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1.
Medicine (Baltimore) ; 100(6): e24593, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578559

RESUMEN

BACKGROUND: The goals of improving quality of life and increasing longevity are receiving growing amounts of attention. Body weight and lipid metabolism are closely related to various complications of diabetes. The aim of this study was to rank SGLT inhibitors according to their efficacy with regard to weight and evaluate the effect of SGLT inhibitors on lipid metabolism at 24 weeks of treatment. METHODS: The Web of Science, PubMed, Cochrane Library, Embase, and Clinical Trials databases were electronically searched to collect randomized controlled trials involving patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the selected studies and extracted the outcome indexes. ADDIS 1.16.5 and STATA 16 software were used to perform the network meta-analysis and draw the plots. RESULTS: Ultimately, 36 studies were selected and included in this study. We found that all SGLT inhibitors were effective at reducing weight; canagliflozin was the most effective. SGLT inhibitors and placebo were not associated with significantly different serum cholesterol levels. SGLT inhibitors lowered serum triglyceride levels and increased serum high-density and low-density lipoprotein cholesterol levels. SGLT inhibitors also reduced the level of alanine aminotransferase. CONCLUSIONS: SGLT inhibitors can bring about weight loss in patients with T2DM and can also improve lipid metabolism. Therefore, patients with hyperlipidemia who have been unsuccessful at losing weight should consider taking SGLT inhibitors. In addition, SGLT inhibitors are hepatoprotective and appear to be safe for patients with mild to moderate liver dysfunction. TRIAL REGISTRATION: CRD42020198516.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Peso Corporal/efectos de los fármacos , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
2.
Nat Commun ; 12(1): 76, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397953

RESUMEN

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.


Asunto(s)
Inflamación/inmunología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células Th17/inmunología , Animales , Autoinmunidad/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Enfermedad Crónica , Colon/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Células HEK293 , Humanos , Inflamación/genética , Ratones Endogámicos C57BL , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Tamaño de los Órganos/efectos de los fármacos , Índice de Severidad de la Enfermedad , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tiofenos/química , Tiofenos/farmacología
3.
Nat Commun ; 12(1): 102, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397994

RESUMEN

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.


Asunto(s)
Tejido Adiposo/metabolismo , Sistemas de Liberación de Medicamentos , Macrófagos/metabolismo , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Hígado Graso/genética , Hígado Graso/patología , Inflamación/genética , Inflamación/patología , Resistencia a la Insulina , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Obesidad/genética , Obesidad/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Pérdida de Peso/efectos de los fármacos
4.
Ecotoxicol Environ Saf ; 208: 111608, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396128

RESUMEN

Lead (Pb) is one of the most toxic heavy metal environmental pollutants due to its widespread use of the industry and it is a harmful substance for human and animal health. This study was conducted to investigate the potential protective effects of ellagic acid (EA) on performance, egg quality, antioxidant parameters, and apoptotic pathway proteins in laying quails exposed to Pb toxicity. A total of 168 (15-week old) laying quails (Coturnix coturnix Japonica) were divided into 6 experimental groups (with similar initial average body weight). Birds were fed 1 of 6 diets for 8 weeks: 1 - Control (basal diet), 2 - Pb (basal diet + 100 mg/kg Pb), 3 - EA-300 (basal diet + 300 mg/kg EA), 4 - EA-500 (basal diet + 500 mg/kg EA), 5 - Pb + EA-300 (basal diet + 100 mg/kg Pb + 300 mg/kg EA), 6 - Pb + EA-500 (basal diet + 100 mg/kg Pb + 500 mg/kg EA). The results showed that adding 100 mg/kg of Pb to basal diet was adversely affected the performance parameters and, feed intake and egg production were significantly decreased by Pb supplementation (P < 0.01). However, the EA supplementation to Pb groups improved the performance parameters. Compared with the Pb alone group, in Pb + EA-500 group increased egg production by 8.4%. There were no significant differences in the Haugh unit, albumen index, and yolk index among groups (P > 0.05). Liver and kidney tissues of Pb group malondialdehyde (MDA) level increased (P < 0.001) and, GSH, GSH-Px, and CAT values decreased (P < 0.001) but, EA supplementation alleviated this condition (P < 0.001). The protein levels of caspase-3 and -9 were significantly increased in the Pb group compared to the control group, whereas EA supplementation alleviated the Pb-induced apoptosis by decreasing caspase-3 and -9 levels in the liver tissue (p < 0.001). In laying quails exposed to Pb toxicity, EA supplementation improves the performance parameters, enhances the antioxidant defense system, and suppresses apoptosis via regulates the expression of caspase-3 and -9. Thus, it was concluded that EA (especially 500 mg/kg) can ameliorate the toxic effects of Pb exposure in quails.


