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1.
Eur J Pharmacol ; 920: 174830, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35182545

RESUMO

We previously demonstrated that GSK-3ß mediates NLRP3 inflammasome activation and IL-1ß production in cardiac fibroblasts (CFs) after myocardial infarction (MI). In this study, we show how GSK-3ß-mediated activation of the NLRP3 inflammasome/caspase-1/IL-1ß pathway leads to apoptosis and pyroptosis of cardiomyocytes (CMs) and CFs. Administration of lipopolysaccharide (LPS)/ATP to primary newborn rat cardiac fibroblasts (RCFs) led to increase in proteins of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, IL-1ß, and IL-18. Additionally, the expression of caspase-3 and N-terminal fragments of gasdermin D (N-GSDMD) and the Bax/Bcl-2 ratio increased. Administration of the GSK-3ß inhibitor SB216763 reduced the levels of apoptosis- and pyroptosis-related proteins regulated by NLRP3 inflammasome activation in RCFs. Next, we transferred the culture supernatant of LPS/ATP-treated RCFs to in vitro primary newborn rat cardiomyocytes (RCMs). The results showed that SB216763 attenuate the upregulation of the ratios of Bax/Bcl-2 and the expression of caspase-3 and N-GSDMD in RCMs. Direct stimulation of RCMs and H9c2 cells with recombinant rat IL-1ß increased the p-GSK-3ß/GSK-3ß and Bax/Bcl-2 ratios and the expression of caspase-3 and N-GSDMD, while both SB216763 and TLR1 (an IL-1ß receptor inhibitor) markedly reduced these effects, as assessed using propidium iodide positive staining and the lactate dehydrogenase release assay. The caspase-11 inhibitor wedelolactone decreased the expression level of N-GSDMD but did not alter the p-GSK-3ß/GSK-3ß ratio. Lastly, we established a Sprague-Dawley rat MI model to confirm that SB216763 diminished the increase in caspase-3 and N-GSDMD expression and the Bax/Bcl-2 ratio in the ischemic area. These data demonstrate that GSK-3ß regulates apoptosis and pyroptosis of RCMs and RCFs due to NLRP3 inflammasome activation in RCFs.


Assuntos
Inflamassomos , Piroptose , Animais , Apoptose , Fibroblastos/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley
2.
Acta Pharmacol Sin ; 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35132192

RESUMO

Connexin 43 (Cx43) is the most important protein in the gap junction channel between cardiomyocytes. Abnormalities of Cx43 change the conduction velocity and direction of cardiomyocytes, leading to reentry and conduction block of the myocardium, thereby causing arrhythmia. It has been shown that IL-1ß reduces the expression of Cx43 in astrocytes and cardiomyocytes in vitro. However, whether caspase-1 and IL-1ß affect connexin 43 after myocardial infarction (MI) is uncertain. In this study we investigated the effects of VX765, a caspase-1 inhibitor, on the expression of Cx43 and cell-to-cell communication after MI. Rats were treated with VX765 (16 mg/kg, i.v.) 1 h before the left anterior descending artery (LAD) ligation, and then once daily for 7 days. The ischemic heart was collected for histochemical analysis and Western blot analysis. We showed that VX765 treatment significantly decreased the infarct area, and alleviated cardiac dysfunction and remodeling by suppressing the NLRP3 inflammasome/caspase-1/IL-1ß expression in the heart after MI. In addition, VX765 treatment markedly raised Cx43 levels in the heart after MI. In vitro experiments were conducted in rat cardiac myocytes (RCMs) stimulated with the supernatant from LPS/ATP-treated rat cardiac fibroblasts (RCFs). Pretreatment of the RCFs with VX765 (25 µM) reversed the downregulation of Cx43 expression in RCMs and significantly improved intercellular communication detected using a scrape-loading/dye transfer assay. We revealed that VX765 suppressed the activation of p38 MAPK signaling in the heart tissue after MI as well as in RCMs stimulated with the supernatant from LPS/ATP-treated RCFs. Taken together, these data show that the caspase-1 inhibitor VX765 upregulates Cx43 expression and improves cell-to-cell communication in rat heart after MI via suppressing the IL-1ß/p38 MAPK pathway.

