RESUMEN
AIMS: Stroke is a major cause of mortality and disability, especially for postmenopausal women. In view of the protective action of estrogen, hormone therapy remains the only effective way to limit this risk. The objective of this study was to investigate the efficiency and underlying mechanisms of estrogen neuroprotection. METHODS: Subcutaneous injection of 17ß-estradiol in rats after ovariectomy (OVX) was used to manipulate estrogen level and explore the effects of estrogen in cerebral ischemic damage both in vivo and in vitro. Silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice and adenosine monophosphate (AMP)-activated kinase (AMPK) inhibitor Compound C were also used to investigate the underlying pathway of estrogen. RESULTS: Estrogen deficiency induced by OVX aggravated brain infarction in experimentally induced cerebral ischemia rats, whereas estrogen pretreatment reduced ischemia-induced cerebral injuries. Neurons of estrogen deficiency models were susceptible to apoptosis under oxygen-glucose deprivation (OGD). In contrast, neurons with estrogen-supplemented serum exhibited restored resistance to cell apoptosis. In OGD neurons, estrogen promoted AMPK activation through estrogen receptor α, and neuroprotection of estrogen was prevented by AMPK inhibition. Estrogen increased SIRT1 expression and activation, and estrogen-induced AMPK activation disappeared in SIRT1 knockout neurons. Moreover, estrogen-induced neuroprotection was abolished in SIRT1 knockout mice and AMPK-inhibited rats. CONCLUSION: Our data support that estrogen protects against ischemic stroke through preventing neuron death via the SIRT1-dependent AMPK pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Estradiol/uso terapéutico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/prevención & control , Transducción de Señal/genética , Sirtuina 1/metabolismo , Animales , Animales Recién Nacidos , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Hipoxia de la Célula/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Estradiol/farmacología , Estrógenos/sangre , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Sirtuina 1/genéticaRESUMEN
Stroke is a leading cause of mortality and disability worldwide. There is growing evidence that metformin (Met) has potent neuroprotective effects; however, its mechanisms remain unclear. We examined the role of the arterial baroreflex and cholinergic-α7 nicotinic acetylcholine receptor (α7nAChR) anti-inflammory pathway in the beneficial effects of Met against stroke. Stroke-prone spontaneously hypertensive rats (SHRSP) were used to observe stroke development indicated by lifespan of SHRSP and the ischemic injury induced by permanent middle cerebral artery occlusion (MCAO). Sinoaortic denervation was used to inactivate the arterial baroreflex. MCAO were also performed in α7nAChR knockout (KO) mice. Briefly, Met increased the life span of SHRSP and reduced the infarct area induced by MCAO. Met also improved the function of arterial baroreflex. The beneficial effects of Met on stroke were markedly attenuated by blunting the arterial baroreflex. Met up-regulated the expression of vesicular acetylcholine transporter (VAChT) and α7nAChR, down-regulated the level of pro-inflammtory cytokines in serum and peri-infarct of ischemic brain. Arterial baroreflex dysfunction decreased the expression of VAchT and α7nAChR, showed upward tendency in the level of pro-inflammtory cytokines. Most importantly, arterial baroreflex dysfunction nearly abolished such effect of Met on cholinergic signaling. In addition, the α7nAChR KO mice also had significantly worse ischemic damage induced by MCAO, and neuroprotection of Met disappeared in α7nAChR KO mice. In conclusion, Met improved the arterial baroreflex function, and then enhancing cholinergic anti-inflammatory pathway in an α7nAChR-dependent manner, thereby effectively prevent ischemic induced brain injury and delayed stroke onset in SHRSP.
Asunto(s)
Arterias/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Metformina/farmacología , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/fisiopatología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Arterias/fisiopatología , Isquemia Encefálica/complicaciones , Citocinas/sangre , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Masculino , Ratones , Ratas , Ratas Endogámicas SHR , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/metabolismo , Proteínas de Transporte Vesicular de Acetilcolina/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/deficiencia , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
Colorectal carcinoma (CRC) is one of the most common cancers globally. It is essential to identify a prognostic predictor for CRC. Pentraxin 3 (PTX3) is a glycoprotein that is secreted by a variety of human cells. It plays an important role in inflammation and immune regulation. Increasing evidence reveals that elevated PTX3 expression is related to poor prognosis in various cancers. The aim of the study was to determine the usefulness of plasma PTX3 level as a prognostic predictor in CRC. Total 184 CRC patients and 216 controls were included. Plasma levels of PTX3 were determined using Enzyme-linked immunosorbent assays. On admission, plasma PTX3 levels in CRC patients were higher than those in controls (11.8 ± 2.5 ng/ml vs. 3.1 ± 0.9 ng/ml, P < 0.001). After resection, plasma PTX3 levels in patients were decreased (6.0 ± 1.4 ng/ml, P = 0.007), and were elevated at the time of relapse (10.8 ± 2.8 ng/ml, P < 0.001). During the 60-month follow-up period, 108 patients suffered from relapse. Plasma PTX3 levels of ≥ 12 ng/ml on admission were associated with relapse (OR: 3.11, 95% CI: 1.74 ~ 6.29), and tumor-free survival rate in those patients with plasma PTX3 levels of ≥ 12 ng/ml was lower than that in other patients (P = 0.001). Furthermore, plasma PTX3 levels on admission showed positive linear correlations with plasma complement 3, 4 and 5b9 levels (P < 0.001, P < 0.001, P < 0.001). Therefore, we propose that PTX3 is an independent prognostic indicator in CRC.