Asunto(s)
Apoptosis/efectos de los fármacos , Coturnix/metabolismo , Ácido Elágico/farmacología , Plomo/toxicidad , Óvulo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Alimentación Animal , Animales , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Coturnix/crecimiento & desarrollo , Suplementos Dietéticos , Ácido Elágico/metabolismo , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Malondialdehído/metabolismo , Óvulo/metabolismo
5.
Eur J Endocrinol ; 184(2): 253-265, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33513125

RESUMEN

Background: Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. Methods: An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. Results: Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15-20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (-1.23 kg, P = 0.006) and BMI (-0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. Conclusion: Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.


Asunto(s)
Insuficiencia Suprarrenal/tratamiento farmacológico , Sistema Cardiovascular/efectos de los fármacos , Terapia de Reemplazo de Hormonas/métodos , Hidrocortisona/administración & dosificación , Calidad de Vida , Insuficiencia Suprarrenal/epidemiología , Insuficiencia Suprarrenal/fisiopatología , Insuficiencia Suprarrenal/psicología , Adulto , Peso Corporal/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Estudios Cruzados , Preparaciones de Acción Retardada , Formas de Dosificación , Esquema de Medicación , Femenino , Humanos , Hidrocortisona/farmacocinética , Irlanda , Masculino , Persona de Mediana Edad , Prioridad del Paciente/estadística & datos numéricos , Calidad de Vida/psicología
6.
Cochrane Database Syst Rev ; 1: CD007654, 2021 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-33454957

RESUMEN

BACKGROUND: This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES: Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. SELECTION CRITERIA: Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. MAIN RESULTS: This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.


Asunto(s)
Fármacos Antiobesidad/efectos adversos , Depresores del Apetito/efectos adversos , Hipertensión/tratamiento farmacológico , Adulto , Fármacos Antiobesidad/uso terapéutico , Depresores del Apetito/uso terapéutico , Sesgo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bupropión/efectos adversos , Bupropión/uso terapéutico , Dieta Reductora , Combinación de Medicamentos , Femenino , Fructosa/efectos adversos , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Humanos , Hipertensión/mortalidad , Lactonas/efectos adversos , Lactonas/uso terapéutico , Masculino , Persona de Mediana Edad , Naltrexona/efectos adversos , Naltrexona/uso terapéutico , Orlistat/efectos adversos , Orlistat/uso terapéutico , Fentermina/efectos adversos , Fentermina/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Retirada de Medicamento por Seguridad , Tiempo , Topiramato/efectos adversos , Topiramato/uso terapéutico
7.
Nat Commun ; 12(1): 443, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33500411

RESUMEN

Exposure to antibiotics in the first days of life is thought to affect various physiological aspects of neonatal development. Here, we investigate the long-term impact of antibiotic treatment in the neonatal period and early childhood on child growth in an unselected birth cohort of 12,422 children born at full term. We find significant attenuation of weight and height gain during the first 6 years of life after neonatal antibiotic exposure in boys, but not in girls, after adjusting for potential confounders. In contrast, antibiotic use after the neonatal period but during the first 6 years of life is associated with significantly higher body mass index throughout the study period in both boys and girls. Neonatal antibiotic exposure is associated with significant differences in the gut microbiome, particularly in decreased abundance and diversity of fecal Bifidobacteria until 2 years of age. Finally, we demonstrate that fecal microbiota transplant from antibiotic-exposed children to germ-free male, but not female, mice results in significant growth impairment. Thus, we conclude that neonatal antibiotic exposure is associated with a long-term gut microbiome perturbation and may result in reduced growth in boys during the first six years of life while antibiotic use later in childhood is associated with increased body mass index.