3.
Mol Cell ; 82(3): 542-554.e6, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35081364

RESUMO

Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicólise , Proteínas de Membrana/metabolismo , Neoplasias/enzimologia , Fosfoglicerato Quinase/metabolismo , Fosfoglicerato Mutase/metabolismo , Fosfopiruvato Hidratase/metabolismo , RNA Longo não Codificante/metabolismo , Hormônios Tireóideos/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Proliferação de Células , Proteínas de Ligação a DNA/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Proteínas de Membrana/genética , Camundongos Nus , Complexos Multienzimáticos , Neoplasias/genética , Neoplasias/patologia , Fosfoglicerato Quinase/genética , Fosfoglicerato Mutase/genética , Fosfopiruvato Hidratase/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/genética , Serina/deficiência , Hormônios Tireóideos/genética , Carga Tumoral , Proteínas Supressoras de Tumor/genética
5.
J Interv Card Electrophysiol ; 63(2): 239-248, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33611692

RESUMO

BACKGROUND: Abnormal ion channel currents caused by myocardial electrical remodeling is one of the main causes of malignant arrhythmias. Glycogen synthase kinase 3ß (GSK-3ß) is the main therapeutic target following ischemia as it regulates nerve cell channels. However, few studies have investigated its role in myocardial electrical remodeling. The present study aimed to investigate the role of GSK-3ß in a rat myocardial infarction (MI)-induced electrical remodeling and potential effects on cardiac ionic channels including KCNJ2/Kir2.1/IK1. METHODS: Ligation of the left anterior descending artery in rats was performed to establish a MI model. The rats were randomly divided into three groups, the sham, MI, and MI + SB group. The animals in the latter group were administered SB216763 (GSK-3ß inhibitor) at a dose of 0.6 mg·kg-1·day-1. The ventricular function was assessed by echocardiography, electrocardiography, and histological analysis 7 days post-surgery. Serum was collected to measure lactate dehydrogenase and cardiac troponin I levels, and the mRNA and protein levels of the KCNJ2/Kir2.1/IK1 channel in the heart tissues were assessed. H9c2 cells were cultured to examine the effects of SB216763 on the protein expression of Kir2.1 channel under hypoxic conditions. RESULTS: The results revealed that SB216763 ameliorated acute cardiac injury and improved myocardial dysfunction. Moreover, SB216763 increased the mRNA and protein expression of Kir2.1 during MI. Furthermore, SB216763 treatment abrogated the decreased expression of Kir2.1 in H9c2 cells under hypoxic conditions. CONCLUSIONS: GSK-3ß inhibition upregulates Kir2.1 expression in a rat model of MI.


Assuntos
Indóis , Miocárdio , Animais , Glicogênio Sintase Quinase 3 beta , Humanos , Indóis/farmacologia , Maleimidas/farmacologia , Ratos
6.
Anat Rec (Hoboken) ; 305(2): 254-264, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34358403

RESUMO

Bilirubin encephalopathy (BE) is a neurological syndrome in newborns, mainly caused by neuronal injury due to excessive oxidative stress produced by unconjugated bilirubin (UCB). Neuroglobin (NGB) can protect the brain by removing oxidative stress species, but its expression and significance in BE are not clear. To address this question, the neonatal BE model was established by injecting UCB into the cerebellomedullary cistern of 7-day-old SD rats. Rats were divided into a sham and BE 6 hr group, BE 12 hr group, BE 24 hr group, and BE 7 d group according to UCB action times. Hematoxylin/eosin and Nissl staining, and electron microscopy were employed to observe the pathological and ultrastructural changes of nerve cells in each group. Immunofluorescence staining was used to detect NGB expression sites and cell types. Western blotting and quantitative PCR served to detect NGB expression and test the mitochondrial apoptosis signal pathway. The results confirm that UCB can lead to pathological damage and ultrastructural changes in rats' temporal cortex, increasing the expression of apoptosis-related proteins Bax, Bcl-2, Cyt c, Caspase-3, and neuronal NGB. UCB promotes NGB expression with an increase in action time and reach a peak at 12 hr. In summary, brain damage induced by UCB will cause an increase in NGB expression, the increasing NGB can inhibit neuron apoptosis in early BE phases. Therefore, promoting the expression of endogenous NGB, to act as a neuroprotective agent may be a potential treatment strategy for BE.


