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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802633

RESUMEN

The current study was designed to investigate the protective role of diosmin against cyclophosphamide-induced premature ovarian insufficiency (POI). Female Swiss albino rats received a single intraperitoneal dose of cyclophosphamide (200 mg/kg) followed by 8 mg/kg/day for the next 15 consecutive days either alone or in combination with oral diosmin at 50 or 100 mg/kg. Histopathological examination of ovarian tissues, hormonal assays for follicle stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH), assessment of the oxidative stress status, as well as measurement of the relative expression of miRNA-145 and its target genes [vascular endothelial growth factor B (VEGF-B) and regulator of cell cycle (RGC32)] were performed. Diosmin treatment ameliorated the levels of E2, AMH, and oxidative stress markers. Additionally, both low and high diosmin doses significantly reduced the histopathological alterations and nearly preserved the normal ovarian reserve. MiRNA-145 expression was upregulated after treatment with diosmin high dose. miRNA-145 target genes were over-expressed after both low and high diosmin administration. Based on our findings, diosmin has a dose-dependent protective effect against cyclophosphamide-induced ovarian toxicity in rats.


Asunto(s)
Diosmina/uso terapéutico , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Caspasa 3/metabolismo , Catalasa/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Colágeno/metabolismo , Ciclofosfamida , Diosmina/farmacología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hormonas/sangre , Malondialdehído/sangre , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/patología , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Ovárica Primaria/sangre , Insuficiencia Ovárica Primaria/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Nutrients ; 13(2)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670347

RESUMEN

Epigallocatechin-3-gallate (EGCG) has been shown to attenuate obesity, fatty liver disease, hepatic inflammation and lipid profiles. Here, we validate the efficacy of EGCG in a murine model of non-alcoholic fatty liver disease (NAFLD) and extend the mechanistic insights. NAFLD was induced in mice by a high-fat diet (HFD) with 30% fructose. EGCG was administered at a low dose (25 mg/kg/day, EGCG-25) or high dose (50 mg/kg/day, EGCG-50) for 8 weeks. In HFD-fed mice, EGCG attenuated body and liver weight by ~22% and 47%, respectively, accompanied by ~47% reduction in hepatic triglyceride (TG) accumulation and ~38% reduction in serum cholesterol, resonating well with previous reports in the literature. In EGCG-treated mice, the hepatic steatosis score and the non-alcoholic steatohepatitis activity score were both reduced by ~50% and ~57%, respectively, accompanied by improvements in hepatic inflammation grade. Liver enzymes were improved ~2-3-fold following EGCG treatment, recapitulating previous reports. Hepatic flow cytometry demonstrated that EGCG-fed mice had lower Ly6C+, MHCII+ and higher CD206+, CD23+ hepatic macrophage infiltration, indicating that EGCG impactedM1/M2 macrophage polarization. Our study further validates the salubrious effects of EGCG on NAFLD and sheds light on a novel mechanistic contribution of EGCG, namely hepatic M1-to-M2 macrophage polarization. These findings offer further support for the use of EGCG in human NAFLD.


Asunto(s)
Catequina/análogos & derivados , Lípidos/sangre , Hígado/efectos de los fármacos , Macrófagos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Tejido Adiposo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Catequina/administración & dosificación , Colesterol/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hígado/patología , Hígado/fisiopatología , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Tamaño de los Órganos/efectos de los fármacos
3.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668635

