RESUMEN
Chagas disease, caused by Trypanosoma cruzi, stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b+ LY6Chigh). Furthermore, both CD11b+ Ly6Clow F4/80high macrophages (MΦ) and recently differentiated CD11b+ Ly6Chigh F4/80high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206high) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.
Asunto(s)
Cardiomiopatía Chagásica , Fenofibrato , Macrófagos , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Animales , Ratones , Cardiomiopatía Chagásica/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Miocardio/patología , Masculino , Trypanosoma cruzi/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Miocarditis/tratamiento farmacológico , Miocarditis/parasitologíaRESUMEN
Chronic cardiomyopathy is one of the most relevant outcomes of Chagas disease associated with parasite persistence and exacerbated inflammatory response. Fenofibrate, a third generation fibric acid derivative and peroxisome proliferator-activated receptor-α ligand, is involved in the regulation of inflammatory response. However, the participation of macrophages in this scenario has not been elucidated. Here we show, for the first time, that macrophages play a fundamental role in the fenofibrate-mediated modulation of heart pro-inflammatory response and fibrosis caused by the infection with Trypanosoma cruzi. Furthermore, macrophages are required for fenofibrate to improve the loss of ventricular function and this restoration correlates with an anti-inflammatory microenvironment. Understanding the contributions of macrophages to the healing properties of fenofibrate reinforces its potential use as a therapeutic drug, with the aim of helping to solve a public health problem, such as chronic Chagas disease.
Asunto(s)
Cardiomiopatías , Cardiomiopatía Chagásica , Enfermedad de Chagas , Fenofibrato , Humanos , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/complicaciones , MacrófagosRESUMEN
OBJECTIVES: The aim of this study was to assess the short-term safety and efficacy of fenofibrate in controlling secondary hypertriglyceridemia in cats. METHODS: This was a prospective cohort study. Seventeen adult cats with hypertriglyceridemia (serum triglycerides [TG] >160 mg/dl) were enrolled. Cats received a median dose of 5 mg/kg (range 3.2-6) fenofibrate (q24h PO) for 1 month. Serum TG, total cholesterol (TC), creatine kinase and liver enzymes (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were evaluated before (t0) and after 1 month (t1) of fenofibrate treatment. RESULTS: The causes of secondary hypertriglyceridemia were diabetes mellitus (DM; 29.4%), obesity (29.4%), hyperadrenocorticism (HAC) and DM (11.7%), HAC without DM (5.9%), hypersomatotropism (HST) and DM (5.9%), hypothyroidism (5.9%), long-term treatment with glucocorticoids (5.9%) and chylothorax (5.9%). Serum TG (t0 median 920 mg/dl [range 237-1780]; t1 median 51 mg/dl [range 21-1001]; P = 0.0002) and TC (t0 median 278 mg/dl [range 103-502]; t1 median 156 mg/dl [range 66-244]; P = 0.0001) concentrations showed a significant decrease after 1 month of fenofibrate treatment. Fifteen cats normalized their TG concentration at t1 (88.2%). Of the eight cats that were hypercholesterolemic at t0, six (75%) normalized their TC concentrations at t1. One of 17 cats (5.9 %) presented with diarrhea; the remaining 16 did not show any adverse effects. CONCLUSIONS AND RELEVANCE: DM and obesity are the most common endocrine causes of secondary hyperlipidemia, although it can also be found in cats with HAC, HST or hypothyroidism. This study suggests that fenofibrate treatment was associated with reduction and normalization of TG and TC concentrations in cats with moderate and severe hypertriglyceridemia, regardless of the cause of secondary hypertriglyceridemia. Further work should focus on controlled studies with a greater number of cases.
Asunto(s)
Enfermedades de los Gatos , Fenofibrato , Hipertrigliceridemia , Hipotiroidismo , Obesidad , Animales , Enfermedades de los Gatos/inducido químicamente , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Fenofibrato/uso terapéutico , Humanos , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/veterinaria , Hipolipemiantes/uso terapéutico , Hipotiroidismo/complicaciones , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/veterinaria , Obesidad/veterinaria , Estudios Prospectivos , TriglicéridosRESUMEN
INTRODUCTION AND OBJECTIVES: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. MATERIAL AND METHODS: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. RESULTS: 562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates. CONCLUSIONS: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization.
