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1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638771

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFß), and its receptors, all of which play a major role in PAH and kidney failure. TGFß is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFß. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.


Assuntos
Rim/metabolismo , Pulmão/metabolismo , PPAR gama/metabolismo , Fibrose Pulmonar/metabolismo , Insuficiência Renal/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , PPAR gama/agonistas , Pioglitazona/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico
2.
Artigo em Chinês | MEDLINE | ID: mdl-34624942

RESUMO

Objective: To investigate the effect and mechanism of PPAR-γ agonist Pioglitazone (PGZ) on the proliferation of malignant mesothelioma (MM) cells. Methods: In December 2019, MM cell lines MSTO-211H and NCI-H2452 were incubated with different final concentrations of PGZ (0, 10, 50, 100, 150, and 200 µmol/L) for different periods of time (24 h, 48 h, and 72 h) , and then the cell proliferation level was detected by CCK8 assay. After given various final concentration of PGZ (0, 10, 50, 100, 150, 200 µmol/L) the for 72 hours, the changes of number and morphology of MM cells were observed under an inverted microscope. The expressions of PPAR-γ and HMGB1 mRNA were determined by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (qRT-PCR) after treatment of MM cells with PGZ of 0, 10, 50, 100 µmol/L for 72 h. The MM cells were treated with PGZ at concentration of 0, 100 µmol/L for 72 h, and the protein expressions of HMGB1 were examined using Western blotting and immunofluorescence; the protein expressions of Ki67 were assessed by immunohistochemistry. Results: The cell viability rate of MM cells was decreased after treated with PGZ (P<0.05) . Cell number in PGZ-treated group was significantly less than that in control group and morphology changes were observed under light microscope. QRT-PCR results revealed significantly increased PPAR-γ mRNA expression in the PGZ-treated group compared to the control group (P<0.05) . There was a significant decrease in the mRNA expression level of HMGB1 in the PGZ-treated group (100 µmol/L) as compared to the control group in MSTO-211H (P<0.05) ; however, the expression level of HMGB1 in NCI-H2452 was an increase or no significant differences (P>0.05) . Western blotting and immunofluorescence results showed that the protein expression of HMGB1 was reduced in the PGZ-treated group compared with the control group in MSTO-211H (P<0.05) , but the protein expression of that in NCI-H2452 was no significant differences (P>0.05) . Immunohistochemistry results showed increased expression of proliferation marker Ki-67. Conclusion: Pioglitazone suppresses the proliferation of MM cells through inhibition of HMGB1 by the activation of PPAR-γ.


Assuntos
Proteína HMGB1 , Mesotelioma/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Humanos
3.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639224

RESUMO

BACKGROUND: Cheonggukjang is a traditional fermented soybean paste that is mostly consumed in Korea. However, the biological activities of Cheonggukjang specific compounds have not been studied. Thus, we aimed to discover a novel dual agonist for PPARα/γ from dietary sources such as Cheonggukjang specific volatile compounds and explore the potential role of PPARα/γ dual agonists using in vitro and in silico tools. METHODS: A total of 35 compounds were selected from non-fermented and fermented soybean products cultured with Bacillus subtilis, namely Cheonggukjang, for analysis by in vitro and in silico studies. RESULTS: Molecular docking results showed that 1,3-diphenyl-2-propanone (DPP) had the lowest docking score for activating PPARα (1K7L) and PPARγ (3DZY) with non-toxic effects. Moreover, DPP significantly increased the transcriptional activities of both PPARα and PPARγ and highly activated its expression in Ac2F liver cells, in vitro. Here, we demonstrated for the first time that DPP can act as a dual agonist of PPARα/γ using in vitro and in silico tools. CONCLUSIONS: The Cheonggukjang-specific compound DPP could be a novel PPARα/γ dual agonist and it is warranted to determine the therapeutic potential of PPARα/γ activation by dietary intervention and/or supplementation in the treatment of metabolic disorders without causing any adverse effects.


Assuntos
Bacillus subtilis/fisiologia , Compostos de Bifenilo/farmacologia , Simulação por Computador , Simulação de Acoplamento Molecular , PPAR alfa/agonistas , PPAR gama/agonistas , Alimentos de Soja/microbiologia , Compostos de Bifenilo/química , Fermentação , Técnicas In Vitro
4.
Molecules ; 26(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34641558

RESUMO

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.