RESUMEN

Launaea nudicaulis is used in folk medicine worldwide to treat several diseases. The present study aimed to assess the antidiabetic activity of L. nudicaulis ethanolic extract and its effect on diabetic complications in streptozotocin-induced hyperglycemic rats. The extract was orally administrated at 250 and 500 mg/kg/day for 5-weeks and compared to glibenclamide as a reference drug at a dose of 5 mg/kg/day. Administration of the extract exhibited a potential hypoglycemic effect manifested by a significant depletion of serum blood glucose concurrent with a significant elevation in serum insulin secretion. After 5-weeks, extract at 250 and 500 mg/kg/day decreased blood glucose levels by about 53.8 and 68.1%, respectively, compared to the initial values (p ≤ 0.05). The extract at the two dosages prevented weight loss of rats from the 2nd week till the end of the experiment, compared to diabetic control rats. The extract further exhibited marked improvement in diabetic complications including liver, kidney and testis performance, oxidative stress, and relative weight of vital organs, with respect to diabetic control. Histopathological examinations confirmed the previous biochemical analysis, where the extract showed a protective effect on the pancreas, liver, kidney, and testis that degenerated in diabetic control rats. To characterize extract composition, UPLC-ESI-qTOF-MS identified 85 chromatographic peaks belonging to flavonoids, phenolics, acyl glycerols, nitrogenous compounds, and fatty acids, with four novel phenolics reported. The potential anti-diabetic effect warrants its inclusion in further studies and or isolation of the main bioactive agent(s).


Asunto(s)
Asteraceae/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Etanol/química , Hipoglucemiantes/uso terapéutico , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Animales , Antioxidantes/metabolismo , Biomarcadores/sangre , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/farmacología , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/fisiopatología , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Malondialdehído/sangre , Metabolómica , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas Wistar , Estreptozocina , Pruebas de Toxicidad Aguda
4.
Molecules ; 26(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671428

RESUMEN

The potential biological activities of Viburnum stellato-tomentosum (VS), a plant mainly found in Costa Rica, have yet to be reported. Supplementation of VS extract for 17 weeks significantly decreased body weight gain, fat weight, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride levels in high-fat diet (HFD)-fed C57BL/6J mice. The molecular mechanisms underlying the anti-obesity and glucose-lowering effects of VS extract were investigated. VS extract suppressed adipocyte hypertrophy by regulating lipogenesis-related CCAAT/enhancer-binding protein α (C/EBPα) and insulin sensitivity-related peroxisome proliferator-activated receptor γ (Pparg) expression in adipose tissue (AT) and hepatic steatosis by inhibiting C/EBPα and lipid transport-related fatty acid binding protein 4 (FABP4) expression. VS extract enhanced muscular fatty acid ß-oxidation-related AMP-activated protein kinase (AMPK) and PPARα expression with increasing Pparg levels. Furthermore, VS extract contained a much higher content of amentoflavone (AMF) (29.4 mg/g extract) compared to that in other Viburnum species. AMF administration decreased Cebpa and Fabp4 levels in the AT and liver, as well as improved insulin signaling-related insulin receptor substrate 1 (Irs1) and glucose transporter 1 (Glut1) levels in the muscle of HFD-fed mice. This study elucidated the in vivo molecular mechanisms of AMF for the first time. Therefore, VS extract effectively diminished obesity and hyperglycemia by suppressing C/EBPα-mediated lipogenesis in the AT and liver, enhancing PPARα-mediated fatty acid ß-oxidation in muscle, and PPARγ-mediated insulin sensitivity in AT and muscle.


Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Dieta Alta en Grasa , Hiperglucemia/tratamiento farmacológico , Metabolismo de los Lípidos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Extractos Vegetales/uso terapéutico , Viburnum/química , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Adipogénesis/efectos de los fármacos , Tejido Adiposo Blanco/patología , Animales , Fármacos Antiobesidad/farmacología , Biflavonoides/farmacología , Peso Corporal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Hígado Graso/sangre , Hígado Graso/complicaciones , Hígado Graso/tratamiento farmacológico , Conducta Alimentaria , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis/efectos de los fármacos , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Hipertrofia , Insulina/metabolismo , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Obesidad/sangre , Obesidad/complicaciones , Tamaño de los Órganos/efectos de los fármacos , Oxidación-Reducción , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos
5.
BMC Cancer ; 21(1): 200, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637083

RESUMEN

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/prevención & control , Carcinoma Ductal Pancreático/secundario , Adhesión Celular/efectos de los fármacos , Agregación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Células Madre Neoplásicas/patología , Tamaño de los Órganos/efectos de los fármacos , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/prevención & control , Neoplasias Peritoneales/secundario , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Peritoneo/patología , Peritonitis/tratamiento farmacológico , Peritonitis/patología
6.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-33562323

