Ed Engl ; 59(23): 8833-8838, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-31943602

RESUMO

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the 1 O2 generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release 1 O2 in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.


Assuntos
Escuridão , Fototerapia/métodos , Oxigênio Singlete/metabolismo , Hipóxia Tumoral/efeitos da radiação , Microambiente Tumoral/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Humanos , Lasers , Imagem Óptica , Polietilenoglicóis/química , Pirrolidinonas/química , Oxigênio Singlete/química , Estilbenos/química
13.
Bioorg Med Chem Lett ; 29(4): 525-528, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30630716

RESUMO

The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Tiazolidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Inibidores Enzimáticos/química , Febuxostat/farmacologia , Tiazolidinas/química
14.
Bioorg Med Chem Lett ; 29(12): 1471-1475, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992164

RESUMO

The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to ß-oxidation. To identify orally available analogs, we tried to block the route of ß-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.


Assuntos
Deutério/uso terapêutico , Receptores Acoplados a Proteínas G/uso terapêutico , Deutério/farmacocinética , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
15.
Bioorg Chem ; 92: 103254, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31518760

RESUMO

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Obesos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
16.
Bioorg Chem ; 92: 103209, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31487621

RESUMO

Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.


Assuntos
Acetatos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Acetatos/química , Animais , Células CHO , Cricetulus , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 26(14): 3947-3952, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29954682

RESUMO

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Óxido Nítrico/química , Trombose Venosa/tratamento farmacológico , Difosfato de Adenosina , Animais , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/química , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Glucosídeos/síntese química , Glucosídeos/química , Células HEK293 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Coelhos , Relação Estrutura-Atividade
19.
Asia Pac J Clin Oncol ; 20(2): 275-284, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36748794

RESUMO

PURPOSE: It is difficult to predict the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) before radical operation. The purpose of this study was to explore the connection between the diffuse reduction of spleen density on computed tomography (DROSD) and the postoperative prognosis of patients with PDAC. PATIENTS AND METHODS: A total of 160 patients with PDAC who underwent radical surgery in the First Affiliated Hospital of Wenzhou Medical University were enrolled. Cox regression analysis was used to cast the overall survival (OS) and evaluate the prognostic factors. Nomogram was used to forecast the possibility of 1-year, 3-year, and 5-year OS. The prediction accuracy and clinical net benefit are performed by concordance index (C-index), calibration curve, time-dependent receiver operating characteristics (tdROC), and decision curve analysis. RESULTS: In multivariable Cox analysis, DROSD is independently related to OS. Advanced age, TNM stage, neutrophil/lymphocyte ratio, and severe complications were also independent prognostic factors. The calibration curves of nomogram showed optimal agreement between prediction and observation. The C-index of nomogram is 0.662 (95%CI, 0.606-0.754). The area under tdROC curve for a 3-year OS of nomogram is 0.770. CONCLUSION: DROSD is an independent risk factor for an OS of PDAC. We developed a nomogram that combined imaging features, clinicopathological factors, and systemic inflammatory response to provide a personalized risk assessment for patients with PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Baço , Estudos Retrospectivos , Prognóstico , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Nomogramas
20.
Nat Commun ; 15(1): 2728, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38553434

RESUMO

Establishing appropriate metal-support interactions is imperative for acquiring efficient and corrosion-resistant catalysts for water splitting. Herein, the interaction mechanism between Ru nanoparticles and a series of titanium oxides, including TiO, Ti4O7 and TiO2, designed via facile non-stoichiometric engineering is systematically studied. Ti4O7, with the unique band structure, high conductivity and chemical stability, endows with ingenious metal-support interaction through interfacial Ti-O-Ru units, which stabilizes Ru species during OER and triggers hydrogen spillover to accelerate HER kinetics. As expected, Ru/Ti4O7 displays ultralow overpotentials of 8 mV and 150 mV for HER and OER with a long operation of 500 h at 10 mA cm-2 in acidic media, which is expanded in pH-universal environments. Benefitting from the excellent bifunctional performance, the proton exchange membrane and anion exchange membrane electrolyzer assembled with Ru/Ti4O7 achieves superior performance and robust operation. The work paves the way for efficient energy conversion devices.

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