RESUMEN
Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed.
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Miocardio , PPAR alfa , PPAR gamma , Humanos , PPAR gamma/agonistas , PPAR gamma/metabolismo , PPAR alfa/agonistas , PPAR alfa/metabolismo , Miocardio/patología , Miocardio/metabolismo , Animales , Cardiotónicos/farmacología , Cardiotónicos/uso terapéuticoRESUMEN
Thiazolidine scaffolds have been investigated for decades, due to their wide range of biological activity. In this way, the main objective of this systematic review was to elucidate the anti-inflammatory activity of thiazolidine derivatives against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. From 9718 identified registers, 13 articles were included, where 11 studies evaluated thiazolidinediones. The summary of relevance demonstrated that seven studies (53.8%) were relevant without restrictions, and 6 (46.2%) were relevant with restrictions. The certainty in cumulative evidence was considered moderate and the six studies included in the meta-analysis demonstrated the positive activity of thiazolidinediones against NO production when compared to the negative LPS control.
RESUMEN
Furin (Fur) is a member of the protease convertase family; its expression is crucial for cleaving and maturing many proteins. Fur also represents a therapeutic target in cancer, autoimmune diseases, and viral infections. Pioglitazone (PGZ) and rosiglitazone (RGZ) are thiazolidinediones prescribed to type 2 diabetes patients and are structurally similar to the known Fur inhibitors naphthofluorescein (NPF) and pirfenidone (PFD). Thus, this study used molecular docking and molecular dynamics to assess and compare the affinities and the molecular interactions of these four ligands with the Fur active site (FurAct) and the recently described Fur allosteric site (FurAll). The 7QXZ Fur structure was used for molecular dockings, and for the best pose complexes, molecular dynamics were run for 100 ns. The best affinities of the ligand/FurAct and ligand/FurAll complexes were with NPF, PGZ, and RGZ, while PFD presented the lowest affinity. Asp154 was the central residue involved in FurAct complex formation, while Glu488 and Asn310 were the central residues involved in FurAll complex formation. This study shows the potential of RGZ, PGZ, and PFD as Fur competitive (FurAct) and non-competitive (FurAll) inhibitors. Therefore, they are candidates for repurposing in response to future emerging diseases through the modulation of Fur activity.
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Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfß1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc.
Asunto(s)
Fibrosis Pulmonar , Esclerodermia Sistémica , Tiazolidinedionas , Humanos , Animales , Ratones , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Leucocitos Mononucleares , Ácido Hipocloroso , PPAR gamma , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , CitocinasRESUMEN
Protein tyrosine phosphatase 1B (PTP1B) is considered a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2DM), since this enzyme plays a significant role to down-regulate insulin and leptin signalling and its over expression has been implicated in the development of insulin resistance, T2DM and obesity. Some thiazolidinediones (TZD) derivatives have been reported as promising PTP1B inhibitors with anti hyperglycemic effects. Recently, lobeglitazone, a new TZD, was described as an antidiabetic drug that targets the PPAR-γ (peroxisome γ proliferator-activated receptor) pathway, but no information on its effects on PTP1B have been reported to date. We investigated the effects of lobeglitazone on PTP1B activity in vitro. Surprisingly, lobeglitazone led to moderate inhibition on PTP1B (IC50 42.8 ± 3.8 µM) activity and to a non-competitive reversible mechanism of action. As lobeglitazone inhibits PTP1B activity in vitro, we speculate that it could also target PTP1B signalling pathway in vivo and thus contribute to potentiate its antidiabetic effects.
