Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Molecules ; 29(12)2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38930917

RESUMO

In the field of human health research, the homeostasis of copper (Cu) is receiving increased attention due to its connection to pathological conditions, including diabetes mellitus (DM). Recent studies have demonstrated that proteins associated with Cu homeostasis, such as ATOX1, FDX1, ATP7A, ATPB, SLC31A1, p53, and UPS, also contribute to DM. Cuproptosis, characterized by Cu homeostasis dysregulation and Cu overload, has been found to cause the oligomerization of lipoylated proteins in mitochondria, loss of iron-sulfur protein, depletion of glutathione, production of reactive oxygen species, and cell death. Further research into how cuproptosis affects DM is essential to uncover its mechanism of action and identify effective interventions. In this article, we review the molecular mechanism of Cu homeostasis and the role of cuproptosis in the pathogenesis of DM. The study of small-molecule drugs that affect these proteins offers the possibility of moving from symptomatic treatment to treating the underlying causes of DM.


Assuntos
Cobre , Diabetes Mellitus , Desenho de Fármacos , Homeostase , Humanos , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Cobre/química , Cobre/metabolismo , Homeostase/efeitos dos fármacos , Animais , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
2.
Int Immunopharmacol ; 123: 110736, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37549513

RESUMO

AIMS: Doxorubicin (DOX) is an effective anti-tumor drug, but the cardiotoxicity severely limits its clinical use. Interestingly, a hypothesis has emerged suggesting an association between DOX-induced cardiotoxicity and mitochondrial disorders and oxidative stress. The mitochonic acid 5 (MA5) shows promise in alleviating mitochondrial dysfunction by promoting mitochondrial ATP synthesis and reducing reactive oxygen species (ROS) accumulation, though its potential in ameliorating DOX-induced cardiotoxicity remains elusive. METHODS: Network pharmacology approach, molecular docking techniques, and molecular dynamics simulation (MDS) were used to reveal the specific drug targets and pharmaceutical mechanisms involved in the treatment of DOX-induced cardiotoxicity using MA5. For experimental verification, cardiomyocytes (H9c2) and mice were exposed to DOX in the presence or absence of MA5. Our investigation involved the assessment of echocardiographic parameters, cardiac enzymes, inflammatory factors, mitochondrial function, myocardial structure, and cardiomyocyte pyroptosis. RESULTS: Among the 100 core targets identified in network pharmacology, MA5 was pharmacologically active against DOX-induced cardiotoxicity via pathways implicated in cancer, prostate cancer, lipids and atherosclerosis. Molecular docking analysis confirmed that MA5 docked well with TNF-α, interleukin-6 (IL-6), and caspase-3. Furthermore, MA5 exhibited a stronger affinity toward TNF-α than IL-6 and caspase-3. Subsequent MDS revealed the stability of binding between MA5 and TNF-α. The DOX-challenged mice also displayed abnormal myocardial enzymogram, disrupted systolic and diastolic function, and elevated inflammation and cardiomyocyte pyroptosis, which could be mitigated by the administration of MA5. Similarly, H9c2 cells exposed to DOX showed increased intracellular ROS production and impaired mitochondrial function, which were relieved by MA5 treatment. CONCLUSION: Our findings suggest that MA5 attenuates DOX-induced cardiac anomalies through the TNF-α-mediated regulation of inflammation and pyroptosis. These insights offer a potential therapeutic strategy for managing DOX-induced cardiac complications, thereby improving the safety and efficacy of cancer treatments.


Assuntos
Miócitos Cardíacos , NF-kappa B , Masculino , Camundongos , Animais , NF-kappa B/metabolismo , Miócitos Cardíacos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Piroptose , Caspase 3/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Interleucina-6/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Simulação de Acoplamento Molecular , Doxorrubicina/efeitos adversos , Estresse Oxidativo , Inflamação/metabolismo , Apoptose
3.
Front Plant Sci ; 14: 1154266, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37077636

RESUMO

Lipid metabolism disorders may considerably contribute to the formation and development of atherosclerosis (AS). Traditional Chinese medicine has received considerable attention in recent years owing to its ability to treat lipid metabolism disorders using multiple components and targets. Verbena officinalis (VO), a Chinese herbal medicine, exhibits anti-inflammatory, analgesic, immunomodulatory, and neuroprotective effects. Evidence suggests that VO regulates lipid metabolism; however, its role in AS remains unclear. In the present study, an integrated network pharmacology approach, molecular docking, and molecular dynamics simulation (MDS) were applied to examine the mechanism of VO against AS. Analysis revealed 209 potential targets for the 11 main ingredients in VO. Further, 2698 mechanistic targets for AS were identified, including 147 intersection targets between VO and AS. Quercetin, luteolin, and kaempferol were considered key ingredients for the treatment of AS based on a potential ingredient target-AS target network. GO analysis revealed that biological processes were primarily associated with responses to xenobiotic stimuli, cellular responses to lipids, and responses to hormones. Cell components were predominantly focused on the membrane microdomain, membrane raft, and caveola nucleus. Molecular functions were mainly focused on DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and transcription factor binding. KEGG pathway enrichment analysis identified pathways in cancer, fluid shear stress, and atherosclerosis, with lipid and atherosclerosis being the most significantly enriched pathways. Molecular docking revealed that three key ingredients in VO (i.e., quercetin, luteolin, and kaempferol) strongly interacted with three potential targets (i.e., AKT1, IL-6, and TNF-α). Further, MDS revealed that quercetin had a stronger binding affinity for AKT1. These findings suggest that VO has beneficial effects on AS via these potential targets that are closely related to the lipid and atherosclerosis pathways. Our study utilized a new computer-aided drug design to identify key ingredients, potential targets, various biological processes, and multiple pathways associated with the clinical roles of VO in AS, which provides a comprehensive and systemic pharmacological explanation for the anti-atherosclerotic activity of VO.

4.
Medicine (Baltimore) ; 98(7): e14479, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762770

RESUMO

INTRODUCTION: Poststroke depression is a serious and common complication of stroke, especially the ischemic poststroke depression. Antidepressants are used in poststroke depression, and acupuncture may be an alternative approach. However, the efficacy and mechanism of acupuncture for poststroke depression has not been confirmed. METHODS/DESIGN: This is a multicenter, central-randomized, single-blind, sham-controlled clinical trial. We will allocate 208 subjects aged between 40 and 80 years old, diagnosed with initial poststroke depression (PSD) within 6 months to 2 groups randomly in a ratio of 1:1. Patients in the experimental group will be treated with traditional acupuncture and placebo pills, whereas the others in the control group will be treated with sham-acupoints acupuncture and antidepressant (fluoxetine hydrochloride tablets). All will be given acupuncture and/or medication treatment for 12 weeks, and then received 12-week follow-up. Patients will be evaluated with the 17-item Hamilton Depression Scale and Se1f-rating Depression Scale for depression state, National Institute of Health Stroke Scale for neurological deficit, Modified Barthel Index for activities of daily living, Treatment Emergent Symptom Scale for side effects of treatments, diagnosis and evaluation criteria of traditional Chinese medicine for stroke (try out) for curative effects of stroke, and clinical global impression for synthesize effect before and the 2nd, 4th, 8th, and 12th week of treatment, 24th week of follow-up. Study on mechanisms of acupuncture will be revealed through the diversity of brain metabolites (choline-containing compounds [Cho], N-acetylaspartate [NAA], myoinositol, glutamine and glutamate complex, creatine [Cr], Cho/Cr, Cho/NAA, Cr/NAA) in bilateral dorsolateral prefrontal cortex and anterior cingulate cortex monitored by proton magnetic resonance spectroscopy, and serum monoamine neurotransmitters (5-hydroxytryptamine, norepinephrine, dopamine) and cytokines (brain-derived neurotrophic factor [BDNF], interleukin [IL]-4, IL-6, IL-10, IL-18, IL-1ß, tumor necrosis factor alpha) before and the 12th week of treatment. Baseline characteristics of patients will be summarized by groups and compared with chi-square for categorical variables, and 2-sample t tests or Wilcoxon rank-sum test for the continuous variables. Primary and secondary outcomes according to the measurement times are applicable to univariate repetitive measurement deviation analysis or 2-sample t tests, or Wilcoxon rank-sum test. CONCLUSION: The present research is designed to investigate efficacy and mechanism of traditional acupuncture therapy on ischemic PSD, also to explore the correlation between cerebra metabolic and serologic factors, and ischemic PSD. With this research, we are looking forward to find out an appropriate alternative nondrug therapy for PSD people to alleviate the adverse effects and drug dependence caused by antidepressants.


Assuntos
Terapia por Acupuntura/métodos , Depressão/etiologia , Depressão/terapia , Projetos de Pesquisa , Acidente Vascular Cerebral/complicações , Atividades Cotidianas , Adulto , Idoso , Antidepressivos/uso terapêutico , Encéfalo/patologia , Citocinas/biossíntese , Depressão/tratamento farmacológico , Feminino , Fluoxetina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/biossíntese , Escalas de Graduação Psiquiátrica , Método Simples-Cego
6.
Tumour Biol ; 39(6): 1010428317706229, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28621238

RESUMO

Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, especially cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in hepatocellular carcinoma have not been extensively studied. The long non-coding RNA CASC2 (cancer susceptibility candidate 2) has been characterised as a tumour suppressor in endometrial cancer and gliomas. However, the role and function of CASC2 in hepatocellular carcinoma remain unknown. In this study, using quantitative real-time polymerase chain reaction, we confirmed that CASC2 expression was downregulated in 50 hepatocellular carcinoma cases (62%) and in hepatocellular carcinoma cell lines compared with the paired adjacent tissues and normal liver cells. In vitro experiments further demonstrated that overexpressed CASC2 decreased hepatocellular carcinoma cell proliferation, migration and invasion as well as promoted apoptosis via inactivating the mitogen-activated protein kinase signalling pathway. Our findings demonstrate that CASC2 could be a useful tumour suppressor factor and a promising therapeutic target for hepatocellular carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética
7.
Tumour Biol ; 39(3): 1010428317695971, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28347229