Asunto(s)
Cirrosis Hepática Biliar/tratamiento farmacológico , Vigilancia de la Población , Ácido Ursodesoxicólico/uso terapéutico , Brasil/epidemiología , Colagogos y Coleréticos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Cirrosis Hepática Biliar/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Abstract Inflammation-related immune responses and bone metabolism lead to extensive tooth loss in periodontitis. Objective: This study aims to investigate the effect of peroxisome proliferator-activated receptor (PPAR) alpha agonist anti-inflammatory treatment in vitro and in ligature-induced experimental periodontitis in vivo . Methodology: Splenocytes were isolated from C57BL/6J mice and cultured for 48 hours under the following conditions: control, P. gingivalis lipopolysaccharide (LPS) (1 µg/ml); experimental, LPS (1 µg/ml) + PPARα agonist (fenofibrate) at 1, 10, 50, 100 µM. MRNA and secreted protein levels of TNF-α expression were detected by RT-qPCR and ELISA, respectively. Silk ligatures (7-0) were tied around maxillary second molars of C57BL/6J mice for two weeks. Optimized doses of fenofibrate (50 µM) and vehicle control were injected into the contralateral side of the palatal gingiva on days three, six, and nine. At day 14, bone resorption, osteoclastogenesis, and gingival mRNA expression levels of TNF-α, IL-1β, IL-6, and RANKL/OPG were measured by micro-computed tomography, Tartrate-resistant acid phosphatase (TRAP) staining, and Real-time quantitative PCR, respectively. Results: TNF-α expression in cultured spleen cells were significantly increased in the presence of LPS, when compared with the control group, and significantly reduced by fenofibrate treatment in a dose-dependent manner from 1-100 µM (p<0.05). Gingival mRNA levels of TNF-α, IL-1β, IL-6, and the ratio of RANKL/OPG, were significantly decreased after injection of fenofibrate, when compared to the control side (p<0.05). Periodontal bone loss and TRAP positive cell formation were significantly decreased on the side with an injection of fenofibrate, as compared to the control side (p<0.05). Conclusions: An anti-inflammatory treatment, PPARα agonist, inhibited inflammation and periodontal bone loss in ligature-induced experimental periodontitis.
RESUMEN
Abstract Fenofibrate is a peroxisome-proliferator-activator α agonist and it is a widely used drug for hyperlipidemia since its approval in 2004. So, in this review we are focusing on the effect of fenofibric acid's mechanism to alleviate type 1 diabetic micro vascular complications like diabetic retinopathy, diabetic cardiomyopathy in animal models, since the drug is safe, efficacious and more economical when compared with the currently available treatment strategies for juvenile diabetic complications and also a profound observation is needed due to the rarity of research in these therapeutic areas. Important preclinical animal studies published from January 2001 to June 2020 were recognised from databases like PubMed and Cochrane central register of controlled trials. Reviewers screened the articles based on the selection criteria and risk of bias was determined using Systematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies. Our literature search yielded a total of 5 studies and after pooling up the data from the 5 preclinical studies, we found that Fenofibrate have the efficacy to prevent type 1 diabetic complications, chiefly diabetic retinopathy and those mechanisms are dependent on peroxisome-proliferator-activator and fibroblast growth factor-21 pathways. Fenofibrate is a well safe and moreover, cost effective medication in preventing type 1 diabetic micro vascular complications especially diabetic retinopathy and also in maintaining the glucose homeostasis in apart from its anti-dyslipidemic effect.
RESUMEN
Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-ß, IL-6, MCP1, and CCR2 than cells from uninfected individuals (HI), irrespectively of the clinical stage, asymptomatic (Asy) or with Chagas heart disease (CHD). Fenofibrate reduces the levels of pro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higher percentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higher percentage of non-classical monocytes than CHD patients or HI. However, no difference in the intermediate monocyte subpopulation was found between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro with T. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes in the Asy group whereas the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD or HI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groups studied. Moreover, fenofibrate treatment of T. cruzi-stimulated cells, increased the frequency of the non-classical subpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in any groups. In conclusion, our results emphasize a potential role for fenofibrate as a modulator of monocyte subpopulations towards an anti-inflammatory and healing profile in different stages of chronic Chagas disease.