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Hipoglucemiantes/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Pirimidinas/química , Tiazolidinedionas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Concentración 50 Inhibidora , Cinética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologíaRESUMEN
BACKGROUND: Chronic diseases, such as obesity and cancer, have high prevalence rates. Both diseases have hyperinsulinemia, hyperglycemia, high levels of IGF-1 and inflammatory cytokines in common. Therefore, these can be considered triggers for cancer development and growth. In addition, low-grade inflammation that modulates the activation of immune cells, cellular metabolism, and production of cytokines and chemokines are common in obesity, cancer, and insulin resistance. Pharmacological strategies are necessary when a change in lifestyle does not improve glycemic homeostasis. In this regard, thiazolidinediones (TZD) possess multiple molecular targets and regulate PPARγ in obesity and cancer related to insulin resistance, while metformin acts through the AMPK pathway. OBJECTIVE: The aim of this study was to review TZD and metformin as pharmacological treatments for insulin resistance associated with obesity and cancer. CONCLUSION: Thiazolidinediones restored adiponectin secretion and leptin sensitivity, reduced lipid droplets in hepatocytes and orexigen peptides in the hypothalamus. In cancer cells, TZD reduced proliferation, production of reactive oxygen species, and inflammation by acting through the mTOR and NFκB pathways. Metformin has similar effects, though these are AMPK-dependent. In addition, both drugs can be efficient against certain side effects caused by chemotherapy.
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Resistencia a la Insulina , Metformina/uso terapéutico , Neoplasias/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Humanos , Hiperglucemia , Hipoglucemiantes/farmacología , InsulinaRESUMEN
The present investigation aimed to characterize the effect of a short-time treatment with a new thiazolidinedione (TZD) derivative, GQ-130, on metabolic alterations in rats fed a high-fat diet (HFD). We investigated whether metabolic alterations induced by GQ-130 were mediated though a mechanism that involves PPARß/δ transactivation. Potential binding and transactivation of PPARα, PPARß/δ or PPARγ by GQ-130 were examined through cell transactivation, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8-week-old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ-130 (10 mg/kg/d) during the last week (HFD-GQ group). In 293T cells, unlike rosiglitazone, GQ-130 did not cause significant transactivation of PPARγ but was able to activate PPARß/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ-130 does not bind directly to PPARß/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARß/δ in the presence of GQ-130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ-130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ-130 was effective in improving HFD-induced metabolic alterations probably through a mechanism that involves PPARß/δ activation.
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Metabolismo Energético/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , PPAR delta/agonistas , PPAR-beta/agonistas , Tiazolidinedionas/farmacología , Animales , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatología , PPAR delta/genética , PPAR delta/metabolismo , PPAR-beta/genética , PPAR-beta/metabolismo , Ratas Wistar , Transducción de Señal , Factores de TiempoRESUMEN
The thiazolidinediones (TZDs) class comprises drugs with hypoglycemic effects, reducing insulin resistance in peripheral tissues. Our group has demonstrated in preliminary in vivo studies that a new TZD, GQ-11, improves insulin resistance as well as modulates cytokines involved in inflammatory process, suggesting an interesting approach for therapeutic alternatives in tissue repair, especially in metabolic decompensation cases, as insulin resistance and ischemia-reperfusion. In this context, the aim of this study was to investigate GQ-11 effects in tissue repair in three different models: insulin resistance in db/db mice, reconstructed human epidermis (RHE) in glycated collagen matrix and ischemia/reperfusion induced by aorta clamping in Wistar rats. In insulin resistance context, GQ-11 treatment upregulated the expression of anti-inflammatory mediators, such as IL-10, TGF-ß and Arg-1, downregulated the expression of pro-inflammatory cytokines both in db/db mice wounds and in macrophage, besides increasing re-epithelization and collagen deposition. In addition, the treatment also induced keratinocytes proliferation and fibroblasts differentiation in RHE. In ischemia-reperfusion model, the same anti-inflammatory effect was observed along with anti-oxidant properties through regulation of enzymes, such as catalase and GPx, as well as by decreasing TBARS formation. Animals imaging by positron emission tomography (PET) indicated significant less 18F-FDG uptake in animal treated with GQ-11 compared to controls, suggesting decrease of the inflammation process related to reperfusion after aorta clamping. Concluding, the dual PPARα/γ agonist GQ-11 has an important antiinflammatory effect, suggesting a new approach to tissue repair management in diabetes and in prevention of ischemia-reperfusion syndrome post-surgery