RESUMEN

Aggressive chemotherapy treatment may lead to male infertility. Prepubertal boys do not produce sperm at this age, however, they have spermatogonial stem cells in their testes. Here, we examined the effect of intraperitoneal injection of cyclophosphamide (CP) on the capacity of immature mice (IM) to develop spermatogenesis in vivo and in vitro [using methylcellulose culture system (MCS)]. Our results show a significant decrease in testicular weight, total number of testicular cells, and the number of Sertoli, peritubular, premeiotic, and meiotic/post-meiotic cells, but an increase in the percentages of damaged seminiferous tubules in CP-treated IM compared to control. The functionality of Sertoli cells was significantly affected. The addition of testosterone to isolated cells from seminiferous tubules of CP-treated IM significantly increased the percentages of premeiotic (CD9-positive cells) and meiotic/post-meiotic cells (ACROSIN-positive cells) developed in MCS compared to control. The addition of FSH did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly decreased the percentages of CD9-positive cells and ACROSIN-positive cells. The addition of IL-1 did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly increased the percentages of VASA-positive cells and BOULE-positive cells compared to IL-1 or testosterone. Addition of TNF significantly increased only CD9-positive cells in MCS compared to control, but in combination with testosterone, it significantly decreased ACROSIN-positive cells compared to testosterone. Our results show a significant impairment of spermatogenesis in the testes of CP-treated IM, and that spermatogonial cells from these mice proliferate and differentiate to meiotic/post-meiotic cells under in vitro culture conditions.


Asunto(s)
Ciclofosfamida/toxicidad , Citocinas/farmacología , Hormonas/farmacología , Infertilidad Masculina/patología , Tamaño de los Órganos/efectos de los fármacos , Espermatogénesis , Espermatogonias/patología , Animales , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Técnicas In Vitro , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/metabolismo , Integrina alfa6/genética , Integrina alfa6/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Mutágenos/toxicidad , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismo , Tetraspanina 29/genética , Tetraspanina 29/metabolismo
7.
Nat Commun ; 12(1): 1118, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602914

RESUMEN

Modern biomedical research and preclinical pharmaceutical development rely heavily on the phenotyping of small vertebrate models for various diseases prior to human testing. In this article, we demonstrate an acoustofluidic rotational tweezing platform that enables contactless, high-speed, 3D multispectral imaging and digital reconstruction of zebrafish larvae for quantitative phenotypic analysis. The acoustic-induced polarized vortex streaming achieves contactless and rapid (~1 s/rotation) rotation of zebrafish larvae. This enables multispectral imaging of the zebrafish body and internal organs from different viewing perspectives. Moreover, we develop a 3D reconstruction pipeline that yields accurate 3D models based on the multi-view images for quantitative evaluation of basic morphological characteristics and advanced combinations of metrics. With its contactless nature and advantages in speed and automation, our acoustofluidic rotational tweezing system has the potential to be a valuable asset in numerous fields, especially for developmental biology, small molecule screening in biochemistry, and pre-clinical drug development in pharmacology.


Asunto(s)
Acústica , Rotación , Pez Cebra/anatomía & histología , Animales , Etanol/farmacología , Imagenología Tridimensional , Larva/anatomía & histología , Larva/efectos de los fármacos , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fenotipo , Transductores
8.
Trop Anim Health Prod ; 53(1): 83, 2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33411117

