RESUMEN
Ergothioneine (ET) is a naturally occurring antioxidant that is synthesized by non-yeast fungi and certain bacteria. ET is not synthesized by animals, including humans, but is avidly taken up from the diet, especially from mushrooms. In the current study, we elucidated the effect of ET on the hCMEC/D3 human brain endothelial cell line. Endothelial cells are exposed to high levels of the cholesterol oxidation product, 7-ketocholesterol (7KC), in patients with cardiovascular disease and diabetes, and this process is thought to mediate pathological inflammation. 7KC induces a dose-dependent loss of cell viability and an increase in apoptosis and necrosis in the endothelial cells. A relocalization of the tight junction proteins, zonula occludens-1 (ZO-1) and claudin-5, towards the nucleus of the cells was also observed. These effects were significantly attenuated by ET. In addition, 7KC induces marked increases in the mRNA expression of pro-inflammatory cytokines, IL-1ß IL-6, IL-8, TNF-α and cyclooxygenase-2 (COX2), as well as COX2 enzymatic activity, and these were significantly reduced by ET. Moreover, the cytoprotective and anti-inflammatory effects of ET were significantly reduced by co-incubation with an inhibitor of the ET transporter, OCTN1 (VHCL). This shows that ET needs to enter the endothelial cells to have a protective effect and is unlikely to act via extracellular neutralizing of 7KC. The protective effect on inflammation in brain endothelial cells suggests that ET might be useful as a nutraceutical for the prevention or management of neurovascular diseases, such as stroke and vascular dementia. Moreover, the ability of ET to cross the blood-brain barrier could point to its usefulness in combatting 7KC that is produced in the CNS during neuroinflammation, e.g. after excitotoxicity, in chronic neurodegenerative diseases, and possibly COVID-19-related neurologic complications.
Asunto(s)
Antioxidantes/farmacología , COVID-19/complicaciones , Células Endoteliales/efectos de los fármacos , Ergotioneína/farmacología , Cetocolesteroles/toxicidad , Enfermedades del Sistema Nervioso/prevención & control , Fármacos Neuroprotectores/farmacología , Antioxidantes/farmacocinética , Apoptosis/efectos de los fármacos , Transporte Biológico , Barrera Hematoencefálica , Encéfalo/irrigación sanguínea , Encéfalo/citología , Línea Celular , Colesterol/metabolismo , Claudina-5 , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/genética , Citocinas/biosíntesis , Citocinas/genética , Evaluación Preclínica de Medicamentos , Ergotioneína/farmacocinética , Humanos , Microvasos/citología , Enfermedades del Sistema Nervioso/etiología , Fármacos Neuroprotectores/farmacocinética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas de Transporte de Catión Orgánico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Simportadores , Proteína de la Zonula Occludens-1RESUMEN
The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.