As tiazolidinadionas (TZDs) compreendem uma classe de fármacos hipoglicemiantes que reduzem a resistência à insulina pelos tecidos periféricos. Dados preliminares in vivo obtidos em nosso grupo de pesquisa mostraram que um dos novos derivados tiazolidínicos, GQ-11, além de aumentar a resposta à insulina, pode inibir citocinas pró-inflamatórias, o que a torna uma alternativa terapêutica promissora no reparo tecidual, em especial, nos casos de descompensação metabólica como ocorre na resistência à insulina e na isquemia/reperfusão. Nesse contexto, o objetivo deste trabalho foi investigar os efeitos da GQ-11 nas etapas do processo de reparo tecidual em três modelos: resistência à insulina utilizando camundongos db/db, epiderme humana reconstruída em matriz de colágeno glicado e isquemia/reperfusão induzida por clampeamento da aorta em ratos Wistar. No contexto de resistência à insulina, o tratamento com GQ-11 induziu a expressão de mediadores anti-inflamatórios como IL-10, TGF-ß e Arg-1 e diminuiu a expressão de citocinas pró-inflamatórias em lesões de camundongos db/db e em macrófagos, além de aumentar a capacidade de re-epitelização e a deposição de colágeno. Além disso, o tratamento também induziu a proliferação de queratinócitos e a diferenciação de fibroblastos em epiderme humana reconstruída em matriz de colágeno glicado. No modelo de isquemia-reperfusão, o mesmo efeito anti-inflamatório da GQ-11 foi observado ao lado de efeitos anti-oxidantes através da regulação de enzimas como catalase, GPx e diminuição de TBARS. O imageamento dos animais através de tomografia por emissão de pósitrons (PET) demonstrou menor captação de 18F-FDG (18F-fluordesoxiglicose), indicando diminuição do processo inflamatório decorrente da reperfusão pós clampeamento aórtico. Dessa forma, conclui-se que GQ-11, um agonista dual de PPARα/γ, tem efeito anti-inflamatório importante, podendo ser um candidato à fármaco com possível aplicação no reparo tecidual no diabetes e na prevenção da síndrome de isquemia-reperfusão desenvolvida após procedimentos cirúrgicos
Asunto(s)
Animales , Ratones , Insulinas , Hipoglucemiantes/agonistas , Inflamación/clasificación , Daño por Reperfusión/clasificación , IsquemiaRESUMEN
Abstract Background: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. Objectives: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. Methods: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. Results: Pioglitazone and VEGFR-2-selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. Conclusions: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway.
Resumo Fundamento: A pioglitazona tem sido amplamente utilizada como droga sensibilizadora da insulina para melhorar o controle glicêmico em pacientes com diabetes mellitus tipo 2. No entanto, o risco cardiovascular bem como os efeitos protetores da pioglitazona ainda são controversos. Objetivos: Neste estudo, investigamos se os efeitos da pioglitazona sobre a apoptose e a hipertrofia de cardiomiócitos ocorrem via regulação da via de sinalização do VEGFR-2. Métodos: os cardiomiócitos foram isolados enzimaticamente dos ventrículos de ratos Sprague-Dawley de 1-3 anos de vida. Os efeitos da pioglitazona e do inibidor seletivo de VEGFR-2 apatinib sobre a taxa de apoptose dos cardiomiócitos foram avaliados por citometria de fluxo, e a hipertrofia avaliada por incorporação de leucina-[3H]. As expressões de VEGFR-2, Akt, P53, e mTOR fosforiladas e não fosforiladas foram determinadas por Western Blotting. Análise de variância (ANOVA) foi usada para avaliar diferenças entre os grupos. Resultados: a pioglitazona e o apatinib reduziram a viabilidade e a hipertrofia de cardiomiócitos induzida por angiotensina II in vitro. Além disso, no mesmo modelo in vitro, a pioglitazona e o apatinib aumentaram significativamente a expressão de Bax e P53 fosforilada, e diminuiu a expressão de VEGFR-2, Akt, e mTOR, que promove hipertrofia de cardiomiócitos. Conclusões: Esses resultados indicam que a pioglitazona induz a apoptose e inibe a hipertrofia de cardiomiócitos pela modulação da via de sinalização de VEGFR-2.