Assuntos
Globinas , Kernicterus , Animais , Globinas/genética , Globinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina , Ratos , Ratos Sprague-Dawley , Lobo Temporal/metabolismo
7.
Front Pharmacol ; 12: 662726, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349643

RESUMO

The aim of this study was to investigate the effects of the GSK-3ß/NF-κB pathway on integrin-associated protein (CD47) expression after myocardial infarction (MI) in rats. An MI Sprague Dawley rat model was established by ligating the left anterior descending coronary artery. The rats were divided into three groups: Sham, MI, and SB + MI (SB216763) groups. Immunohistochemistry was used to observe the changes in cardiac morphology. A significant reduction in the sizes of fibrotic scars was observed in the SB + MI group compared to that in the MI group. SB216763 decreased the mRNA and protein expression of CD47 and NF-κB during MI. Primary rat cardiomyocytes (RCMs) and the H9c2 cell line were used to establish in vitro hypoxia models. Quantitative real-time PCR and western blotting analyses were conducted to detect mRNA and protein expression levels of CD47 and NF-κB and apoptosis-related proteins, respectively. Apoptosis of hypoxic cells was assessed using flow cytometry. SB216763 reduced the protein expression of CD47 and NF-κB in RCMs and H9c2 cells under hypoxic conditions for 12 h, and alleviated hypoxia-induced apoptosis. SN50 (an NF-κB inhibitor) also decreased CD47 protein expression in RCMs and H9c2 cells under hypoxic conditions for 12 h and protected cells from apoptosis. GSK-3ß upregulates CD47 expression in cardiac tissues after MI by activating NF-κB, which in turn leads to myocardial cell damage and apoptosis.

8.
Int Immunopharmacol ; 99: 107918, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34320458

RESUMO

OBJECT: Ninjurin2 (nerve injury induced protein 2, NINJ2) is a molecule which mediates cell-to-cell and cell-to-extracellular matrix interactions in the nervous system. Clinical study shows NINJ2 is associated with the development of postherpetic neuralgia. However, it is lack of direct evidence that NINJ2 participated in neuropathic pain. In this study, we aim to investigate the role of NINJ2 in the development of neuropathic pain in spared sciatic nerve injury rats and the underlying mechanism. METHOD: Spared sciatic nerve injury (SNI) models were established. The level of NINJ2 and p-p65 (a NF-κB family member) were measured in SNI rats by western blots and immunofluorescent staining. Lentivirus encoding small interfering RNA targeting NINJ2 (RNAi) was intrathecally injected into rats. Then the change of pain behavior of rats induced by NINJ2 RNAi was tested by Von-Frey hairs. The change of p-p65 in the spinal cord in rats after NINJ2 RNAi treatment was also measured by western blots. inhibitor of p-p65-induced change of TNF-α, IL-1ß, and IL-6 levels were measured by ELISA. RESULTS: NINJ2 and p-p65 were increased in the spinal cord of SNI rats on the 3, 7, 14th days after modeling. NINJ2 were mainly expressed in neurons, and co-located with p-p65 in the spinal dorsal horn. When down regulating the level of NINJ2 by RNAi, the development of pain in SNI rats was partially blocked. Phosphorylation of p65 was also inhibited by NINJ2 RNAi. Blocking the phosphorylation of NF-κB pathway could inhibit the increase of TNF-α, IL-1ß, and IL-6 in the spinal cord of SNI rats. CONCLUSION: NINJ2 protein was increased in the spinal cord of SNI rats. It participated in the development of nerve injury-induced neuropathic pain by activating neuroinflammation in the spinal cord via NF-κB pathway. This study provides a new target to investigate the mechanism of neuropathic pain.