Assuntos
Benzofenantridinas/química , Isoquinolinas/química , PPAR alfa/agonistas , PPAR gama/agonistas , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Benzofenantridinas/farmacologia , Cristalografia por Raios X , Regulação da Expressão Gênica , Genes Reporter , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Isoquinolinas/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Relação Estrutura-Atividade
5.
Biochim Biophys Acta Gen Subj ; 1865(11): 129973, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34352342

RESUMO

BACKGROUND: Obesity and type 2 diabetes mellitus, which are widespread throughout the world, require therapeutic interventions targeted to solve clinical problems (insulin resistance, hyperglycaemia, dyslipidaemia and steatosis). Several natural compounds are now part of the therapeutic repertoire developed to better manage these pathological conditions. Cladosporols, secondary metabolites from the fungus Cladosporium tenuissimum, have been characterised for their ability to control cell proliferation in human colon cancer cell lines through peroxisome proliferator-activated receptor gamma (PPARγ)-mediated modulation of gene expression. Here, we report data concerning the ability of cladosporols to regulate the differentiation of murine 3T3-L1 preadipocytes. METHODS: Cell counting and MTT assay were used for analysing cell proliferation. RT-PCR and Western blotting assays were performed to evaluate differentiation marker expression. Cell migration was analysed by wound-healing assay. RESULTS: We showed that cladosporol A and B inhibited the storage of lipids in 3T3-L1 mature adipocytes, while their administration did not affect the proliferative ability of preadipocytes. Moreover, both cladosporols downregulated mRNA and protein levels of early (C/EBPα and PPARγ) and late (aP2, LPL, FASN, GLUT-4, adiponectin and leptin) differentiation markers of adipogenesis. Finally, we found that proliferation and migration of HT-29 colorectal cancer cells were inhibited by conditioned medium from cladosporol-treated 3T3-L1 cells compared with the preadipocyte conditioned medium. CONCLUSIONS: To our knowledge, this is the first report describing that cladosporols inhibit in vitro adipogenesis and through this inhibition may interfere with HT-29 cancer cell growth and migration. GENERAL SIGNIFICANCE: Cladosporols are promising tools to inhibit concomitantly adipogenesis and control colon cancer initiation and progression.


Assuntos
Naftóis/farmacologia , PPAR gama/agonistas , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Naftóis/química , Células Tumorais Cultivadas
6.
Exp Cell Res ; 406(1): 112736, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273404

RESUMO

Electric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signalling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPARγ) agonists. We investigated the effect of electric fields on primary differentiated and glioma stem cell (GSCs) migration, finding opposing preferences for anodal and cathodal migration, respectively. We next sought to determine whether chemically disrupting Akt through PTEN upregulation with the PPARγ agonist, pioglitazone, would modulate electrotaxis of these cells. We found that directed cell migration was significantly inhibited with the addition of pioglitazone in both differentiated GBM and GSCs subtypes. Western blot analysis did not demonstrate any change in PPARγ expression with and without exposure to EF. In summary we demonstrate opposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.


Assuntos
Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Neuroglia/metabolismo , PPAR gama/genética , Resposta Táctica , Anilidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Eletricidade , Eletrodos , Campos Eletromagnéticos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , PPAR gama/agonistas , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
7.
Sci Transl Med ; 13(596)2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078742

RESUMO

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.


Assuntos
Adrenoleucodistrofia , PPAR gama/agonistas , Adrenoleucodistrofia/tratamento farmacológico , Encéfalo , Células Endoteliais , Humanos , Oligodendroglia
8.
J Biol Chem ; 297(1): 100814, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34081964