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Animales , Ratas , Apoptosis/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/efectos de los fármacos , Tiazolidinedionas/farmacología , Hipoglucemiantes/farmacología , Transducción de Señal/efectos de los fármacos , Ratas Sprague-Dawley , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Pioglitazona , Hipertrofia/inducido químicamente , Hipertrofia/patología , Animales Recién NacidosRESUMEN
Resumen La diabetes mellitus tipo 2 es una de las enfermedades metabólicas que afecta a diferentes órganos, uno en el cual es el riñón. Una de las principales complicaciones microvasculares es la nefropatía diabética, siendo la principal causa de insuficiencia renal crónica a nivel mundial. De ahí la importancia de las recomendaciones en la utilización o no de los fármacos antihiperglicemiantes, basadas en sus efectos beneficiosos a nivel de la función renal en relación con la tasa de filtración glomerular estimada y la relación albumina/creatinina en pacientes con diabetes mellitus tipo 2 y enfermedad renal. En estudios recientes se han evaluado antihiperglicemiantes con un impacto beneficioso a nivel de desenlaces cardiovascular y renal. En el presente artículo se revisan las acciones y los efectos de los diferentes grupos de medicamentos como la metformina, los inhibidores de la dipeptidil peptidasa 4, los agonistas de la GLP-1, tiazolidinedionas, sulfonilureas, inhibidores del cotransportador de sodio-glucosa tipo 2 e insulinas en la función renal en cuanto a las dosis de cada fármaco, tanto el uso de dosis establecidas, disminución de la dosis o el no uso del medicamento con base en el empeoramiento de la tasa de filtración glomerular estimada. Con respecto a la metodología aplicada para el desarrollo del artículo, se seleccionó artículos a partir de palabras claves como diabetes mellitus tipo 2, antihiperglicemiantes en la función renal, tasa de filtración glomerular estimada y relación albumina/creatinina; se emplearon artículos de revistas reconocidas que no superaran 5 años en su publicación, sin embargo, se utilizaron artículos que superaran este tiempo, dado que aportaban datos importantes para el artículo de revisión.
Abstract Type 2 diabetes mellitus is one of the metabolic diseases that affects different organs, one of which is the kidney. One of the main microvascular complications is diabetic nephropathy, being the main cause of chronic renal failure worldwide. Hence the importance of recommendations on the use or non-use of antihyperglycemic drugs based on their beneficial effects on kidney function, expressed by the estimated glomerular filtration rate and the albumin / creatinine ratio in patients with type 2 diabetes mellitus and kidney disease. Recent studies have shown antihyperglycemic agents with beneficial impact in cardiovascular and renal endpoints. In the present article we will review the actions and effects of different groups of drugs such as metformin, inhibitors of dipeptidyl peptidase 4, GLP-1 agonists, thiazolidinediones, sulfonylureas, SGLT-2 inhibitors and insulins in renal function in relation to the doses of each drug, both the use of established doses, reduction of the dose or non-use of the drug based on the worsening of the estimated glomerular filtration rate. With respect to the methodology applied for the development of the article, a selection of articles was made based on key words such as type 2 diabetes mellitus, antihyperglycemic agents in renal function, estimated glomerular filtration rate and albumin/ creatinine ratio. Prestigious journal articles were used with less than 5 years since its publication, however articles that exceed this time were used as they provided important data in the review article.