Assuntos
Moléculas de Adesão Celular Neuronais/imunologia , Neuralgia/imunologia , Nervo Isquiático/lesões , Fator de Transcrição RelA/imunologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Masculino , Ratos Sprague-Dawley , Nervo Isquiático/imunologia , Medula Espinal/imunologia
9.
Biomed Pharmacother ; 137: 111376, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33588266

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, especially in developing countries. To date, several approaches have been proposed for the prevention and treatment of CVDs. However, the increased risk of developing cardiovascular events that result in hospitalization has become a growing public health concern. The pathogenesis of CVDs has been analyzed from various perspectives. Recent data suggest that regulatory RNAs play a multidimensional role in the development of CVDs. Studies have identified several mRNA modifications that have contributed to the functional characterization of various cardiac diseases. RNA methylation, such as N6-methyladenosine, N1-methyladenosine, 5-methylcytosine, N7-methylguanosine, N4-acetylcytidine, and 2'-O-methylation are novel epigenetic modifications that affect the regulation of cell growth, immunity, DNA damage, calcium signaling, apoptosis, and aging in cardiomyocytes. In this review, we summarize the role of RNA methylation in the pathophysiology of CVDs and the potential of using epigenetics to treat such disorders.


Assuntos
Doenças Cardiovasculares/genética , Epigênese Genética/genética , RNA/genética , RNA/metabolismo , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Humanos , Metilação , Processamento de Proteína Pós-Traducional
10.
Mol Ther Nucleic Acids ; 23: 347-354, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33425492

RESUMO

The pairwise interaction between transcription factors (TFs) plays an important role in enhancer-promoter loop formation. Although thousands of TFs in the human genome have been found, only a few TF pairs have been demonstrated to be related to loop formation. It is still a challenge to determine which TF pairs could be involved in the enhancer-promoter regulation network. This work describes a computational framework to identify TF pairs in enhancer-promoter regulation. By integrating different levels of data derived from Promoter Capture Hi-C, chromatin immunoprecipitation sequencing (ChIP-seq) of histone marks, RNA-seq, protein-protein interaction (PPI), and TF motif, we identified 361 significant TF pairs and constructed a TF interaction network. From the network, we found several hub-TFs, which may have important roles in the regulation of long-range interactions. Our studies extended TF pairs identified in other experimental and computational approaches. These findings will help the further study of long-range interactions between enhancers and promoters.

11.
Bioorg Chem ; 107: 104634, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33476867

RESUMO

A series of novel indole derivatives were synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (MGC803, EC-109 and PC-3). Among these analogues, 2-(5-methoxy-1H-indol-1-yl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (V7) showed the best inhibitory activity against MGC803 cells with an IC50 value of 1.59 µM. Cellular mechanisms elucidated that V7 inhibited colony formation, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, indole analogue V7 inhibited NEDDylation pathway and MAPK pathway against MGC803 cells.


Assuntos
Antineoplásicos/farmacologia , Indóis/química , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Enzimas de Conjugação de Ubiquitina/metabolismo
12.
Eur J Drug Metab Pharmacokinet ; 46(1): 129-139, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33140264

