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1.
Anticancer Res ; 40(6): 3071-3080, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487601

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma affects nearly 500,000 people annually. Augmenting PPARγ functional activation is linked with multiple anti-carcinogenic processes in aerodigestive cell lines and animal models. PPARγ/RXRα heterodimers may be key partners in this activation. MATERIALS AND METHODS: CA 9-22 and NA cell lines were treated with the PPARγ agonist ciglitazone and/or the RXRα agonist 9-cis-retinoic acid. PPARγ functional activation, cellular proliferation, apoptosis activity, and phenotype were subsequently analyzed. RESULTS: Ciglitazone and 9-cis-retinoic acid independently activated PPARγ and down-regulated the carcinogenic phenotype in vitro. Combination treatment significantly augmented these effects, further decreasing proliferation (p<0.0001), and increasing PPARγ functional activation (p<0.0001), apoptosis (p<0.05), and adipocyte differentiation markers (p<0.0001). CONCLUSION: The efficacy of the combination of ciglitazone and 9-cis-retinoic acid afforded lowering treatment concentrations while maintaining desired therapeutic outcomes, optimistically supporting the feasibility and practicality of this novel treatment option.


Assuntos
Neoplasias Bucais/tratamento farmacológico , PPAR gama/metabolismo , Retinoides/uso terapêutico , Tiazolidinedionas/uso terapêutico , Humanos , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Retinoides/farmacologia , Taxa de Sobrevida , Tiazolidinedionas/farmacologia
2.
Molecules ; 25(9)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365556

RESUMO

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.


Assuntos
Infecções por Coronavirus/patologia , PPAR gama/agonistas , Plantas Medicinais/química , Pneumonia Viral/patologia , Tiazolidinedionas/farmacologia , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/antagonistas & inibidores , Óleos de Peixe/farmacologia , Humanos , Ligantes , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Alimentos Marinhos/análise , Especiarias/análise
3.
Medicine (Baltimore) ; 99(17): e19833, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332631

RESUMO

The study aimed to investigate the association between the risk of hepatocellular carcinoma and thiazolidinediones use among type 2 diabetic patients who had risk factors for hepatocellular carcinoma.A population-based case-control study was performed using the database of the Taiwan National Health Insurance Program. The cases consisted of 23580 type 2 diabetic subjects aged 20 to 84 years with newly diagnosed hepatocellular carcinoma between 2000 and 2011. The sex- and age-matched controls consisted of 23580 randomly selected type 2 diabetic subjects without hepatocellular carcinoma between 2000 and 2011. Ever use of thiazolidinediones was defined as subjects who had at least 1 prescription of thiazolidinediones before the index date. Never use of thiazolidinediones was defined as subjects who did not have a prescription of thiazolidinediones before the index date. The odds ratio and 95% confidence interval for the association between hepatocellular carcinoma and cumulative duration of thiazolidinediones use was measured by a multivariable logistic regression model.Among subjects with any 1 of the comorbidities including alcohol-related disease, cirrhosis, hepatitis B infection, hepatitis C infection, and other chronic hepatitis, a multivariable logistic regression model demonstrated that there was a negative association between hepatocellular carcinoma and every 1-year increase of cumulative duration of thiazolidinediones use (adjusted odds ratio 0.94, 95% confidence interval 0.92-0.97).There was a negative association in a duration-dependent manner between the risk of hepatocellular carcinoma and thiazolidinediones use among type 2 diabetic patients who had risk factors for hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemiantes/uso terapêutico , Neoplasias Hepáticas/epidemiologia , Tiazolidinedionas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia , Tiazolidinedionas/efeitos adversos , Adulto Jovem
4.
J Asian Nat Prod Res ; 22(5): 425-433, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012734

RESUMO

A series of novel parthenolide-thiazolidinedione hybrids have been synthesized via a click chemistry-mediated coupling between parthenolide and thiazolidinedione, and evaluated for their cytotoxic activities. The results indicated that all the hybrids showed moderate cytotoxic effects on human cancer cell lines, including human erythroleukemia cell line (HEL), prostate (PC3), and breast (MDA-MB-231) by MTT assay. In particular, compound VI-6 exhibited the best cytotoxic activities against the MDA-MB-231 cells with IC50 value of 2.07 µM, which was about eight times more active than that of the original compound (PTL). These interesting results might be used to develop novel lead scaffolds for potential anticancer agents.