Asunto(s)
Enfermedad de Chagas , Fenofibrato , Animales , Citocinas/metabolismo , Fenofibrato/metabolismo , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Monocitos/metabolismoRESUMEN
BACKGROUND: Ischemic heart disease is the leading cause of death in the world and is associated with dyslipidemia, high blood pressure, diabetes mellitus, and other factors. OBJECTIVE: To determine the clinical effectiveness on the lipid profile of the rosuvastatin + fenofibric acid combination in Colombian patients with high cardiovascular risk and mixed dyslipidemia. METHODS: Longitudinal observational study in a random sample of patients with a diagnosis of mixed dyslipidemia and moderate, high, or very high cardiovascular risk who were treated with rosuvastatin + fenofibric acid. Anthropometric, clinical, laboratory, comorbidity, and pharmacological variables were identified. Effectiveness on the lipid profile was determined. RESULTS: A total of 386 patients were analyzed. They had a mean age of 60.8 ± 11.4 years, 53.1% were female, and 75.6% had high/very high cardiovascular risk. The initial evaluation showed a mean LDL cholesterol of 138.4 ± 67.1 mg/dL and triglycerides of 679.7 ± 573.6 mg/dL. At the end of follow-up, mean LDL cholesterol was 87.5 ± 41.2 mg/dL (reduced by 43.3%; P < .001), and triglycerides were 243.5 ± 170.5 mg/dL (reduced by 64.2%; P < .001). Only 35.4% (n = 73) of patients with very high risk reached the goal of metabolic control, compared to 61.6% (n = 53) with high risk and 55.4% (n = 46) with moderate risk. Belonging to the very high-risk group was associated with a lower probability of achieving the control goal (OR: 0.32; 95%CI: 0.192-0.539). CONCLUSION: The combination of rosuvastatin + fenofibric acid is an effective option in patients with mixed dyslipidemia and high cardiovascular risk, providing a therapeutic alternative for those conditions that require it.
Asunto(s)
Dislipidemias , Fenofibrato , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Rosuvastatina Cálcica , Anciano , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Colombia , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/tratamiento farmacológico , Femenino , Fenofibrato/análogos & derivados , Fenofibrato/uso terapéutico , Fluorobencenos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Rosuvastatina Cálcica/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
IL-10 is an anti-inflammatory cytokine that plays a significant role in the modulation of the immune response in many pathological conditions, including infectious diseases. Infection with Trypanosoma cruzi (T. cruzi), the etiological agent of Chagas disease, results in an ongoing inflammatory response that may cause heart dysfunction, ultimately leading to heart failure. Given its infectious and inflammatory nature, in this work we analyzed whether the lack of IL-10 hinders the anti-inflammatory effects of fenofibrate, a PPARα ligand, in a murine model of Chagas heart disease (CHD) using IL-10 knockout (IL-10 KO) mice. Our results show fenofibrate was able to restore the abnormal cardiac function displayed by T. cruzi-infected mice lacking IL-10. Treatment with fenofibrate reduced creatine kinase (CK) levels in sera of IL-10 KO mice infected with T. cruzi. Moreover, although fenofibrate could not modulate the inflammatory infiltrates developing in the heart, it was able to reduce the increased collagen deposition in infected IL-10 KO mice. Regarding pro-inflammatory mediators, the most significant finding was the increase in serum IL-17. These were reduced in IL-10 KO mice upon fenofibrate treatment. In agreement with this, the expression of RORγt was reduced. Infection of IL-10 KO mice increased the expression of YmI, FIZZ and Mannose Receptor (tissue healing markers) that remained unchanged upon treatment with fenofibrate. In conclusion, our work emphasizes the role of anti-inflammatory mechanisms to ameliorate heart function in CHD and shows, for the first time, that fenofibrate attains this through IL-10-dependent and -independent mechanisms.
Asunto(s)
Cardiomiopatía Chagásica/tratamiento farmacológico , Fenofibrato/uso terapéutico , Hipolipemiantes/uso terapéutico , Interleucina-10/metabolismo , Miocardio/patología , Trypanosoma cruzi/fisiología , Tripanosomiasis/tratamiento farmacológico , Animales , Células Cultivadas , Cardiomiopatía Chagásica/inmunología , Creatina Quinasa/sangre , Modelos Animales de Enfermedad , Humanos , Interleucina-10/genética , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Tripanosomiasis/inmunología , Cicatrización de HeridasRESUMEN
Abstract Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE.