RESUMO

BACKGROUND AND OBJECTIVE: Rapamycin and its semi-synthetic analogues (rapalogues) are frequently used in combination with other prescribed medications in clinical settings. Although the inhibitory effects of rapalogues on cytochrome P450 enzymes (CYPs) have been well examined, the inhibition potentials of rapalogues on human esterases have not been investigated. Herein, the inhibition potentials and inhibitory mechanisms of six marketed rapalogues on human esterases are investigated. METHODS: The inhibitory effects of six marketed rapalogues (rapamycin, zotarolimus, temsirolimus, everolimus, pimecrolimus and tacrolimus) on three major esterases, including human carboxylesterases 1 (hCES1A), human carboxylesterases 2 (hCES2A) and butyrylcholinesterase (BuChE), were assayed using isozyme-specific substrates. Inhibition kinetic analyses and docking simulations were performed to investigate the inhibitory mechanisms of the rapalogues with strong hCES2A inhibition potency. RESULTS: Zotarolimus and pimecrolimus displayed strong inhibition of human hCES2A but these agents did not inhibit hCES1A or BuChE. Further investigation demonstrated that zotarolimus could strongly inhibit intracellular hCES2A in living HepG2 cells, with an estimated IC50 value of 4.09 µM. Inhibition kinetic analyses revealed that zotarolimus inhibited hCES2A-catalyzed fluorescein diacetate hydrolysis in a mixed manner, with the Ki value of 1.61 µM. Docking simulations showed that zotarolimus could tightly bind on hCES2A at two district ligand-binding sites, consistent with its mixed inhibition mode. CONCLUSION: Our findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carboxilesterase/antagonistas & inibidores , Simulação por Computador , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Carboxilesterase/química , Carboxilesterase/metabolismo , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Técnicas In Vitro/métodos , Simulação de Acoplamento Molecular/métodos , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
13.
Oncol Rep ; 43(4): 1113-1124, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32323780

RESUMO

Inflammasomes can identify endogenous danger signals as an inflammatory immune response. As the most common inflammasome, the NLR pyrin family domain containing 3 (NLRP3) inflammasome is associated with the pathogenesis of different tumors. However, the function of the NLRP3 inflammasome in esophageal cancer (EC) has rarely been reported. Herein, the expression levels of the components of NLRP3 inflammasome and Ki­67 were analyzed by immunohistochemistry. Furthermore, correlations between the NLRP3 inflammasome and Ki­67 along with the clinicopathological features of EC patients were evaluated. The components of the NLRP3 inflammasome were also assessed by western blot analysis and quantitative PCR. NLRP3 was silenced or overexpressed in different esophageal squamous cell carcinoma (ESCC) cell lines, and cell viability, migration and invasion were assessed by CCK­8 and Transwell assays. The present results showed that high NLRP3 expression in the tumor specimens was significantly associated with TNM stage and T category. Spearman's correlation analysis revealed a positive correlation between NLRP3 and the Ki­67 proliferation index. The mRNA and protein levels of NLRP3, apoptosis­associated speck­like protein containing a CARD (ASC), cleaved caspase­1, and interleukin (IL)­1ß in tumor tissues were higher than those in non­cancerous tissues. The level of secreted IL­1ß in tumor tissues was also increased, as compared to that in normal tissues. Silencing of NLRP3 in KYSE­70 and TE13 cells strongly attenuated cell viability, decreased cell mobility in wound­healing assays and greatly diminished the ability of cell migration and invasion in the Transwell system. Overexpression of NLRP3 in KYSE­510 and EC9706 cells markedly promoted the proliferation, migration and invasion. Collectively, these results revealed that the the NLRP3 inflammasome is upregulated in human ESCC tissues and promotes ESCC progression. Hence, NLRP3 could be a promising new candidate diagnostic and prognostic target.