RESUMEN

This experiment examines the effects of bamboo charcoal (BC) powder, bamboo vinegar (BV), and their combination (BCV) in the diet of laying hens on performance, egg quality, relative organ weights, and intestinal bacterial populations. A total of 320 laying hens (36 weeks of age) were divided into 4 treatment groups, with 10 replicates per treatment and 8 hens per replicate. They were fed on a control diet, the control diet supplemented with 0.8% BC, the control diet supplemented with 0.4% BV, or the control diet supplemented with a combination of BC (0.8%) and BV (0.4%) from 36 to 51 weeks of age. Egg production increased in the hens fed the BV and BCV diets during 48 to 51 weeks of age (P < 0.05). Damaged egg rate decreased in the hens fed the BV and BCV diets for the whole experiment (P < 0.05). Shell thickness was highest in the BCV-fed group at week 43, and shell strength was higher in the BV-fed group at week 51 (P < 0.05). Supplementation of BC or BCV in the diet resulted in a decreased abdominal fat pad (P < 0.05). In the ileal content, the population of Salmonella spp. decreased in the BV and BCV groups and the population of Lactobacillus spp. increased in the BV group (P < 0.05). The present results indicate that feeding BV or BCV alleviates damaged egg rate and decreases intestinal pathogenic bacteria, while feeding BC benefits by reducing abdominal fat. These results suggest that the effect of BCV seems to be induced by the synergistic effect of BC and BV, and that the BCV contributes to the effective use of bamboo on the laying hen's production.


Asunto(s)
Ácido Acético/metabolismo , Carbón Orgánico/metabolismo , Pollos/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Óvulo/efectos de los fármacos , Poaceae/química , Ácido Acético/administración & dosificación , Alimentación Animal/análisis , Animales , Bacterias/efectos de los fármacos , Carbón Orgánico/administración & dosificación , Dieta/veterinaria , Suplementos Dietéticos/análisis , Femenino , Polvos/administración & dosificación , Polvos/metabolismo , Distribución Aleatoria
9.
Poult Sci ; 100(3): 100831, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33516471

RESUMEN

The objective of this study was to investigate the effects in ovo injection of black cumin (BC) extract on chick's quality and response of thermally challenged broiler chickens. A total of 700 hatching eggs of broiler chickens (Marshall) were assigned to 7 treatments of 100 eggs each and incubated using the conventional protocol (37.8°C) for the first 10 d and then exposed to a high temperature (39.6°C) for 6 h daily from day 10 until day 18 of the incubation. At embryonic day 17.5, the eggs were randomly allotted to 7 treatment groups, viz.: eggs without in ovo injection (WA), eggs injected with 0.9% saline solution (SA), 3 mg ascorbic acid (AA), 2 mg BC (TB), 4 mg BC (FB), 6 mg BC (SB), and 8 mg BC (EB) extracts. Experiment was laid out in a Completely Randomized Design. After hatching, the chicks were reared separately according to in ovo treatments for 8 wk. Data were collected on hatchability, chick quality, internal organs, growth performance, plasma superoxide dismutase, malondialdehyde, and triiodothyronine (T3). The results showed that the hatchability of the eggs in the AA group was similar to that of SB eggs and higher than that of the other treatment groups. The intestinal weights of SB and EB birds were significantly higher (P < 0.05) than those of TB, SA, and WA. The final weights of the birds of SB and AA were higher (P < 0.05) than those of other treatments. The feed conversion ratio of the birds of TB and FB was comparable to that of EB and WA but higher than that of SB and AA. At hatch, the creatinine of the birds in SA and WA was similar to that of EB, FB, and TB but higher (P < 0.05) than that of AA and SB. Also, the plasma malondialdehyde, T3, and superoxide dismutase of SB and AA birds were better (P < 0.05) than those of the control groups. Overall, it was concluded that 6 mg of BC extract improved the antioxidant status and posthatch performance of thermally challenged broiler chickens.


Asunto(s)
Peso Corporal , Pollos , Respuesta al Choque Térmico , Nigella sativa , Óvulo , Extractos Vegetales , Animales , Ácido Ascórbico , Peso Corporal/efectos de los fármacos , Respuesta al Choque Térmico/efectos de los fármacos , Calor , Nigella sativa/química , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Distribución Aleatoria
10.
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
11.
Ecotoxicol Environ Saf ; 208: 111610, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396130