Assuntos
Antineoplásicos , Tiazolidinedionas , Linhagem Celular Tumoral , Proliferação de Células , Química Click , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos
5.
Am J Respir Cell Mol Biol ; 62(2): 143-156, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577451

RESUMO

Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator-activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post-transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve "repurposing" or "repositioning" of pioglitazone for the treatment of clinical PAH.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , PPAR gama/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Tiazolidinedionas/farmacologia
6.
Diabetes Res Clin Pract ; 159: 107990, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31866530

RESUMO

AIMS: This meta-analysis was conducted to investigate the fracture risk among patients with T2DM treated with sulfonylurea. METHODS: The PubMed and other databases were searched for eligible studies. Both randomized controlled trials and observational studies that compared the fracture risk of sulfonylurea to other hypoglycemic agents were included. Pooled risk ratios and 95% confidence intervals were calculated. Subgroup analysis and meta-regression analyses were conducted to explore the source of heterogeneity. RESULTS: A total of 11 studies involving 255,644 individuals were included in our meta-analysis. In comparing sulfonylurea users with patients who had not taken sulfonylurea, the pooled risk ratio for developing fracture was 1.14 (95% confifidence interval, 1.08-1.19). In subgroup analyses, the pooled risk ratio of bone fracture in patients receiving sulfonylurea versus thiazolidinedione, metformin and insulin was 0.90 (95% CI, 0.76-1.06), 1.25 (95% CI, 1.18-1.32) and 0.81 (95% CI, 0.74-0.89) respectively. Meta regression showed that age and gender were not related to the effect of sulfonylurea on fracture. CONCLUSIONS: Sulfonylurea use was associated with 14% increase in the risk of developing fracture in T2DM. The risk of fracture caused by sulfonylurea was similar to thiazolidinedione, higher than metformin and lower than insulin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Compostos de Sulfonilureia/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Fraturas Ósseas/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Fatores de Risco , Tiazolidinedionas/uso terapêutico
7.
Eur J Med Chem ; 185: 111812, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31703818

RESUMO

Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 µM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Metaloproteases/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Humanos , Ácidos Hidroxâmicos/química , Metaloproteases/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/química
8.
Int J Mol Sci ; 20(24)2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31835389

RESUMO

Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound 6b exerts an excellent inhibitory activity against HDAC6 with an IC50 value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound 6b dose-dependently induces the acetylation level of α-tubulin via inhibition of HDAC6 in human neuroblastoma SH-SY5Y cell line. Moreover, compound 6b efficiently reverses methamphetamine-induced morphology changes of SH-SY5Y cells via regulating acetylation landscape of α-tubulin. Collectively, compound 6b represents a novel HDAC6-isoform selective inhibitor and demonstrates promising therapeutic potential for the treatment of methamphetamine addiction.


Assuntos
Descoberta de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases , Tiazolidinedionas , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Transtornos Relacionados ao Uso de Anfetaminas/enzimologia , Linhagem Celular Tumoral , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Tiazolidinedionas/síntese química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia
9.
PLoS Med ; 16(12): e1002999, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31877127

RESUMO

BACKGROUND: Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication-including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)-can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. METHODS AND FINDINGS: We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367-2.963, p < 0.001; 2.352, 95% CI 2.123-2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071-1.340, p = 0.002; 1.496, 95% CI 1.342-1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099-1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776-1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915-1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. CONCLUSIONS: Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemia/mortalidade , Insulina/efeitos adversos , Metformina/efeitos adversos , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Hipoglicemia/complicações , Hipoglicemiantes/efeitos adversos , Incidência , Insulina/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/uso terapêutico , Resultado do Tratamento
10.
Physiol Res ; 68(Suppl 2): S107-S120, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31842574

RESUMO

Patients with diabetes mellitus are at an increased risk of bone fractures. Several groups of effective antidiabetic drugs are available, which are very often given in combination. The effects of these medications on bone metabolism and fracture risk must not be neglected. Commonly used antidiabetic drugs might have a positive, neutral or negative impact on skeletal health. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have adverse effects on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT-2 inhibitors). The effect of insulin on bone is discussed and the risk of fractures in patients using insulin seems to be unrelated to insulin as itself. The aim of the review is to summarize effects of antidiabetic treatment on bone - bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat patients with diabetes mellitus regarding the risk of osteoporotic fractures. In this review the problem of how to treat osteoporosis in patient with diabetes is also discussed.