Assuntos
Movimento Celular , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Apoptose , Caspase 1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Regulação para Cima
14.
RSC Adv ; 10(7): 3626-3635, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-35492646

RESUMO

Thrombin inhibition therapy is a practical strategy to reduce thrombotic and cardiovascular risks via blocking the formation of blood clots. This study aimed to identify naturally occurring thrombin inhibitors from licorice (one of the most popular edible herbs), as well as to investigate their inhibitory mechanisms. Among all tested licorice constituents, licochalcone A was found as the most efficacious agent against human thrombin (IC50 = 7.96 µM). Inhibition kinetic analyses demonstrated that licochalcone A was a mixed inhibitor against thrombin-mediated Z-Gly-Gly-Arg-AMC acetate hydrolysis, with a K i value of 12.23 µM. Furthermore, mass spectrometry-based chemoproteomic assays and molecular docking simulations revealed that licochalcone A could bind to human thrombin at both exosite I and the catalytic site. In summary, our findings demonstrated that the chalcones isolated from licorice were a new class of direct thrombin inhibitors, also suggesting that licochalcone A was a promising lead compound for developing novel anti-thrombotic agents.

15.
J Cardiol ; 74(6): 475-482, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31324570

RESUMO

Atrial fibrillation (AF) causes severe cardiac dysrhythmia among patients with cardiovascular diseases. AF increases the risk of stroke and heart failure and is a growing public health concern. AF is also associated with various disease conditions such as hypertension, coronary artery disease, aging, and diabetes mellitus. The mechanism underlying AF is not completely understood due to its complexity. However, experimental and clinical data have revealed that the prevalence of this disease is associated with atrial arrhythmogenic remodeling. Currently, there are no biomarkers that are available for the early diagnosis of AF. Several studies have proposed microRNAs (miRNAs) as useful biomarkers for the diagnosis of AF due to their stability and easy availability both in atrial tissue and circulating blood. miRNAs play an important role in the development of the heart. The dysregulation of miRNA expression is associated with cardiac remodeling. Genetic factors strongly contribute to the pathogenesis of AF. Recently, single nucleotide polymorphisms (SNPs) in various genes and miRNAs have been reported to be associated with AF. The aim of this review was to discuss the correlation between SNPs in miRNAs and AF, including those miRNAs that are commonly reported as potential biomarkers for AF.


Assuntos
Fibrilação Atrial/sangue , MicroRNAs/sangue , Polimorfismo de Nucleotídeo Único , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/genética , Biomarcadores/sangue , Átrios do Coração/fisiopatologia , Humanos
16.
J Clin Pharmacol ; 59(6): 890-899, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30861159

RESUMO

The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.


Assuntos
Transplante de Rim , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Algoritmos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Coortes , Citocromo P-450 CYP3A/genética , Combinação de Medicamentos , Feminino , Interação Gene-Ambiente , Variação Genética , Humanos , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Transplantados
17.
Neuroscience ; 406: 62-72, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826523

RESUMO

Chemokines are important regulators of immune, inflammatory, and neuronal responses in peripheral and central pain pathway. The aim of this study was to investigate whether chemokine (C-X-C motif) ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) involve in the development of bone cancer pain (BCP) and the regulation of morphine analgesia in rats. The change of pain behaviors in BCP rats were measured by testing paw withdrawal threshold (PWT). The levels of CXCL13, CXCR5 and signal pathway proteins (p-p38, p-ERK and p-AKT etc.) in the spinal cord were measured via western blots. The expression of CXCL13 and CXCR5 in spinal cord was increased in BCP rats. The BCP rats showed decrease of PWTs, which was relieved by CXCR5i. Intrathecally injection of murine recombinant CXCL13 (mrCXCL13) decreased the PWTs of BCP rats and opposed morphine-induced analgesia in BCP rats. In BCP rats, the signal pathway proteins (p38, ERK and AKT) in the spinal cord were activated. CXCL13 and morphine had contrary effect on the phosphorylation of these proteins. MrCXCL13 directly increased the levels of p-p38, p-ERK and p-AKT in BCP rats. However, morphine decreased the levels of these proteins in BCP rats. While blocking the activation of p-p38, p-ERK and p-AKT, morphine analgesia was enhanced. These results suggest CXCL13 participated in bone cancer pain and opposed morphine analgesia via p38, ERK and AKT pathways. It may be a target to enhance pain management in cancer pain patients.