Asunto(s)
Antibacterianos/efectos adversos , Infecciones Bacterianas/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Trastornos del Crecimiento/inducido químicamente , Animales , Estatura/efectos de los fármacos , Estatura/fisiología , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Niño , Preescolar , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Heces/microbiología , Femenino , Estudios de Seguimiento , Microbioma Gastrointestinal/fisiología , Vida Libre de Gérmenes , Trastornos del Crecimiento/microbiología , Trastornos del Crecimiento/fisiopatología , Humanos , Recién Nacido , Mucosa Intestinal/microbiología , Masculino , Ratones , Embarazo , Factores de Riesgo , Factores Sexuales
8.
J Cell Mol Med ; 25(4): 2279-2284, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33421348

RESUMEN

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.


Asunto(s)
Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Hipoglucemiantes/farmacología , Metformina/farmacología , Obesidad/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Animales , Asma/inmunología , Asma/patología , Peso Corporal/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Linfocito CD4 , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Humanos , Inflamación , Interleucina-4/antagonistas & inhibidores , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Obesidad/inmunología , Obesidad/patología , Ovalbúmina/administración & dosificación , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
9.
Eur J Endocrinol ; 184(2): 267-276, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33434161

RESUMEN

Objective: The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design: Ongoing, open-label, observational registry (NCT00903110). Methods: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.


Asunto(s)
Trastornos del Crecimiento/tratamiento farmacológico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Estatura , Peso Corporal/efectos de los fármacos , Niño , Femenino , Crecimiento/efectos de los fármacos , Humanos , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Síndrome de Laron/genética , Estudios Longitudinales , Masculino , Seguridad del Paciente , Pubertad , Resultado del Tratamiento , Adulto Joven
10.
Life Sci ; 265: 118769, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33309717

RESUMEN

AIMS: Investigate the role of melatonin on the regulation of body temperature in aged animals that have impaired melatonin production. MATERIAL AND METHODS: Aged Male Wistar rats were randomly assigned to the following groups: 1) control (vehicle added to the water bottles during the dark phase) and 2) melatonin-treated (10 mg/kg melatonin added to the water bottles during the dark phase). Before and after 16 weeks of vehicle or melatonin treatment, control group and melatonin-treated animals were acutely exposed to 18 °C for 2 h for an acute cold challenge and thermal images were obtained using an infrared camera. After 16 weeks, animals were euthanized and brown and beige adipocytes were collected for analysis of genes involved in the thermogenesis process by real-time PCR, and the uncoupling protein expression was evaluated by immunoblotting. Browning intensity of beige adipocytes were quantified by staining with hematoxylin-eosin. KEY FINDINGS: Chronic melatonin supplementation induced a minor increase in body mass and increased the animal's thermogenic potential in the cold acute challenge. Brown and beige adipocytes acted in a coordinated and complementary way to ensure adequate heat production. SIGNIFICANCE: Melatonin plays an important role in the thermoregulatory mechanisms, ensuring greater capacity to withstand cold and, also, participating in the regulation of energy balance.


Asunto(s)
Regulación de la Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Respuesta al Choque por Frío/efectos de los fármacos , Suplementos Dietéticos , Melatonina/farmacología , Animales , Frío/efectos adversos , Immunoblotting , Masculino , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa
11.
Chemosphere ; 262: 128009, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33182144

RESUMEN

Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of individuals in subsequent generations. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of Bisphenol A (BPA) which is an endocrine disruptor. However, the lack of efficient evaluation of BPS leaves doubts about the relevant substitute of BPA. Few studies of transgenerational inheritance have examined the effects of environmental exposures to endocrine disruptors on the immune system. In this study, we analyzed the transgenerational effects of BPS on intestinal inflammation and its consequence in metabolism. In this study, only F0 pregnant mice were exposed to BPS (1.5 µg/kg bw/day) from gestational day 0 until weaning of offspring. In this work, both F1 and F2 male offspring developed an inflammatory response in the ileum and colon at adulthood after F0 mothers were exposed to BPS; this phenomenon disappeared in F3. This inflammatory response in F1 male offspring is associated with a significant decrease of blood cholesterol without modification of metabolic status. Further, in F3 offspring male, the decrease of gut inflammatory response is associated with a decrease of fat weight and with an increase of blood glucose and cholesterol level. A sex-specific profile is observed in female offspring. We also observed that early life exposure to BPS was associated with strong abnormal intestinal immune status. The study presented here demonstrates that the immune system, like other organ systems, is vulnerable to transgenerational effects caused by environmental exposures.


