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1.
Biol Trace Elem Res ; 202(2): 401-409, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37145256

RESUMEN

Compiling evidence supports that selenium plays a vital role in glucose metabolism. Triglyceride-glucose index (TyG) and triglyceride-glucose-body mass index (TyG-BMI) are commonly used in epidemiologic studies to evaluate insulin resistance and cardiovascular disease (CVD) risks. This study is aimed to investigate the association between whole blood selenium concentration and TyG and TyG-BMI. A total of 6290 participants (age ≥ 20 years) from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were included. Multiple linear regression models were used to examine the association between blood selenium quartiles and TyG and TyG-BMI. Subgroup analysis stratified by diabetes status was also performed. The adjusted model showed a positive association between TyG and blood selenium concentration (ß [95%CI] = 0.099 [0.063, 0.134], p < 0.001) and TyG-BMI (ß [95%CI] = 3.185 [2.102, 4.268], p < 0.001). The association persisted after stratification by diabetes status (p < 0.001). Participants were stratified into four quartiles based on selenium concentration (Q1: 1.08-2.24 µmol/L, Q2: 2.25-2.42 µmol/L, Q3: 2.43-2.62 µmol/L, Q4: 2.63-8.08). Compared with the Q1 group, TyG in the Q3 and Q4 groups was significantly higher (ß = 0.075 [95%CI 0.039 to 0.112] and ß = 0.140 [95%CI 0.103 to 0.176], respectively). Additionally, TyG-BMI in the Q2, Q3, and Q4 groups was higher than that in the Q1 group (ß = 1.189 [95%CI 0.065 to 2.314], ß = 2.325 [95%CI 1.204 to 3.446], and ß = 4.322 [95%CI 3.210 to 5.435], respectively). Blood level of selenium was positively associated with TyG and TyG-BMI, indicating that excessive blood selenium may be associated with impaired insulin sensitivity and increased risk of cardiovascular disease.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus , Resistencia a la Insulina , Selenio , Adulto , Humanos , Adulto Joven , Índice de Masa Corporal , Encuestas Nutricionales , Enfermedades Cardiovasculares/epidemiología , Glucosa , Triglicéridos , Glucemia , Factores de Riesgo , Biomarcadores
2.
Front Immunol ; 13: 740805, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35242127

RESUMEN

Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.


Asunto(s)
Diabetes Mellitus Tipo 1 , Sorafenib , Animales , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Interleucina-12 , Ratones , Ratones Endogámicos NOD , Sorafenib/farmacología , Sorafenib/uso terapéutico , Células TH1
3.
Mol Reprod Dev ; 88(6): 405-415, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34032349

RESUMEN

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.


Asunto(s)
Glucocorticoides/toxicidad , Células de Sertoli/fisiología , Espermatogénesis/efectos de los fármacos , Animales , Proteínas de Unión al Calcio/análisis , Corticosterona/toxicidad , Síndrome de Cushing/sangre , Síndrome de Cushing/inducido químicamente , Síndrome de Cushing/fisiopatología , Ácido Dicloroacético/farmacología , Hormona Folículo Estimulante/sangre , Ácido Láctico/metabolismo , Hormona Luteinizante/sangre , Masculino , Meiosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Orquitis/inducido químicamente , Orquitis/metabolismo , Fagocitosis/efectos de los fármacos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/análisis , Células de Sertoli/metabolismo , Recuento de Espermatozoides , Espermatozoides/patología , Testículo/metabolismo , Testosterona/sangre
4.
J Environ Qual ; 45(6): 1865-1873, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27898772

RESUMEN

Nutrient runoff losses from cropping fields can lead to nonpoint source pollution; however, the level of nutrient export is difficult to evaluate, particularly at the regional scale. This study aimed to establish a novel yet simple approach for estimating total nitrogen (TN) and total phosphorus (TP) runoff losses from regional paddy fields. In this approach, temporal changes of nutrient concentrations in floodwater were coupled with runoff-processing functions in rice ( L.) fields to calculate nutrient runoff losses for three site-specific field experiments. Validation experiments verified the accuracy of this method. The geographic information system technique was used to upscale and visualize the TN and TP runoff losses from field to regional scales. The results indicated that nutrient runoff losses had significant spatio-temporal variation characteristics during rice seasons, which were positively related to fertilizer rate and precipitation. The average runoff losses over five study seasons were 20.21 kg N ha for TN and 0.76 kg P ha for TP. Scenario analysis showed that TN and TP losses dropped by 7.64 and 3.0%, respectively, for each 10% reduction of fertilizer input. For alternate wetting and drying water management, the corresponding reduction ratio was 24.7 and 14.0% respectively. Our results suggest that, although both water and fertilizer management can mitigate nutrient runoff losses, the former is significantly more effective.


Asunto(s)
Sistemas de Información Geográfica , Nitrógeno/análisis , Oryza , Fósforo/análisis , Agricultura , Fertilizantes , Movimientos del Agua
5.
Cancer Sci ; 105(4): 473-80, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24450414

RESUMEN

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-κB (NF-κB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively. We have identified 2-methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK. 2-MS inhibits both interleukin-6-induced and constitutively-activated STAT3, as well as tumor necrosis factor-α-induced NF-κB activation. 2-MS specifically inhibits JAK and IKKß kinase activities but has little effect on activities of other kinases tested. The inhibitory effects of 2-MS on STAT3 and NF-κB signaling can be eliminated by DTT or glutathione and can last for 4 h after a pulse treatment. Furthermore, 2-MS inhibits growth and induces death of tumor cells, particularly those with constitutively-activated STAT3 or NF-κB signaling. We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-κB pathways, is a promising anticancer drug candidate.


Asunto(s)
Quinasa I-kappa B/biosíntesis , Janus Quinasa 2/biosíntesis , FN-kappa B/genética , Naftoquinonas/administración & dosificación , Factor de Transcripción STAT3/biosíntesis , Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Quinasa I-kappa B/genética , Interleucina-6/biosíntesis , Janus Quinasa 2/genética , Medicina Tradicional China , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT3/genética , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis
6.
J Biol Chem ; 288(20): 14417-14427, 2013 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-23580655

RESUMEN

Signal transducers and activators of transcription 1 (STAT1) transduces signals from cytokines and growth factors, particularly IFN-γ, and regulates expression of genes involved in cell survival/death, proliferation, and migration. STAT1 is activated through phosphorylation on its tyrosine 701 by JAKs and is inactivated through dephosphorylation by tyrosine phosphatases. We discovered a natural compound, wedelolactone, that increased IFN-γ signaling by inhibiting STAT1 dephosphorylation and prolonging STAT1 activation through specific inhibition of T-cell protein tyrosine phosphatase (TCPTP), an important tyrosine phosphatase for STAT1 dephosphorylation. More interestingly, wedelolactone inhibited TCPTP through interaction with the C-terminal autoinhibition domain of TCPTP. We also found that wedelolactone synergized with IFN-γ to induce apoptosis of tumor cells. Our data suggest a new target for anticancer or antiproliferation drugs, a new mechanism to regulate PTPs specifically, and a new drug candidate for treating cancer or other proliferation disorders.


Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Regulación Neoplásica de la Expresión Génica , Interferón gamma/metabolismo , Factor de Transcripción STAT1/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Genes Reporteros , Células Hep G2 , Humanos , Monoéster Fosfórico Hidrolasas/metabolismo , Fosforilación , Extractos Vegetales/farmacología , Regiones Promotoras Genéticas , Interferencia de ARN
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