Resumo A glomerulopatia por lipoproteínas (GLP) é uma patologia rara que causa síndrome nefrótica e/ou insuficiência renal. Na microscopia, a GLP é caracterizada pela presença de trombos de lipoproteínas em capilares glomerulares dilatados devido a diferentes mutações no gene da ApoE. O gene da ApoE está localizado no cromossomo 19q13.2 e pode ser identificado em quase todas as lipoproteínas séricas. A ApoE age como fator de proteção na arterioesclerose por conta de sua interação com a depuração de lipoproteínas mediada por receptores e com o receptor de colesterol. Dentre os polimorfismos mais comuns destacam-se ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3 e ApoE4/4. A GLP pode acometer indivíduos de todas as faixas etárias, com discreta predominância do sexo masculino. Pacientes afetados tipicamente apresentam dislipidemia, hiperlipoproteinemia tipo III e proteinúria. O tratamento da GLP é conduzido com fenofibrato, antilipêmicos, corticosteroides, LDL-aferese, troca de plasma, antiplaquetários, anticoagulantes, uroquinase e transplante renal. Recidiva no enxerto renal indica a existência de componentes patogênicos do complexo humoral extraglomerular resultante de metabolismo lipoproteico anômalo, possivelmente associado a ApoE.
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Adulto , Persona de Mediana Edad , Enfermedades Renales/patología , Enfermedades Renales/terapia , Apolipoproteínas E/genética , Factores Sexuales , Trasplante de Riñón , Resultado del Tratamiento , Enfermedades Renales/complicaciones , Enfermedades Renales/genética , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/etiología , Mutación , Hipolipemiantes/uso terapéuticoRESUMEN
Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation. In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways. Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.
Asunto(s)
Cardiomiopatía Chagásica/tratamiento farmacológico , Fenofibrato/uso terapéutico , Nitroimidazoles/uso terapéutico , Tripanocidas/uso terapéutico , Disfunción Ventricular/tratamiento farmacológico , Animales , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/complicaciones , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Diástole/efectos de los fármacos , Fenofibrato/administración & dosificación , Fibrosis/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/parasitología , Inflamación/fisiopatología , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos BALB C , FN-kappa B/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Nitroimidazoles/administración & dosificación , Nitroimidazoles/efectos adversos , PPAR alfa/agonistas , Volumen Sistólico/efectos de los fármacos , Tripanocidas/administración & dosificación , Tripanocidas/efectos adversos , Trypanosoma cruzi/efectos de los fármacos , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Disfunción Ventricular/etiología , Función Ventricular/efectos de los fármacosRESUMEN
Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.
Asunto(s)
Angiotensina II/metabolismo , Antioxidantes/uso terapéutico , Fenofibrato/uso terapéutico , Resistencia a la Insulina/fisiología , Síndrome Metabólico/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Animales , Catalasa/sangre , Modelos Animales de Enfermedad , Insulina/sangre , Masculino , NADPH Oxidasa 4 , NADPH Oxidasas/sangre , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ratas , Ratas Wistar , Superóxido Dismutasa/sangre , Superóxido Dismutasa-1/sangre , Triglicéridos/sangreRESUMEN
Abstract The hypolipidemic activity of friedelin isolated from Azima tetracantha Lam., Salvadoraceae, was studied in Triton WR-1339 and high-fat diet-induced hyperlipidemic rats. In Triton WR-1339 induced hyperlipidemic rats, treatment with friedelin (50 and 70 mg/kg) showed a significant (p < 0.01) lipid-lowering effect as assessed by reversal of plasma levels of total cholesterol (TC), triacylglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). In high-fat diet fed hyperlipidemic rats, treatment with friedelin (50 and 70 mg/kg) caused lowering of lipid levels in plasma and liver. The hypolipidemic activity of friedelin was compared with fenofibrate, a known lipid-lowering drug, in both models.
RESUMEN
Fenofibrate is widely prescribed as a hypolipidemic drug and is well tolerated by most patients. We present the case of a 40-year-old woman who developed severe immune thrombocytopenia while on fenofibrate treatment. Clinical features included spontaneous bruising on the feet and hands, a purpuric rash, and menorrhagia. All the laboratory results were normal except for the finding of isolated thrombocytopenia. The subsequent evolution was favorable after fenofibrate removal and with the administration of immunoglobulin G (IgG) plus corticosteroids. Drug-induced thrombocytopenia is briefly reviewed, and a possible mechanism responsible for causing this side effect of fenofibrate is suggested. This is the first reported case of fenofibrate-induced immune thrombocytopenia.