RESUMEN

Hepatic oxidative stress, as one important mechanism of cadmium (Cd)-induced hepatic toxicity, could, as known, be ameliorated by vitamin E (VE). However, the underlying mechanism remains to be elucidated. To investigate whether the antioxidant vitamin E can protect against Cd-induced sub-chronic liver injury associated with oxidative stress and nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway, male Sprague-Dawley rats (nine-week-old) were randomly divided into four groups (eight rats/group), namely, control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2) and VE+Cd (100 mg/kg VE+5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for four weeks. Cd-exposure alone resulted in reduced liver weight, liver histological alteration and oxidative stress, accumulation of Cd in the liver, elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO-1, GCLC, GCLM and GST). However, the co-treatment of Cd and VE significantly ameliorated the changes mentioned above, and promoted the expression of genes and proteins of Nrf2 pathway related molecules in comparison to the Cd-exposure alone. Our results indicate that the protective effect of VE against Cd-induced sub-chronic hepatic damage in rats is associated with the inhibition of oxidative stress and activation of Nrf2 pathway.


Asunto(s)
Antioxidantes/farmacología , Cadmio/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Contaminantes Ambientales/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Vitamina E/farmacología , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal
12.
Ecotoxicol Environ Saf ; 208: 111714, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396045

RESUMEN

Studies on the effects of unintentional intake of pyrethroid pesticides that are akin to actual human exposure settings are very rare. Such an exposure is primarily by consuming the food products as routine diet that contain residual levels of pyrethroids. In this study, rats were orally administered for 15 months with a mixture of pyrethroids at a dose that is one-fifth (high dose; HD) or one-twenty fifth (low dose; LD) of the residual levels commonly present in the average amount of rice and vegetables consumed by Indian population. Lipid profile, kidney and liver function were assessed. Lipid peroxidation, nitric oxide, antioxidant enzyme activities and histopathological changes were analyzed in the liver, lung, kidney, pancreas, testes, caput, cauda and prostate. The effect on the male reproductive system as a function of sperm count, enzyme activity of 3ß-HSD and 17ß-HSD and the expression profile of genes involved in spermatogenesis, steroidogenesis, genetic reprogramming and apoptosis of male gametes were evaluated. Significant increase in the relative organ weight, perturbations in the activities of antioxidant enzymes, lipid profile and liver function were observed in both LD and HD groups. Damage to the anatomical architecture was evident in all the tissues due to pyrethroid toxicity. Exposure to LD and HD of pyrethroid mixture resulted in decreased sperm count, activities of 3ß-HSD and 17ß-HSD, impaired capacitation and acrosome reaction and perturbations in the expression of genes that govern male gamete production. Results of our study indicate that exposure to pyrethroids for longer durations even at doses that are far below the residual levels present in the food consumed will result in severe damage to general physiological processes as well as reproductive function.


Asunto(s)
Exposición Dietética/efectos adversos , Plaguicidas/toxicidad , Piretrinas/toxicidad , Animales , Antioxidantes/metabolismo , Fertilización/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Tamaño de los Órganos/efectos de los fármacos , Residuos de Plaguicidas/toxicidad , Ratas , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Espermatozoides/patología , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología
13.
Am J Physiol Endocrinol Metab ; 320(3): E527-E538, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33427051

RESUMEN

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.


Asunto(s)
Desarrollo Fetal/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Nutrientes/metabolismo , Animales , Metabolismo Energético/efectos de los fármacos , Femenino , Sangre Fetal/metabolismo , Peso Fetal/efectos de los fármacos , Feto/efectos de los fármacos , Feto/metabolismo , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/embriología , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Placenta/efectos de los fármacos , Placentación/efectos de los fármacos , Embarazo , Ovinos
14.
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
15.
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
16.
Ecotoxicol Environ Saf ; 203: 110974, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32888622