RESUMO

Nuclear receptors (NRs) activate transcription of target genes in response to binding of ligands to their ligand-binding domains (LBDs). Typically, in vitro assays use either gene expression or the recruitment of coactivators to the isolated LBD of the NR of interest to measure NR activation. However, this approach ignores that NRs function as homo- as well as heterodimers and that the LBD harbors the main dimerization interface. Cofactor recruitment is thereby interconnected with oligomerization status as well as ligand occupation of the partnering LBD through allosteric cross talk. Here we present a modular set of homogeneous time-resolved FRET-based assays through which we investigated the activation of PPARγ in response to ligands and the formation of heterodimers with its obligatory partner RXRα. We introduced mutations into the RXRα LBD that prevent coactivator binding but do not interfere with LBD dimerization or ligand binding. This enabled us to specifically detect PPARγ coactivator recruitment to PPARγ:RXRα heterodimers. We found that the RXRα agonist SR11237 destabilized the RXRα homodimer but promoted formation of the PPARγ:RXRα heterodimer, while being inactive on PPARγ itself. Of interest, incorporation of PPARγ into the heterodimer resulted in a substantial gain in affinity for coactivator CBP-1, even in the absence of ligands. Consequently, SR11237 indirectly promoted coactivator binding to PPARγ by shifting the oligomerization preference of RXRα toward PPARγ:RXRα heterodimer formation. These results emphasize that investigation of ligand-dependent NR activation should take NR dimerization into account. We envision these assays as the necessary assay tool kit for investigating NRs that partner with RXRα.


Assuntos
Proteína de Ligação a CREB/metabolismo , PPAR gama/metabolismo , Multimerização Proteica , Receptor X Retinoide alfa/metabolismo , Benzoatos/farmacologia , Células HEK293 , Humanos , Ligantes , Mutação/genética , Coativador 1 de Receptor Nuclear/metabolismo , PPAR gama/agonistas , PPAR gama/química , Domínios Proteicos , Multimerização Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Reprodutibilidade dos Testes , Receptor X Retinoide alfa/química , Receptor X Retinoide alfa/genética , Retinoides/farmacologia , Rosiglitazona/farmacologia , Ativação Transcricional/genética
9.
Eur J Med Chem ; 222: 113542, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118723

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) is a valuable drug target for diabetic treatment and ligands of PPARγ have shown potent anti-diabetic efficacy. However, to overcome the severe side effects of current PPARγ-targeted drugs, novel PPARγ ligands need to be developed. Sulindac, an identified ligand of PPARγ, is widely used in clinic as a non-steroidal anti-inflammatory drug. To explore its potential application for diabetes, we designed and synthesized a series of sulindac derivatives to investigate their structure-activity relationship as PPARγ ligand and potential anti-diabetic effect. We found that meta-substitution in sulindac's benzylidene moiety was beneficial to PPARγ binding and transactivation. Z rather than E configuration of the benzylidene double bond endowed derivatives with the selectivity of PPARγ activation. The indene fluorine is essential for binding and regulating PPARγ. Compared with rosiglitazone, compound 6b with benzyloxyl meta-substitution and Z benzylidene double bond weakly induced adipogenesis and PPARγ-targeted gene expression. However, 6b potently improved glucose tolerance in a diabetic mice model. Unlike rosiglitazone, 6b was devoid of apparent toxicity to osteoblastic formation. Thus, we provided some useful guidelines for PPARγ-based optimization of sulindac and an anti-diabetic lead compound with less side effects.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Sulindaco/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulindaco/síntese química , Sulindaco/química
10.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L545-L552, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34159801

RESUMO

Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Peroxisome proliferator-activated receptor-γ (PPARγ) plays a key role in normal lung development and was found deregulated following LPD exposure. The objective of this article was to investigate the effects of nebulized curcumin, a natural PPARγ agonist, to prevent IUGR-related abnormal lung development. We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment. Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in mean linear intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect, and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI [F(1,39) = 12.67, P = 0.001] and radial alveolar count at P21 [F(1,40) = 6.065, P = 0.0182]. Immunohistochemistry for fatty acid binding protein 4 (FABP4), a major regulator of PPARγ pathway, showed a decreased FABP4+ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of profibrotic pathways observed at P11 in LPD-exposed animals. Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.


Assuntos
Displasia Broncopulmonar/prevenção & controle , Curcumina/farmacologia , Dieta com Restrição de Proteínas/efeitos adversos , Alvéolos Pulmonares/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Masculino , Nebulizadores e Vaporizadores , PPAR gama/agonistas , PPAR gama/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-Dawley
11.
Alcohol Clin Exp Res ; 45(7): 1359-1369, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34120346

RESUMO

BACKGROUND: Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero. METHODS: We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. RESULTS: We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero. CONCLUSIONS: PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.