Asunto(s)
Fenofibrato/efectos adversos , Hipolipemiantes/efectos adversos , Púrpura Trombocitopénica Idiopática/inducido químicamente , Adulto , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina G/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/fisiopatologíaRESUMEN
Several clinical trials have substantiated the efficacy of the co-administration of statins like atorvastatin (ATO) and fibrates. Without information currently available about the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the effect when both drugs were co-administered. The purpose of this study was to investigate the pharmacokinetic profile of tablets containing ATO 20 mg, or the combination of ATO 20 mg with fenofibrate (FNO) 160 mg administered to healthy Mexican volunteers. This was a randomized, two-period, two-sequence, crossover study; 36 eligible subjects aged between 20-50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for ATO as the reference and ATO and FNO as the test product for bioequivalence design. The estimation computed (90% confidence intervals) for ATO and FNO combination versus ATO for Cmax, AUC0-t and AUC0-∞, were 102,09, 125,95, and 120,97%, respectively. These results suggest that ATO and FNO have no relevant clinical-pharmacokinetic drug interaction.
RESUMEN
Browning is characterized by the formation of beige/brite fat depots in subcutaneous white adipose tissue (sWAT). This study aimed to examine whether the chronic activation of PPARalpha by fenofibrate could induce beige cell depots in the sWAT of diet-induced obese mice. High-fat fed animals presented overweight, insulin resistance and displayed adverse sWAT remodeling. Fenofibrate significantly attenuated these parameters. Treated groups demonstrated active UCP-1 beige cell clusters within sWAT, confirmed through higher gene expression of PPARalpha, PPARbeta, PGC1alpha, BMP8B, UCP-1, PRDM16 and irisin in treated groups. PPARalpha activation seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription, indicating that fenofibrate increased the expression of genes typical of brown adipose tissue (BAT) in the sWAT, characterizing the formation of beige cells. These findings put forward a possible role of PPARalpha as a promising therapeutic for metabolic diseases via beige cell induction.
Asunto(s)
Fármacos Antiobesidad/farmacología , Fenofibrato/farmacología , Obesidad/tratamiento farmacológico , Grasa Subcutánea/efectos de los fármacos , Animales , Fármacos Antiobesidad/uso terapéutico , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Tamaño de la Célula , Transdiferenciación Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Fenofibrato/uso terapéutico , Expresión Génica , Canales Iónicos/genética , Canales Iónicos/metabolismo , Leptina/sangre , Masculino , Ratones Endogámicos C57BL , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , PPAR alfa/agonistas , PPAR alfa/metabolismo , Grasa Subcutánea/patología , Proteína Desacopladora 1RESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The etiology and pathogenesis of PD are still unknown, however, many evidences suggest a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction. The peroxisome proliferator-activated receptor (PPAR) ligands, a member of the nuclear receptor family, have anti-inflammatory activity over a variety of rodent's models for acute and chronic inflammation. PPAR-α agonists, a subtype of the PPAR receptors, such as fenofibrate, have been shown a major role in the regulation of inflammatory processes. Animal models of PD have shown that neuroinflammation is one of the most important mechanisms involved in dopaminergic cell death. In addition, anti-inflammatory drugs are able to attenuate toxin-induced parkinsonism. In this study we evaluated the effects of oral administration of fenofibrate 100mg/kg 1h after infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the SNpc. First, we assessed the motor behavior in the open field for 24h, 7, 14 and 21 days after MPTP. Twenty-two days after surgery, the animals were tested for two-way active avoidance and forced swimming for evaluation regarding cognitive and depressive parameters, respectively. Twenty-three days after infusion of the toxin, we quantified DA and turnover and evaluated oxidative stress through the measurement of GSH (glutathione peroxidase), SOD (superoxide dismutase) and LOOH (hydroperoxide lipid). The data show that fenofibrate was able to decrease hypolocomotion caused by MPTP 24h after injury, depressive-like behavior 22 days after the toxin infusion, and also protected against decreased level of DA and excessive production of reactive oxygen species (ROS) 23 days after surgery. Thus, fenofibrate has shown a neuroprotective effect in the MPTP model of Parkinson's disease.