RESUMEN

Ammonia (NH3), an environmental pollutant, poses a serious threat to human and avian health. Although previous studies have showed that NH3 caused kidney injury, the molecular mechanisms of nephrotoxicity induced by NH3 remain unclear. To explore the mechanisms of NH3 nephrotoxicity, a total of 36 broiler chicks at one day of age were exposed to NH3. After 42 days of exposure, blood samples were collected to determine creatinine and uric acid; and kidney samples were weighted and then collected to detect ultrastructural changes, oxidative stress parameters, ATPases, necroptosis- and mitochondrial dynamics-related genes. The results showed that chickens exposed to NH3 showed lower relative kidney weight and an increase concentration in serum creatinine and uric acid. NH3 exposure caused nephrocyte necrosis and increased the expression of necroptosis-related genes (TNF-α, RIPK1, RIPK3, MLKL, and JNK). Besides, the activities of antioxidant systems (SOD, CAT, GSH-Px, and T-AOC) were reduced, whereas the concentrations of H2O2 and MDA were elevated. Lower activities of ATPases were obtained in NH3 treatment groups. Furthermore, the mitochondrial fission-related genes drp1 and mff were activated, and mitochondrial fusion-related genes opa1, mfn1 and mfn2 were suppressed after NH3 exposure. Based on the above results, we conclude that NH3 caused-oxidative stress and mitochondrial dysfunction mediated nephrocyte necroptosis in chickens. This study may provide new insight into NH3 nephrotoxicity.


Asunto(s)
Amoníaco/toxicidad , Contaminantes Ambientales/toxicidad , Riñón/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Necroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Pollos , Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Riñón/ultraestructura , Pruebas de Función Renal , Dinámicas Mitocondriales/genética , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética
17.
PLoS One ; 15(9): e0238164, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32877416

RESUMEN

PURPOSE: Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients. METHODS: Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome. RESULTS: Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1ß, IL-12p40, MIP-1ß, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis. CONCLUSION: Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome.


Asunto(s)
Pruebas Hematológicas , Oxaliplatino/efectos adversos , Esplenomegalia/inducido químicamente , Animales , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Fenotipo , Bazo/efectos de los fármacos , Bazo/patología , Esplenomegalia/metabolismo , Esplenomegalia/patología , Factores de Tiempo
18.
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
19.
Life Sci ; 261: 118366, 2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-32871182

RESUMEN

AIMS: Intensive care unit-acquired weakness (ICU-AW) is a complex spectrum of disability that delays recovery of critically ill-immobilized patients with sepsis. Much discrepancy remain on the use of corticosteroids and their impact on muscle regeneration in critical illness management. Therefore, the aim of this study is to investigate whether hydrocortisone (HCT) modulates muscle mass turnover in ICU-AW induced by sepsis with limb immobilization (SI). MAIN METHODS: Sepsis by cecal ligation puncture (CLP) with forelimb-immobilization were performed in rats. The study consisted of four groups: Sham (left forelimb-immobilization), Sham HCT (left forelimb-immobilization + HCT), SI (CLP + left forelimb-immobilization) and SI HCT (CLP + left forelimb-immobilization + HCT). Motor force, blood and muscle sampling were assessed. KEY FINDINGS: HCT prevented body weight loss associated with SI and attenuated systemic and muscular inflammation. Besides, myosin was restituted in SI HCT group in conjunction to muscle mass and strength restoration. Pro-hypertrophic calcineurin (PP2B-Aß) and nuclear factor of activated T-cells C3 (NFATc3) but not protein kinase B (Akt) were re-activated by HCT. Finally, pro-atrophic extracellular signal-regulated kinases (ERK1/2) and p38 mitogen-activated protein kinases (p38) but not nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) were inhibited in SI HCT group. SIGNIFICANCE: This study unravels new molecular events thought to control muscle protein synthesis in ICU-AW induced by sepsis and limb immobilization. HCT has a potential to fine-tune muscle-signaling pathways and to reduce the negative outcomes of ICU-AW.


Asunto(s)
Extremidades/patología , Hidrocortisona/uso terapéutico , Inmovilización , Unidades de Cuidados Intensivos , Debilidad Muscular/tratamiento farmacológico , Atrofia Muscular/tratamiento farmacológico , Sepsis/complicaciones , Transducción de Señal , Animales , Peso Corporal , Modelos Animales de Enfermedad , Hidrocortisona/farmacología , Hipertrofia , Mediadores de Inflamación/sangre , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Modelos Biológicos , Debilidad Muscular/sangre , Debilidad Muscular/complicaciones , Atrofia Muscular/sangre , Atrofia Muscular/complicaciones , Miosinas/metabolismo , Factores de Transcripción NFATC/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas Wistar , Sepsis/sangre
20.
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
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