Assuntos
Arteríolas/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Etanol/administração & dosagem , Óxido Nítrico Sintase/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Rosiglitazona/administração & dosagem , Animais , Arteríolas/patologia , Arteríolas/fisiopatologia , Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/prevenção & controle , Etanol/efeitos adversos , Feminino , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Gravidez , Ratos , Ratos Sprague-Dawley , Superóxidos/análise
12.
Cardiovasc Diabetol ; 20(1): 109, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006325

RESUMO

Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia-reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin-angiotensin-aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , PPAR gama/agonistas , Pioglitazona/uso terapêutico , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipoglicemiantes/efeitos adversos , PPAR gama/metabolismo , Pioglitazona/efeitos adversos , Medição de Risco , Fatores de Risco , Transdução de Sinais , Resultado do Tratamento
13.
Biol Pharm Bull ; 44(5): 659-668, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952822

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and non-esterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , PPAR gama/agonistas , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Adiponectina/análise , Adiponectina/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/sangue , Obesidade/etiologia , PPAR gama/metabolismo , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Ratos , Tetrazóis/química , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Ganho de Peso/efeitos dos fármacos
14.
Drug Des Devel Ther ; 15: 1725-1734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953542

RESUMO

Purpose: Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. Subjects and Methods: A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. Results: The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. Conclusion: The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. Trial Registration Number: NCT02854748, Registered on August 7, 2016.


Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , PPAR gama/agonistas , Pirimidinas/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Oral , Adulto , Compostos Benzidrílicos/administração & dosagem , Interações Medicamentosas , Tolerância a Medicamentos , Glucosídeos/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Tiazolidinedionas/administração & dosagem , Adulto Jovem
16.
Future Med Chem ; 13(14): 1175-1183, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34013764

RESUMO

Background: PPARγ is known to be a key regulator of metabolism and storage of lipids and glucose and to be implicated in the pathology of severe syndromes like obesity, diabetes, atherosclerosis and cancer. Methods: As a continuation of the authors' studies on oxyprenylated secondary metabolites as effective PPARγ agonists, the authors describe herein the chemical synthesis of natural O-prenyl cinnamaldehydes and cinnamyl alcohols and preliminary data on their in vitro effects on PPARγ transcription. Results: Among the panel of eight compounds tested, three - namely, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)acrylaldehyde, (2E)-3-(4-((E)3,7-dimethylocta-2,6-dienyloxy)-3-methoxyphenyl)prop-2-en-1-ol and boropinal A - exerted activity in a dose-dependent manner. Conclusion: O-prenyl cinnamaldehydes and cinnamyl alcohols have the potential to effectively interact with PPARγ receptor.


Assuntos
Acroleína/análogos & derivados , Neopreno/química , PPAR gama/metabolismo , Propanóis/química , Acroleína/química , Acroleína/farmacologia , Genes Reporter , Células HEK293 , Humanos , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona/química , Pioglitazona/farmacologia , Propanóis/farmacologia , Relação Estrutura-Atividade , Ativação Transcricional/efeitos dos fármacos
17.
Am J Physiol Heart Circ Physiol ; 320(6): H2222-H2239, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33834866

RESUMO

Extracellular matrix (ECM) exerts a series of biological functions and contributes to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the role of periostin in vascular calcification has yet to be fully investigated. As found in this study, recombinant periostin accelerated the thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS) ex vivo, which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition and suppressed PPARγ expression. Mechanistically, periostin caused overactivation of glycolysis and mitochondrial dysfunction in VSMCs as assessed by extracellular acidification rate, oxygen consumption rate, and mitochondrial respiratory chain complex activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients undergoing computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score in patients with coronary artery calcification (CAC). There was also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.NEW & NOTEWORTHY Periostin caused arterial calcification, overactivated glycolysis, and damaged OXPHOS. PPARγ agonists alleviated periostin-promoted arterial calcification and corrected abnormal glycolysis and unbalanced mitochondrial homeostasis. There exists a relationship between periostin and lactate in patients with CAC.