Assuntos
Osso e Ossos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Animais , Conservadores da Densidade Óssea/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Humanos , Incretinas/farmacologia , Insulina/farmacologia , Metformina/farmacologia , Osteoporose/complicações , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Compostos de Sulfonilureia/efeitos adversos , Tiazolidinedionas/efeitos adversos
11.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683749

RESUMO

 In an effort to improve the antimicrobial activity of norfloxacin, a series of hybrid norfloxacin-thiazolidinedione molecules were synthesized and screened for their direct antimicrobial activity and their anti-biofilm properties. The new hybrids were intended to have a new binding mode to DNA gyrase, that will allow for a more potent antibacterial effect, and for activity against current quinolone-resistant bacterial strains. Moreover, the thiazolidinedione moiety aimed to include additional anti-pathogenicity by preventing biofilm formation. The resulting compounds showed promising direct activity against Gram-negative strains, and anti-biofilm activity against Gram-positive strains. Docking studies and ADMET were also used in order to explain the biological properties and revealed some potential advantages over the parent molecule norfloxacin.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Norfloxacino/análogos & derivados , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Domínio Catalítico , DNA Girase/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacologia , Água/química
12.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
14.
Am J Cardiol ; 124 Suppl 1: S12-S19, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31741435

RESUMO

Type 2 diabetes mellitus has long been recognized as a major risk factor for adverse atherosclerotic cardiovascular disease events; however, recent data indicate that heart failure is now emerging as the most common and morbid cardiovascular complication of type 2 diabetes mellitus. When heart failure develops in patients with type 2 diabetes, prognosis is ominous, highlighting the need for glucose-lowering therapies that can prevent heart failure, improve outcomes, or both. Prior to 2008, there was a paucity of randomized controlled trials evaluating long-term cardiovascular outcomes with glucose-lowering therapies. This changed after guidance on the assessment of novel glucose-lowering agents was issued by both the US Food and Drug Administration and the European Medicines Agency. Since then, significant progress has been made as a result of large cardiovascular outcomes trials. Though randomized controlled trials on insulin, sulfonylureas, and metformin are still limited, cardiovascular outcomes trials on newer glucose-lowering agents have included hundreds of thousands of patients with multiple years of follow-up. The increased risk of thiazolidinediones on heart failure had been well theorized and is now established; however, the increase in heart failure hospitalization with certain dipeptidyl peptidase-4 inhibitors was unexpected. The reasons for discrepancies with regard to heart failure risk with different dipeptidyl peptidase-4 inhibitors remain unclear, and further mechanistic studies are ongoing. The role of glucagon-like peptide-1 receptor agonists among patients with heart failure also remains unclear, and their effects may differ in patients with and without established heart failure, particularly those with decompensated heart failure with reduced ejection fraction.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/epidemiologia , Tiazolidinedionas/uso terapêutico , Acarbose/uso terapêutico , Diabetes Mellitus Tipo 2/epidemiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Resultado do Tratamento
15.
Molecules ; 24(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590284

RESUMO

The thiazolidinedione 49 (TD49) is an effective algaecide against harmful algae; however, its potential effects on the immune function of the edible bay scallop are unclear. Therefore, the present work studied the effects of TD49 on the immune response in bay scallop by evaluating activities of acid phosphatase (ACP), alkaline phosphatase (ALP), and superoxide dismutase (SOD), as well as nitric oxide (NO) levels, total protein content, and expression of immune genes (CTL-6, PGRP, PrxV, MT, and Cu/Zn-SOD) at 3-48 h post-exposure (hpe) to TD49. The activities of ACP and ALP significantly increased in TD49-treated groups at 3-24 hpe, whereas NO levels decreased significantly in 0.58 and 0.68 µM of TD49 at 6-24 hpe, after which the level was similar to that in the untreated control. Moreover, SOD activity significantly increased in all three concentration groups at 3-6 hpe, while it decreased at 12 hpe in the 0.68 µM TD49 treatment group. Notably, total protein content increased with TD49 treatment at each time interval. The results revealed that variable effects on the expression of immune-related genes were observed after treatment with TD49. The findings demonstrate that exposure of scallops to TD49 changes immune responses and expression of immune-related genes. We hypothesize that TD49 may disrupt immune system in bay scallop. The current investigation highlights the potential negative effects of using TD49 as an algaecide on marine economic bivalves to control harmful algal blooms in marine environments.