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Humanos , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Metformina/antagonistas & inhibidoresRESUMEN
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are responsible for high mortality rates in critical patients. Despite >50â¯years of intensive research, there is no pharmacologically effective treatment to treat ALI. PPARs agonists, chemically named thiazolidinediones (TZDs) have emerged as potential drugs for the treatment of ALI and ARDS due to their anti-inflammatory efficacy. The present study aims to evaluate the potential anti-inflammatory effects of new TZDs derivatives, LPSF/GQ-2 and LPSF/RA-4, on ALI induced by LPS. BALB/c mice were divided into five groups: 1) Control; 2) LPS intranasal 25⯵g; 3) LPSF/GQ-2 30â¯mg/kgâ¯+â¯LPS; 4) LPSF/RA-4 20â¯mg/kgâ¯+â¯LPS; and 5) DEXA 1â¯mg/Kgâ¯+â¯LPS. BALF analyses revealed that LPSF/GQ-2 and LPSF/RA-4 reduced NO levels in BALF and inflammatory cell infiltration induced by LPS. MPO levels were also reduced by the LPSF/GQ-2 and LPSF/RA-4 pre-treatments. In contrast, histopathological analyses showed better tissue protection with LPSF/GQ-2 than DEXA and LPSF/RA-4 groups. Similarly, LPSF/GQ-2 reduced inflammatory markers (IL-1, iNOS, TNFα, IL-1ß, IL-6) better than LPSF/RA-4. The LPSF/GQ-2 anti-inflammatory action could be attributed to the inhibition of NFκB, ERK, p38, and PARP pathways. In contrast, LPSF/RA-4 had no effect on the expression of p38, JNK, NFκB. The present study indicates that LPSF/GQ-2 presents a potential therapeutic role as an anti-inflammatory drug for ALI.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , FN-kappa B/metabolismo , Neumonía/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Masculino , Ratones , Receptores Activados del Proliferador del Peroxisoma/agonistas , Transducción de SeñalRESUMEN
AIM: The lipogenic effect of pioglitazone (PGZ), an insulin (INS) sensitizer, is well established. However, few studies have evaluated PGZ effects in preventing weight loss in cancer. We investigated PGZ effects, alone or associated with INS, on INS resistance, cachexia and metabolic abnormalities induced by Walker-256 tumor in rats. MAIN METHODS: PGZ (5.0mg·kg-1, oral) or PGZ+INS (NPH, 1.0UI·kg-1, sc), were once-daily administered during 12days, starting on the day inoculation of Walker-256 tumor cells. Rats were separated in small (about 17g) and big (about 30g) tumor-bearing. KEY FINDINGS: Big tumor-bearing rats showed greater cachexia, blood triacylglycerol and free fatty acids and INS resistance. PGZ and PGZ+INS treatments did not change tumor growth and food intake, but reduced several abnormalities such as INS resistance, increased blood free fatty acids, retroperitoneal fat wasting and body weight loss in small tumor-bearing rats. The prevention of retroperitoneal fat wasting did not involve reduction of tumor necrosis factor-α expression increased. In big tumor-bearing rats, PGZ and PGZ+INS treatments reversed the high blood triacylglycerol and free fatty acids levels, but had no effect on other parameters. SIGNIFICANCE: PGZ and PGZ+INS improved INS peripheral sensitivity, possibly by decreasing blood free fatty acids, and reduced fat tissue wasting and body weight loss in small tumor-bearing rats. The results suggest clinical benefits of PGZ in preventing INS resistance, adipose tissue wasting and weight loss when the tumor is small, i.e., in less severe cachexia.
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Caquexia/tratamiento farmacológico , Resistencia a la Insulina , Tiazolidinedionas/farmacología , Pérdida de Peso/efectos de los fármacos , Animales , Masculino , Pioglitazona , Ratas , Ratas Wistar , Tiazolidinedionas/uso terapéuticoRESUMEN
BACKGROUND: Atherosclerosis is a complex disorder with a multifactorial pathogenesis. We previously indicated that the new TZD LPSF/GQ-02 inhibits hepatic steatosis and inflammation, which are reported as risk factors for atherosclerosis development. Here, we explored the effects of LPSF/GQ-02 on atherosclerosis in LDLr-/- mice comparing two treatment periods. METHODS AND RESULTS: LDLr-/- mice were fed a high-fat diet for 10 and 12 weeks and received oral treatment with LPSF/GQ-02 (30mg/kg/day) or pioglitazone (20mg/kg/day) for 15 and 30 days, respectively. Both treatment protocols with LPSF/GQ-02 resulted in lower collagen density in the atherosclerotic lesions. In addition, the treatment for 15 days also decreased mRNA levels of CD40, MCP-1, ABCG1 and upregulated PPARα, whereas the 30-days treatment reduced the protein levels of LOX-1, p-IκBα and p-NFκB. CONCLUSION: This study provides evidence that LPSF/GQ-02 affects the composition and growth of atherosclerotic lesions in LDLr-/- mice. Moreover, our data also support previous findings showing anti-inflammatory properties of LPSF/GQ-02 and reinforce the therapeutic potential of this TZD for treating atherosclerosis and inflammation-related disorders.