Asunto(s)
Citocinas/análisis , Disruptores Endocrinos/toxicidad , Intestinos/inmunología , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Sulfonas/toxicidad , Animales , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Heces/química , Femenino , Inflamación , Intestinos/crecimiento & desarrollo , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología
12.
Aquat Toxicol ; 231: 105722, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33360311

RESUMEN

The current study investigated the effect of environmentally relevant mixtures of estrogens at levels representative of receiving waters on the metabolome of the Sydney rock oyster, Saccostrea glomerata. Oysters were exposed to a "low" and a "high" mixture of (xeno) estrogens (representative of Australian and global receiving waters respectively) for 7 days and digestive gland, gill, and gonad tissue were sampled for quantification of polar metabolites by 1H NMR spectroscopy. Exposure to both mixtures lowered body mass and altered the metabolite profile in the digestive glands. Comparatively, gills, and ovaries demonstrated lesser sensitivity to the mixtures, with significant metabolomic alterations observed only for the high mixture. The male gonad did not respond to either estrogenic exposure. In the responsive tissues, major metabolites including amino acids, carbohydrates, intermediates of the tricarboxylic acid cycle and ATP were all down-regulated and exhibited tissue-specific patterns of down-regulation with the greatest proportion of metabolites down-regulated due to estrogenic exposure in the digestive gland. Exposure to (xeno) estrogen mixtures representative of concentrations reported in receiving waters in Australia and globally can impact the metabolome and associated energy metabolism, especially in the digestive gland, translating to lower pools of available ATP energy for potential cellular homeostasis, somatic maintenance and growth, reproduction and fitness.


Asunto(s)
Exposición a Riesgos Ambientales , Estrógenos/toxicidad , Metaboloma/efectos de los fármacos , Especificidad de Órganos , Ostreidae/metabolismo , Animales , Australia , Peso Corporal/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de los fármacos , Femenino , Glucólisis/efectos de los fármacos , Masculino , Metabolómica , Ostreidae/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/metabolismo , Razón de Masculinidad , Testículo/efectos de los fármacos , Testículo/metabolismo , Contaminantes Químicos del Agua/toxicidad
13.
J Ethnopharmacol ; 266: 113461, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33039625

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine, which is composed of ten herbal drugs and two animal drugs. It has long been used for the treatment of diabetic peripheral neuropathy (DPN). AIM OF STUDY: Wnt/ß-catenin pathway is considered as an essential and direct driver of myelinogenesis. This study aims to evaluate the protective effect of JMT against DPN dynamically during a 16-weeks' treatment, and to investigate the underlying mechanism in which the Wnt/ß-catenin pathway is involved. MATERIALS AND METHODS: Diabetic model was induced by single intraperitoneal injection of Streptozotocin (STZ) using male Sprague-Dawley rats. The model rats were divided into five groups and administrated with JMT at three doses (0.437, 0.875, and 1.75 g/kg per day), neurotropin (positive drug, 2.67 NU/kg per day), and placebo (deionized water), respectively, for continuous 8 weeks (n = 9-10), 12 weeks (n = 8-10), or 16 weeks (n = 7-9). Meanwhile, rats in control group were administrated with placebo (n = 10 for 8 weeks, n = 9 for 12 and 16 weeks, respectively). Blood glucose and body weight were monitored every four weeks. Mechanical allodynia was assessed using mechanical withdrawal threshold (MWT) test. The morphological change of sciatic nerves were observed by transmission electron microscope (TEM) and hematoxylin and eosin (HE) stain. The mRNA and protein levels of targeted genes were evaluated by quantitative real time-PCR and western bolt, respectively. Myelin protein zero (MPZ) and mediators involved in Wnt/ß-catenin pathway, such as ß-catenin, glycogen synthase kinase 3ß (GSK-3ß), and WNT inhibitory factor-1 (WIF-1), were compared among different groups after treatment of 8, 12, and 16 weeks, respectively. RESULTS: The mechanical allodynia and peripheral nerve morphology were degenerated in DPN rats over time, and notably improved after JMT-treatment of 12 and 16 weeks. The decreased MPZ level in DPN rats were also significantly amended by JMT. More importantly, we found that the suppressed Wnt/ß-catenin pathway in sciatic nerves of DPN rats was overtly up-regulated by JMT in a time-dependent manner. Among the three doses, JMT at the middle dose showed the best effect. CONCLUSIONS: JMT effectively ameliorated diabetic-induced peripheral neuropathy, which was mediated by the activation of Wnt/ß-catenin signaling pathway. This study provided new perspective to understand the neuroprotective mechanism of JMT.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/fisiopatología , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Estreptozocina
14.
PLoS One ; 15(12): e0240070, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33382700