Assuntos
Herbicidas/efeitos adversos , Pectinidae/imunologia , Tiazolidinedionas/efeitos adversos , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Herbicidas/química , Imunidade/efeitos dos fármacos , Pectinidae/efeitos dos fármacos , Pectinidae/metabolismo , Frutos do Mar , Superóxido Dismutase/metabolismo , Tiazolidinedionas/química
16.
Proc Natl Acad Sci U S A ; 116(46): 23232-23242, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31659023

RESUMO

PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene's transcription start site (TSS) in human but not mouse adipocytes. The -4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.


Assuntos
Adipócitos/metabolismo , Amidoidrolases/metabolismo , PPAR gama/metabolismo , Tecido Adiposo/metabolismo , Amidoidrolases/genética , Animais , Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Humanos , Masculino , Camundongos , Obesidade/genética , Fenótipo , Tiazolidinedionas
17.
PLoS One ; 14(10): e0224236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31639149

RESUMO

BACKGROUND: It has been found that thiazolidinediones (TZDs) may play a protective role in animal models of Parkinson's disease (PD), while the results remain controversial whether TZDs protect against Parkinson's disease in humans. The purpose of this meta-analysis is to explore the association between TZDs use and the incidence of PD in diabetic patients. METHODS: A systematic online search was conducted to find studies published up to 31 December 2018. In our exploratory meta-analysis, studies comparing incidence of PD between TZD-treated and non-TZD-treated groups of diabetic patients were included. Data analysis was performed using a random or fixed effects model and expressed as odds ratios (OR) with 95% confidence interval (95% CI). We used the Cochrane Collaboration's Review Manager 5.3 software to analyze data. RESULTS: In total, 5 retrospective observational cohort studies were identified which met the inclusion criteria. The pooled odds ratio (OR) was 0.70 [95% CI, 0.51 to 0.96; p = 0.03] in a random-effects model, indicating a 30% lower risk of developing PD in diabetic patients treated with TZDs compared with non-TZD-treated patients. CONCLUSION: In this exploratory meta-analysis, we found that TZDs use was associated with reduced risk of PD in diabetic patients. However, this meta-analysis was not registered online although we followed a protocol designed for it. Further prospective observational studies with larger sample size and more strict inclusion criteria including controlling for diabetes complication severity index, hypoglycemic drugs combination, sex ratio, and comorbidity are needed to guide whether RCTs are warranted. And RCTs can better determine whether TZDs use could lower incidence of PD in diabetic patients.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Doença de Parkinson/prevenção & controle , Tiazolidinedionas/uso terapêutico , Humanos , Doença de Parkinson/etiologia , Prognóstico , Comportamento de Redução do Risco
18.
Proc Natl Acad Sci U S A ; 116(44): 22179-22188, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611383

RESUMO

Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity-conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.


Assuntos
PPAR gama/química , Sítios de Ligação , Células HEK293 , Humanos , PPAR gama/agonistas , PPAR gama/metabolismo , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia
19.
Mol Biol Rep ; 46(6): 6485-6494, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571108

RESUMO

Obesity and diabetes are both associated risk factors for developing breast cancer and poor patient outcomes. Adipose cells are an important endocrine system and are the main producer of adiponectin, with lean patients having higher circulating levels. Patients with diabetes are often treated with thiazolidinediones, glitazones, which also increase adiponectin production. Importantly high circulating levels of adiponectin and treatment with glitazone are associated with increased breast cancer patient survival. This study investigates the potential of using adipose tissue laden with glitazones to act as a drug depot, increase adiponectin levels, and locally release glitazones to inhibit breast cancer cell proliferation. The breast cancer cell lines MCF-7 and MBA-MD-231, and the normal breast epithelial cell line MCF-10A were exposed to media containing a range of concentrations of recombinant adiponectin, pioglitazone, or conditioned media obtained from pioglitazone laden adipose tissue to determine the impact of the different treatments on cell proliferation. The MCF-7 cells demonstrated the greatest reduction in proliferation upon exposure to adiponectin and pioglitazone with lower reductions observed in the MDA-MD-231 and MCF-10a cell lines. All three cell lines exhibited reductions in proliferation in the presence of pioglitazone loaded adipose tissue. Additionally, adiponectin and pioglitazone levels were higher in the media from glitazone loaded adipose tissue. Drug loaded adipose tissue could potentially be used to deliver adiponectin and glitazone to breast cancer cells and inhibit proliferation. Future research will examine the potential efficacy of this treatment approach in vivo.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/citologia , Neoplasias da Mama/metabolismo , Tiazolidinedionas/farmacologia , Tecido Adiposo/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Feminino , Humanos , Células MCF-7
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