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Antiinflamatorios/farmacología , Aterosclerosis/tratamiento farmacológico , Receptores de LDL/deficiencia , Tiazolidinedionas/farmacología , Animales , Antiinflamatorios/uso terapéutico , Aorta/efectos de los fármacos , Aorta/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Transporte Biológico/efectos de los fármacos , Colesterol/metabolismo , Colágeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Receptores X del Hígado/metabolismo , Masculino , Ratones , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Tiazolidinedionas/uso terapéutico , Factores de TiempoRESUMEN
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPARγ) agonists used in treating type 2 diabetes that may exhibit beneficial pleiotropic effects on endothelial cells. In this study, we characterized the effects of three new TZDs [GQ-32 (3-biphenyl-4-ylmethyl-5-(4-nitro-benzylidene)-thiazolidine-2,4-dione), GQ-169 (5-(4-chloro-benzylidene)-3-(2,6-dichloro-benzyl)-thiazolidine-2,4-dione), and LYSO-7 (5-(5-bromo-1H-indol-3-ylmethylene)-3-(4-chlorobenzyl)-thiazolidine-2,4-dione)] on endothelial cells. The effects of the new TZDs were evaluated on the production of nitric oxide (NO) and reactive oxygen species (ROS), cell migration, tube formation and the gene expression of adhesion molecules and angiogenic mediators in human umbilical vein endothelial cells (HUVECs). PPARγ activation by new TZDs was addressed with a reporter gene assay. The three new TZDs activated PPARγ and suppressed the tumor necrosis factor α-induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. GQ-169 and LYSO-7 also inhibited the glucose-induced ROS production. Although NO production assessed with 4-amino-5-methylamino-2',7'-difluorofluorescein-FM probe indicated that all tested TZDs enhanced intracellular levels of NO, only LYSO-7 treatment significantly increased the release of NO from HUVEC measured by chemiluminescence analysis of culture media. Additionally, GQ-32 and GQ-169 induced endothelial cell migration and tube formation by the up-regulation of angiogenic molecules expression, such as vascular endothelial growth factor A and interleukin 8. GQ-169 also increased the mRNA levels of basic fibroblast growth factor, and GQ-32 enhanced transforming growth factor-ß expression. Together, the results of this study reveal that these new TZDs act as partial agonists of PPARγ and modulate endothelial cell activation and endothelial dysfunction besides to stimulate migration and tube formation.
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Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Tiazolidinedionas/farmacología , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Óxido Nítrico/metabolismo , PPAR gamma/agonistas , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
Asunto(s)
Aterosclerosis/metabolismo , Obesidad/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Receptores de LDL/genética , Sulfonas/farmacología , Tiazolidinedionas/farmacología , Adiponectina/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Aorta Torácica/patología , Aterosclerosis/sangre , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Densidad Ósea , Línea Celular , HDL-Colesterol/sangre , Factores de Crecimiento de Fibroblastos/genética , Transportador de Glucosa de Tipo 4/genética , Humanos , Leptina/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Noqueados , Modelos Moleculares , Miocardio/metabolismo , Obesidad/sangre , Obesidad/tratamiento farmacológico , Obesidad/patología , Sulfonas/uso terapéutico , Tiazolidinedionas/uso terapéuticoRESUMEN
Obesity and type 2 diabetes mellitus (T2DM) epidemics, which have already spread, imply the possibility of both conditions being closely related. Thus, the goal of the present review was to draw a parallel between obesity, adipose tissue (AT) changes, and T2DM development. To this end, a search was conducted in PubMed, MEDLINE and SciELO databases, using the following key words and their combinations: obesity; diabetes; insulin resistance; diet; weight loss; adipocin; inflammation markers; and interleukins. Based on a literature review, AT dysfunction observed in obesity is characterised by adipocyte hypertrophy, macrophage infiltration, impaired insulin signalling and insulin resistance. In addition, there is release of inflammatory adipokines and an excessive amount of NEFA promoting ectopic fat deposition and lipotoxicity in muscle, liver and pancreas. Recent evidence supports the hypothesis that the conception of AT as a passive energy storage organ should be replaced by a dynamic endocrine organ, which regulates metabolism through a complex adipocyte communication with the surrounding microenvironment. The present review demonstrates how glucose homeostasis is changed by AT dysfunction. A better understanding of this relationship enables performing nutritional intervention strategies with the goal of preventing T2DM.