RESUMO

The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method. Moreover, the functions of G-protein signaling modulator 2 were examined using small-interfering RNAs in vitro. The results showed that G-protein signaling modulator 2 was clearly overexpressed in hepatocellular carcinoma tissues and cell lines and that the G-protein signaling modulator 2 expression level was related to tumor size and hepatitis B virus infection. Furthermore, G-protein signaling modulator 2 knockdown studies suggested that G-protein signaling modulator 2 accelerates cell growth, cell cycle, migration, and invasion and inhibits apoptosis, acting as an oncogene in hepatocellular carcinoma. Western blotting indicated that silencing of G-protein signaling modulator 2 in HepG2 and SMMC-7721 cells increased the expression levels of Bax, caspase-3, and E-cadherin, while notably suppressing the cyclin-dependent kinase 4, cyclin-dependent kinase 6, CyclinD1, Snail1, Vimentin, and matrix metallopeptidase 9 expression levels, compared with that in the control groups. In addition, we found that G-protein signaling modulator 2 can affect the expression of key proteins involved in protein kinase B activation. In conclusion, high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic biomarker and therapeutic target for treatment of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Apoptose/genética , Carcinoma Hepatocelular/patologia , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
8.
Oncotarget ; 8(6): 9451-9465, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28035067

RESUMO

Long non-coding RNAs (lncRNAs) have been identified as critical players in multiple cancers and lncRNAs are tightly linked to cancer progression. However, only little amount of lncRNAs have been identified to participate in the molecular mechanisms of the progression of hepatocellular carcinoma. In this study, we found that lncRNA-AK058003 is down-regulated in hepatocellular carcinoma tissues and it is associated with the relapse and metastasis of the cancer. Furthermore, lncRNA-AK058003 acts as a tumor suppressor, suppressing hepatocellular carcinoma cell proliferation and metastasis in vitro and in vivo. lncRNA-AK058003 can reduce mRNA stabilizing protein HuR, which results in the inhibition of the expression of γ-synuclein. In addition, a bioinformatics study indicated that γ-synuclein is a target of miR-15a. To verify whether lncRNA-AK058003 plays a role in miR-15a-mediated inhibition of γ-synuclein, we demonstrated that lncRNA-AK058003 is very likely to be a precursor of miR-15a. Collectively, lncRNA-AK058003 can reduce the expression of mRNA stabilizing protein HuR and act as a precursor of miR-15a to suppress γ-synuclein-mediated cell proliferation and the metastasis of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , gama-Sinucleína/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/secundário , Movimento Celular , Proliferação de Células , Biologia Computacional , Bases de Dados Genéticas , Regulação para Baixo , Proteína Semelhante a ELAV 1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Modelos de Riscos Proporcionais , RNA Longo não Codificante/genética , Transdução de Sinais , Fatores de Tempo , gama-Sinucleína/genética
9.
Tumour Biol ; 37(2): 2023-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26337275

RESUMO

To investigate the expression level of NEK2 in 40 tissue specimens of primary liver cancer and to search for clues whether the effect of NEK2 depletion plays a role on biological behaviors of HepG2 cells and the relevant molecular mechanism are the objectives of this study. Real-time PCR and immunohistochemistry assessed expression level of NEK2 in specimens of cancerous tissues and carcinoma-adjacent tissues. The NEK2 expression level in HepG2, Huh7, SMMC, and 7402 cells was detected by real-time PCR and western blot to screen experimental cell line. To assess the expression levels of NEK2 mRNA and protein, an effective siRNA transfected into the HepG2 cells was designed. CCK8 and colony-forming assays were performed to verify short-term and long-term proliferative activities, respectively. Capacity of apoptosis and cell cycle changes were assessed by flow cytometry. Ability of transference and invasion was measured by Transwell Chambers. Western blot approach was used to determine the protein expression levels. There was significantly high expression level of NEK2 in cancerous tissues compared to adjacent tissues. The expression of NEK2 was higher in HepG2 cells than other cell lines. Real-time PCR and western blot shown there were obviously down-regulated NEK2 expression in the NEK2-siRNA group compared to control groups. The capacity of amplification and invasion was inhibited distinctly, and FCM revealed the apoptosis rate was increased and G1 phase was arrested in NEK2-siRNA group. Western blot indicated that low expression of NEK2 in HepG2 cells could increase the expression levels of Bax, caspase-3, P21, and TIMP-1, but significantly suppressed the c-myc, c-jun, Bcl-2, cyclinD1, CDK4, MMP2, and MMP9 expression levels and the phosphorylation levels of ERK, JNK, and P38 compared with the control groups. Our findings demonstrated that NEK2 could be a valuable carcinogenic factor and a promising therapeutic target for primary liver cancer; NEK2 may regulate proliferation, apoptosis, and other biological behaviors of HepG2 cells via MAPK signal pathway.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Quinases Relacionadas a NIMA/metabolismo , Adulto , Idoso , Apoptose/fisiologia , Western Blotting , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/fisiologia , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...