Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav) Unidad Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Tlalpan, 14330, Mexico City, Mexico.
Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados (Cinvestav), 07360, Mexico City, Mexico.
Pharmacol Rep. 2022 Dec;74(6):1315-1325. doi: 10.1007/s43440-022-00398-5. Epub 2022 Aug 5.
COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation.
C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient (Lps del) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin-eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization.
A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals.
S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection.
COVID-19，由 SARS-CoV-2 病毒感染引起的疾病，在过去的 2 年里已成为全球主要的公共卫生问题。SARS-CoV-2 依赖性激活先天免疫受体导致与快速疾病演变相关的强烈局部和全身炎症反应。Spike（S）病毒蛋白的受体结合域（RBD）对于病毒感染及其在靶细胞中的相互作用分子仍然在鉴定中。另一方面，寻找具有潜在治疗用途的易获取天然分子的研究非常活跃，并且仍然是一个积极的研究领域。
用重组 S-RBD 对 C57BL6/J（对照）和 Toll 样受体（TLR）4 缺陷（Lps del）小鼠进行雾化。通过酶联免疫吸附试验（ELISA）测定支气管肺泡灌洗液（BAL）中肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6 的产生。通过苏木精-伊红（H&E）染色定量回收的 BAL 中的肺浸润细胞。在选定的动物组中，在雾化前 2 小时通过腹腔内（ip）给予天然化合物 Jacareubin 或地塞米松。
S-RBD 雾化在对照小鼠中迅速诱导 TNF-α 和 IL-6 的肺产生和细胞浸润，但在 Lps del 小鼠中则没有。在对照动物的 BAL 中，Jacareubin 或地塞米松预处理可预防 S-RBD 诱导的 TNF-α 和 IL-6 分泌。
S-RBD 结构域以 TLR4 依赖的方式在 C57BL6/J 小鼠中促进肺 TNF-α 和 IL-6 的产生。黄烷酮 Jacareubin 具有潜在的抗 COVID-19 特性，加上先前测试的抗炎活性、安全性和耐受性，使其成为一种有价值的药物，可进一步研究用于治疗 SARS-CoV-2 感染引起的细胞因子产生。