RESUMEN
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that improve insulin-mediated glucose uptake and possess beneficial vasculoprotective actions. However, because undesirable side effects are associated with these drugs, novel TZDs are under development. In this study, we evaluated the biological activity of LYSO-7, a new indole-thiazolidine, on PPAR activation, inflammation and atherogenesis using a gene reporter assay, lipopolysaccharide (LPS)-activated RAW 264.7 cell culture, and a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. LYSO-7 shows low cytotoxicity in RAW 264.7 cells and at 2.5µmol/L induces PPARα and PPARγ transactivation as well as inhibits LPS-induced nitrite production and the mRNA gene expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). In addition, treatment with LYSO-7 reduces the development of atherosclerosis in LDLr(-/-) mice, improves the lipid profile, blood glucose levels, and downregulates CD40 and CD40L expression without affecting the body weight of the animals. Altogether, our data show that LYSO-7 possesses anti-inflammatory properties and that treatment with this TZD attenuates atherosclerosis progression in LDLr(-/-) mice by modulating lipid metabolism and inflammation. Thus, LYSO-7 shows potential as a new drug candidate for the treatment of atherosclerosis.
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Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Indoles/uso terapéutico , Receptores de LDL/deficiencia , Tiazolidinedionas/uso terapéutico , Tiazolidinas/uso terapéutico , Animales , Línea Celular , Indoles/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Activados del Proliferador del Peroxisoma/agonistas , Tiazolidinedionas/farmacología , Tiazolidinas/farmacologíaRESUMEN
The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors involved in lipid metabolism and glucose utilization, in cell growth, differentiation and apoptosis, and in the regulation of pro-inflammatory genes expression such as cyclooxygenase-2 (COX-2). PPARγ is the main isoform in the renal inner medulla where it is believed to possess nephroprotective actions. In this kidney zone, COX-2 acts as an osmoprotective gene and its expression is modulated by changes in interstitial osmolarity. In the present work we evaluated whether hyperosmolar-induced COX-2 expression is modulated by PPARγ in renal epithelial cells MDCK subjected to high NaCl medium. The results presented herein show that ligand-activated PPARγ repressed COX-2 expression. But more important, the present findings show that hyperosmolar medium decreased PPARγ protein and increases the PPARγ phosphorylated form, which is inactive. ERK1/2 and p38 activation precedes PPARγ disappearance and induced-COX-2 expression. Therefore, the decrease in PPARγ expression is required for hyperosmotic induction of COX-2. We also found that PGE2, the main product of COX-2 in MDCK cells, induced these changes in PPARγ protein. Our results may alert on the long term use of thiazolidinediones (TZD) since they could affect renal medullary function that depends on COX-2 for cellular protection against osmotic stress.
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Ciclooxigenasa 2/metabolismo , Riñón/enzimología , PPAR gamma/metabolismo , Anilidas/farmacología , Animales , Secuencia de Bases , Células Cultivadas , Cartilla de ADN , Dinoprostona/metabolismo , Perros , Células Epiteliales/enzimología , Riñón/citología , Fosforilación , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , Proteínas Quinasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Cloruro de Sodio/farmacología , Tiazolidinedionas/farmacologíaRESUMEN
The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted arenealdehydes and KOH using ultrasound irradiation is reported. The desired compounds were obtained in a few min (10-30 min) with moderate to good yields (25-81%).
Asunto(s)
Tiazolidinedionas/síntesis química , Tiazolidinedionas/efectos de la radiación , Ultrasonido/métodos , Catálisis , Hidróxidos/química , Hidróxidos/efectos de la radiación , Indicadores y Reactivos , Compuestos de Potasio/química , Compuestos de Potasio/efectos de la radiaciónRESUMEN
Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPARγ) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI) and PPARγ in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals.