RESUMEN
The thymus, a site to culture the naïve T lymphocytes, is susceptible to atrophy or involution due to aging, inflammation, and oxidation. Epigallocatechin-3-gallate (EGCG) has been proven to possess anti-inflammatory, antioxidant, and antitumor activity. Here, we investigate the effects of EGCG on thymic involution induced by lipopolysaccharide (LPS), an endotoxin derived from Gram-negative bacteria. The methodology included an in vivo experiment on female Kunming mice exposed to LPS and EGCG. Morphological assessment of thymic involution, immunohistochemical detection, and thymocyte subsets analysis by flow cytometry were further carried out to evaluate the potential role of EGCG on the thymus. As a result, we found that EGCG alleviated LPS-induced thymic atrophy, increased mitochondrial membrane potential and superoxide dismutase levels, and decreased malondialdehyde and reactive oxygen species levels. In addition, EGCG pre-supplement restored the ratio of thymocyte subsets, the expression of autoimmune regulator, sex-determining region Y-box 2, and Nanog homebox, and reduced the number of senescent cells and collagen fiber deposition. Western blotting results indicated that EGCG treatment elevated LPS-induced decrease in pAMPK, Sirt1 protein expression. Collectively, EGCG relieved thymus architecture and function damaged by LPS via regulation of AMPK/Sirt1 signaling pathway. Our findings may provide a new strategy on protection of thymus from involution caused by LPS by using EGCG. And EGCG might be considered as a potential agent for the prevention and treatment of thymic involution.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Catequina , Lipopolisacáridos , Transducción de Señal , Sirtuina 1 , Timo , Animales , Catequina/análogos & derivados , Catequina/farmacología , Sirtuina 1/metabolismo , Ratones , Femenino , Timo/efectos de los fármacos , Timo/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , AtrofiaRESUMEN
BACKGROUND: More than 2 billion women are experiencing the menopausal transition in China, and some of these women have hypertension. Limited studies has focused on perimenopausal syndrome and hypertension in a specific population, so we aimed to investigate the prevalence of perimenopausal syndrome and hypertension and to analyse their relationships and risk factors in perimenopausal women in South China. METHODS: This cross-sectional study included 3553 women aged 40 to 60 years from South China. We collected medical report, lifestyle, blood sample, general condition questionnaire, and modified Kupperman index (mKMI) data. Multivariate logistic regression analysis was performed to identify risk factors for perimenopausal syndrome and hypertension during perimenopause. RESULTS: The prevalence of hypertension in perimenopause patients was 16.58%, and the prevalence of perimenopausal syndrome was 9.9%. Compared with women without hypertension during perimenopause, women with HTN during perimenopause had an increased risk of perimenopausal syndrome (26.4% vs. 8.7%, P < 0.001). Lipid levels and urinary tract infections were risk factors for hypertension and perimenopausal syndrome, in addition to the presence of breast nodules, the intake of snacks at night, high-salt diets, red meat and sugar-sweetened beverages, and a history of smoking and drinking for perimenopausal syndrome and the presence of gestational hypertension and diabetes for hypertension. CONCLUSION: We concluded that perimenopausal syndrome and HTN are common in perimenopausal women in South China, and the associations between them are strong and positive. Perimenopausal syndrome shares some common risk factors with HTN during perimenopause, such as BMI and dyslipidaemia. Therefore, gynaecological endocrinologists in China should consider screening for perimenopausal syndrome in hypertensive perimenopausal women, and appropriate management of perimenopause is needed to alleviate these conditions.
Asunto(s)
Hipertensión , Perimenopausia , Femenino , Humanos , Prevalencia , Estudios Transversales , Factores de Riesgo , Hipertensión/epidemiología , China/epidemiologíaRESUMEN
PURPOSE: The relationship between vitamin D levels and cancer incidence and mortality in individuals with metabolic syndrome (MetS) remains poorly explored. Herein, we aimed to determine the association between 25-hydroxyvitamin D [25(OH)D] concentrations and the risk of 16 cancer incidence types and cancer/all-cause mortality in patients with MetS. METHODS: We enrolled 97,621 participants with MetS at recruitment from the UK Biobank cohort. The exposure factor was baseline serum 25(OH)D concentrations. The associations were examined using Cox proportional hazards models, which were displayed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Over a median follow-up period of 10.92 years for cancer incidence outcomes, 12,137 new cancer cases were recorded. We observed that 25(OH)D concentrations were inversely related to the risk of colon, lung, and kidney cancer, and HRs (95% CI) for 25(OH)D ≥ 75.0 vs. < 25.0 nmol/L were 0.67 (0.45-0.98), 0.64 (0.45-0.91), and 0.54 (0.31-0.95), respectively. The fully adjusted model revealed a null correlation between 25(OH)D and the incidence of stomach, rectum, liver, pancreas, breast, ovary, bladder, brain, multiple myeloma, leukemia, non-Hodgkin lymphoma, esophagus, and corpus uteri cancer. Over a median follow-up period of 12.72 years for mortality outcomes, 8286 fatalities (including 3210 cancer mortalities) were documented. An "L-shaped" nonlinear dose-response correlation was detected between 25(OH)D and cancer/all-cause mortality; the respective HRs (95% CI) were 0.75 (0.64-0.89) and 0.65 (0.58-0.72). CONCLUSION: These findings emphasize the importance of 25(OH)D in cancer prevention and longevity promotion among patients with MetS.
Asunto(s)
Síndrome Metabólico , Neoplasias , Deficiencia de Vitamina D , Femenino , Humanos , Síndrome Metabólico/epidemiología , Síndrome Metabólico/complicaciones , Estudios Prospectivos , Incidencia , Vitamina D , Neoplasias/epidemiología , Calcifediol , Factores de RiesgoRESUMEN
TcpC is a multifunctional virulence factor of uropathogenic E. coli (UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-type E. coli CFT073 (CFT073wt) and LPS-induced in vitro NETosis with CFT073wt or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.
Asunto(s)
Proteínas de Escherichia coli/metabolismo , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Ubiquitinación , Factores de Virulencia/metabolismo , Animales , Cromatina/metabolismo , Citrulinación , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/patología , Proteínas de Escherichia coli/genética , Histonas/metabolismo , Evasión Inmune , Ratones , Mutación , Complejo de la Endopetidasa Proteasomal/metabolismo , Arginina Deiminasa Proteína-Tipo 4/genética , Pielonefritis/inmunología , Pielonefritis/patología , Transcripción Genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Escherichia coli Uropatógena/metabolismo , Escherichia coli Uropatógena/patogenicidad , Factores de Virulencia/genéticaRESUMEN
TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.
Asunto(s)
Proteínas de Escherichia coli/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal/fisiología , Escherichia coli Uropatógena/patogenicidad , Factores de Virulencia/metabolismo , Animales , Línea Celular , Femenino , Humanos , Evasión Inmune/fisiología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Pielonefritis/inmunología , Pielonefritis/microbiología , Receptores Toll-Like/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Escherichia coli Uropatógena/inmunología , Escherichia coli Uropatógena/metabolismo , Virulencia/fisiologíaRESUMEN
AIM: To investigate the mechanisms underlying the protective effects of sodium tanshinone IIA sulfonate (STS) in an ischemia-reperfusion (I/R)-induced rat myocardial injury model. METHODS: Male SD rats were iv injected with STS, STS+LY294002 or saline (NS) for 15 d. Then the hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. Cardiac function, infarction size and area at risk were assessed. Cell apoptosis was evaluated with TUNEL staining, DNA laddering and measuring caspase-3 activity. In addition, isolated cardiomyocytes of neonatal rats were pretreated with the above drugs, then exposed to H2O2 (200 mol/L) for 1 h. Cell apoptosis was detected using flow cytometric assay. The levels of p-Akt, p-FOXO3A and Bim were examined with immunoblotting. RESULTS: Compared to NS group, administration of STS (20 mg/kg) significantly reduced myocardial infarct size (40.28%±5.36% in STS group vs 59.52%±7.28% in NS group), and improved the myocardial function as demonstrated by the increased values of dp/dtmax, LVDP and coronary flow at different reperfusion time stages. Furthermore, STS significantly decreased the rate of apoptotic cells (15.11%±3.71% in STS group vs 38.21%±7.83% in NS group), and reduced caspase-3 activity to nearly a quarter of that in NS group. Moreover, STS significantly increased the phosphorylation of Akt and its downstream target FOXO3A, and decreased the expression of pro-apoptotic gene Bim. Co-treatment with the PI3K inhibitor LY294002 (40 mg/kg) partially countered the protective effects induced by STS treatment. In isolated cardiomyocytes, STS exerted similar protective effects as shown in the ex vivo I/R model. CONCLUSION: STS pretreatment reduces infarct size and improves cardiac function in an I/R-induced rat myocardial injury model via activation of Akt/FOXO3A/Bim-mediated signal pathway.
Asunto(s)
Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Fenantrenos/farmacología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Cardiotónicos/farmacología , Cromonas/farmacología , Modelos Animales de Enfermedad , Citometría de Flujo , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Masculino , Proteínas de la Membrana/metabolismo , Morfolinas/farmacología , Infarto del Miocardio/etiología , Daño por Reperfusión Miocárdica/complicaciones , Miocitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the type V phosphodiesterase (PDE-5) inhibitor erection-provoking test with audio-visual sexual stimulation in the diagnosis of erectile dysfunction. METHODS: A total of 853 out-patients diagnosed with erectile dysfunction were divided into an injury and a non-injury group. After scored on IIEF-5 questionnaires, all the patients received oral administration of PDE-5 inhibitors and, 30 minutes later, audio-visual sexual stimulation. The data on penile erection were recorded with Rigiscan Plus. RESULTS: The patients with mild, moderate and severe ED accounted for 18.8, 31.9 and 49.3% in the injury group, and 50.6, 39.8 and 9.6% in the non-injury group, with statistic differences between the two groups in the mild and severe parts (P < 0.05). The rates of conspicuous effectiveness, effectiveness, ineffectiveness and total effectiveness of the combined method were 13.0, 14.5, 72.5 and 27.5% in the injury group, but 55.7, 20.7, 23.6 and 76.4% in the non-injury group, with significant differences (P < 0.05). CONCLUSION: The PDE-5 inhibitor erection-provoking test with audio-visual sexual stimulation is a simple, practical, safe and effective method for the differentiation of organic from psychological erectile dysfunction.
Asunto(s)
Disfunción Eréctil/fisiopatología , Erección Peniana/fisiología , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/administración & dosificación , Adulto , Anciano , Disfunción Eréctil/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Erección Peniana/psicología , Estimulación Luminosa/métodos , Sensibilidad y Especificidad , Conducta Sexual , Encuestas y Cuestionarios , Televisión , Adulto JovenRESUMEN
OBJECTIVE: To investigate the clinical characteristics, diagnosis, treatment and prognosis of deep sarcoma of the penis. METHODS: The pathological and clinical data of 2 cases of deep sarcoma of the penis were analyzed retrospectively and the literature reviewed. RESULTS: Both of the cases were treated by total penectomy. Epithelioid angiosarcoma of the penis was confirmed by postoperative pathology in one patient, who died of pulmonary metastasis in the eighth month after the operation; and epithelioid sarcoma of the penis was confirmed in the other, who died of brain metastasis in the second month after the operation. CONCLUSION: Deep sarcoma of the penis is rare but can be diagnosed pathologically. Total penectomy is the main option for its treatment. Node dissection, with poor prognosis, is not recommended unless adenopathy is palpable.