Assuntos
Analgésicos Opioides/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Dor do Câncer/tratamento farmacológico , Quimiocina CXCL13/administração & dosagem , Morfina/administração & dosagem , Medula Espinal/efeitos dos fármacos , Analgesia/métodos , Animais , Neoplasias Ósseas/metabolismo , Dor do Câncer/metabolismo , Método Duplo-Cego , Feminino , Injeções Espinhais , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
18.
Am J Cardiovasc Drugs ; 19(3): 237-247, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30714088

RESUMO

Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease (CHD). Many guidelines recommend LDL-C as a primary treatment target, and statins represent the cornerstone of treatment for lipid management. Recently revised guidelines recommend even more intense management of LDL-C, especially in patients at moderate and high risk. However, LDL-C levels in the Chinese population differ from those in Western populations, and the benefits and safety of the maximum allowable dose of statins have yet to be determined. Furthermore, in practice, many patients do not achieve the increasingly stringent LDL-C goals. Consequently, alternative approaches to lipid management are required. Combination therapy with ezetimibe and a statin, which have complementary mechanisms of action, is more effective than statin monotherapies, even at high doses. Several clinical studies have consistently shown that combination therapy with ezetimibe and simvastatin lowers LDL-C more potently than statin monotherapies. Moreover, the safety and tolerability profile of the combination therapy appears to be similar to that of low-dose statin monotherapies. This review discusses the role of simvastatin in combination with ezetimibe in controlling dyslipidemia in Chinese patients, particularly the efficacy and safety of combination therapy in light of recently published clinical data.


Assuntos
Ezetimiba/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Sinvastatina/administração & dosagem , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Dislipidemias/tratamento farmacológico , Ezetimiba/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Sinvastatina/efeitos adversos
19.
Eur J Med Chem ; 157: 50-61, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30075402

RESUMO

Novel bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment as antiproliferative agents by targeting tubulin were synthesized and their preliminary structure activity relationships (SARs) were explored. Among all these chemical agents, 2-(Benzo[d]oxazol-2-ylthio)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (4d) exhibited the potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.45 µM by induction of G2/M pahse arrest and cell apoptosis. In addition, 4d could change the membrane potential (ΔΨ) of the mitochondria against MGC-803 cells. Importantly, 4d acted as a novel tubulin polymerization inhibitor binding to colchicine site with an IC50 value of 3.35 µM.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Microtúbulos/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
20.
Int J Mol Med ; 42(1): 625-632, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29693156

RESUMO

The aim of the present study was to analyze the role of leucine­rich repeat­containing G­protein coupled receptor 6 (Lgr6) in the proliferation and invasion of colorectal cancer (CRC) cells, and to investigate its possible mechanisms. The expression of Lgr6 in CRC tissues was observed by real time­quantitative polymerase chain reaction and western blotting. Then cell viability, apoptosis and cell invasion was measured by MTT, flow cytometry or Matrigel­Transwell system, respectively in CRC cells after transfected with Lgr6 siRNA or Lgr6 vector. Furthermore, the expression of apoptosis­associated protein and PI3K/AKT signaling (phosphorylated­PI3K, phosphorylated­AKT, t­PI3K, t­AKT) were measured by real­time PCR/or western blot analysis. The results demonstrated that the level of Lgr6 was higher in CRC tissues than that in adjacent tissues, and Lgr6 overexpression increased CRC proliferation, and invasion of CRC cells in vitro. Notably, suppressing the expression of Lgr6 in CRC cells increased the expression of B­cell lymphoma-2 (Bcl­2)­associated X protein and caspase­3, but decreased the expression of Bcl­2 at the mRNA and protein levels. Lgr6 also had the ability to regulate the phosphoinositide 3­kinase/AKT signaling pathway. It was concluded that Lgr6 has a tumor­promoting role in the development of CRC, and may serve as a potential diagnostic and prognostic biomarker for the disease.


Assuntos
Apoptose , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação para Baixo/genética , Receptores Acoplados a Proteínas G/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Regulação para Cima/genética
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