RESUMEN

Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18-19%), and its precursor, glutamine (17-22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.


Asunto(s)
Aprendizaje por Asociación/efectos de los fármacos , Encéfalo/efectos de los fármacos , Función Ejecutiva/efectos de los fármacos , Metaboloma/efectos de los fármacos , Nitratos/farmacología , Nitrito de Sodio/farmacología , Animales , Ansiedad/inducido químicamente , Ansiedad/psicología , Ácido Araquidónico/antagonistas & inhibidores , Ácido Araquidónico/metabolismo , Conducta Animal/efectos de los fármacos , Tamaño Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Epinefrina/metabolismo , Femenino , Glutamina/metabolismo , Ácido Linoleico/antagonistas & inhibidores , Ácido Linoleico/metabolismo , Masculino , Metaboloma/fisiología , Norepinefrina/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Refuerzo en Psicología , Pez Cebra/metabolismo , Ácido gamma-Aminobutírico/metabolismo
15.
PLoS One ; 15(12): e0243846, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33315911

RESUMEN

Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.


Asunto(s)
Antihipertensivos/uso terapéutico , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Hidralazina/uso terapéutico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol en la Dieta , Citocinas/sangre , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Hidralazina/administración & dosificación , Hidralazina/farmacología , Hipertensión/fisiopatología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinasas de la Matriz/sangre , Modelos Biológicos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Inhibidor Tisular de Metaloproteinasa-1/sangre
16.
Nat Commun ; 11(1): 5808, 2020 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-33199701

RESUMEN

Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.


Asunto(s)
Biocatálisis , Homeostasis , Metabolismo , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Transducción de Señal , Adipocitos Blancos/efectos de los fármacos , Adipocitos Blancos/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Biocatálisis/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Línea Celular , Tamaño de la Célula/efectos de los fármacos , Genotipo , Glucosa/farmacología , Homeostasis/efectos de los fármacos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Células Musculares/citología , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Proteína de Unión al GTP rac1/metabolismo
17.
Nat Commun ; 11(1): 5145, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33051459

RESUMEN

Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.


Asunto(s)
Metabolismo Energético/efectos de los fármacos , Grasas/metabolismo , Leptina/administración & dosificación , Obesidad/tratamiento farmacológico , Delgadez/tratamiento farmacológico , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Adulto , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Energía , Femenino , Humanos , Masculino , Obesidad/metabolismo , Obesidad/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Delgadez/metabolismo , Delgadez/fisiopatología , Adulto Joven
18.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020469

RESUMEN

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Asunto(s)
Adipocitos/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Peso Corporal/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , Receptores de la Hormona Gastrointestinal/deficiencia , Receptores de la Hormona Gastrointestinal/metabolismo
19.
Life Sci ; 261: 118364, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-32866516