Assuntos
Aorta Torácica/metabolismo , Moléculas de Adesão Celular/metabolismo , Doença da Artéria Coronariana/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Miócitos de Músculo Liso/metabolismo , PPAR gama/metabolismo , Calcificação Vascular/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/farmacologia , Angiografia por Tomografia Computadorizada , Regulação para Baixo , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ácido Láctico/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio , PPAR gama/agonistas , Pioglitazona/farmacologia , Ratos
18.
Chem Pharm Bull (Tokyo) ; 69(4): 333-351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790079

RESUMO

A novel series of 7-substituted-2-[3-(2-furyl)acryloyl]-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to clarify structure-activity relationships for peroxisome proliferator-activated receptor γ (PPARγ) partial agonist activity and identify more efficacious PPARγ partial agonists with minor adverse effects. Among the derivatives synthesized, compound 26v with a 2-(2,5-dihydropyrrol-1-yl)-5-methyloxazol-4-ylmethoxy group at the 7-position of the tetrahydroisoquinoline structure exhibited stronger PPARγ agonist and antagonist activities (EC50 = 6 nM and IC50 = 101 nM) than previously reported values for compound 1 (EC50 = 13 nM and IC50 = 512 nM). Compound 26v had very weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and showed higher oral absorption (Cmax = 11.4 µg/mL and area under the curve (AUC) = 134.7 µg·h/mL) than compound 1 (Cmax = 7.0 µg/mL and AUC = 63.9 µg·h/mL) in male Sprague-Dawley (SD) rats. A computational docking calculation revealed that 26v bound to PPARγ in a similar manner to that of compound 1. In male Zucker fatty rats, 26v and pioglitazone at 10 and 30 mg/kg for 4 weeks similarly reduced plasma triglyceride levels, increased plasma adiponectin levels, and attenuated increases in plasma glucose levels in the oral glucose tolerance test, while only pioglitazone decreased hematocrit values. In conclusion, 6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives provide a novel scaffold for selective PPARγ partial agonists and 26v attenuates insulin resistance possibly by adiponectin enhancements with minor adverse effects.


Assuntos
PPAR gama/agonistas , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Técnicas de Química Sintética , Descoberta de Drogas , Humanos , Masculino , Modelos Moleculares , PPAR gama/metabolismo , Ratos Sprague-Dawley , Ratos Zucker , Tetra-Hidroisoquinolinas/síntese química
19.
J Alzheimers Dis ; 81(2): 557-568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814447

RESUMO

BACKGROUND: The REFLECT trials were conducted to examine the treatment of mild-to-moderate Alzheimer's disease utilizing a peroxisome proliferator-activated receptor gamma agonist. OBJECTIVE: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. METHODS: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. RESULTS: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFα, FABP-3, and PPY) correctly classified treatment response with 100%accuracy across study arms for REFLECT Phase II trial (AVA100193) and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98%of treatment responders. CONCLUSION: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , PPAR gama/uso terapêutico , Medicina de Precisão , Rosiglitazona/uso terapêutico , Doença de Alzheimer/metabolismo , Humanos , PPAR gama/agonistas , Medicina de Precisão/métodos , Tiazolidinedionas/uso terapêutico
20.
Food Chem Toxicol ; 152: 112183, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33836209

RESUMO

T-2 toxin, the most virulent toxin produced by the Fusarium genus, is thought to be the main cause of fatal cardiomyopathy known as Keshan disease. However, the mechanisms of T-2 toxin-induced cardiac toxicity and possible targets for its treatment remain unclear. In the present study, male Wistar rats were administered with 2 mg/kg b. w. T-2 toxin (i.g.) and sacrificed on day 7 after exposure. The hematological indices (CK, LDH) and electrocardiogram were significantly abnormal, the ultrastructure of mitochondria in the heart was changed, and the percentage of collagen area was significantly increased in the T-2 toxin-treated group. Meanwhile, T-2 toxin activated the TGF-ß1/Smad2/3 signalling pathway, and also activated PPAR-γ expression in rats and H9C2 cells. Further application of PPAR-γ agonist (pioglitazone) and antagonist (GW9662) in H9C2 cells revealed that the up-regulation of PPAR-γ expression induced by T-2 toxin is a self-preservation phenomenon, and increasing exogenous PPAR-γ can alleviate the increase in TGF-ß1 caused by T-2 toxin, thereby playing a role in relieving cardiac fibrosis. These findings for the first time demonstrate that T-2 toxin can regulate the expression of PPAR-γ and that PPAR-γ has the potential to serve as an effective therapeutic target in T-2 toxin-induced cardiac fibrosis of rats.


Assuntos
Cardiomiopatias/metabolismo , Fibrose/metabolismo , PPAR gama/metabolismo , Toxina T-2/toxicidade , Anilidas/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Linhagem Celular , Colágeno/metabolismo , Fibrose/induzido quimicamente , Fibrose/complicações , Fibrose/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Pioglitazona/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
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