RESUMEN

AIMS: Prenatal hypoxia (PH) could affect peripheral vascular tone of the offspring, thus increasing the risk of cardiovascular diseases in adult. However, it's still unknown whether functions of coronary arteries (COA) in adult offspring would be influenced by PH. The present study aimed at effects of PH on vascular tone of COA and its related mechanisms. METHODS: Coronary arteries of adult offspring exposed to hypoxic or normoxic circumstances during gestational day 5 to 21 were collected. Wire myograph system, whole-cell patch clamp technique, IonOptix MyoCam system, PCR, and western blot were used to detect vascular function of adult offspring COA. KEY FINDINGS: PH significantly attenuated serotonin- and phorbol 12, 13-dibutyrate (PDBu)-induced constriction. Iberiotoxin potentiated PDBu-induced constriction and the effect was augmented by PH, however, no significant differences were found in whole-cell BKCa channel currents and its protein expression. Nifedipine inhibited PDBu-mediated constriction and the inhibitory effect was reduced in PH group, and whole-cell calcium channel current was decreased in offspring COA. Besides, PH reduced the capability of calcium release from the endoplasmic reticulum in COA. The phosphorylated PKCß protein expression at Ser660 site, not Thr641 site, was significantly decreased in PH offspring. Chronic hypoxia during pregnancy attenuated PDBu-mediated constriction in offspring COA, presumably through decreased phosphorylated PKCß at serine660 sites and decreased intracellular calcium-related weaker PKC activation. SIGNIFICANCE: The findings provided new information on the influence of prenatal hypoxia on COA, and suggested potential use of PKCß-serine660 for early prevention of coronary heart diseases in developmental origins.


Asunto(s)
Calcio/metabolismo , Vasos Coronarios/fisiopatología , Hipoxia/complicaciones , Espacio Intracelular/metabolismo , Fosfoserina/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Proteína Quinasa C beta/metabolismo , Vasoconstricción , Animales , Peso Corporal/efectos de los fármacos , Cafeína/farmacología , Canales de Calcio/metabolismo , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Femenino , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Embarazo , Ratas Sprague-Dawley , Serotonina/metabolismo , Acetato de Tetradecanoilforbol
20.
Life Sci ; 261: 118353, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-32877649

RESUMEN

AIMS: Polycystic ovary syndrome (PCOS) is a widespread chronic reproductive disorder that is associated with metabolic disturbances. Traditionally, the marjoram plant is well-known to restore hormonal balance and regulate the menstrual cycle. We aimed to investigate the ameliorative effects of marjoram extract on hormonal profiles, body and ovaries weight, insulin sensitivity, inflammation, and oxidative stress in a rat model of PCOS. MAIN METHODS: A 75 postpubertal (42 days old) female Wistar rats were randomly assigned into five groups (control, dehydroepiandrosterone (DHEA) induced-PCOS model, marjoram-treated PCOS rats, metformin-treated PCOS rats and the combination of marjoram+metfomin treated PCOS model). PCOS induction was performed by subcutaneous injection of DHEA 60 mg/kg daily for 24 days. Ovaries weight, adiponectin, hormonal levels, inflammatory, and oxidative stress biomarker levels were measured at the end of the treatment period using ELISA assay. KEY FINDINGS: The current study showed that marjoram significantly decreased ovaries' weight and the estradiol levels (P-value<0.05) compared to the DHEA group. Interestingly, marjoram improved insulin sensitivity as manifested by a significant increase in the adiponectin serum levels (P-value<0.05). Marjoram alone or in combination with metformin prominently decreased the IL-6 level and improved the levels of ovarian SOD and GPx enzymes (P-value<0.05). Additionally, the group treated with the combination of marjoram and metformin remarkably decreased the level of TBARS (P-value<0.05). SIGNIFICANCE: The present study established the beneficial effects of marjoram administration on DHEA-induced PCOS in female Wistar rats. The mechanistic effect includes improvement in the hormonal levels, ovaries weight, insulin sensitivity, antioxidants, and anti-inflammatory parameters.


Asunto(s)
Origanum/química , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Adiponectina/sangre , Animales , Biomarcadores/sangre , Peso Corporal/efectos de los fármacos , Deshidroepiandrosterona , Femenino , Hormonas Esteroides Gonadales/sangre , Mediadores de Inflamación/sangre , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/patología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Síndrome del Ovario Poliquístico/sangre , Ratas Wistar
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