Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.

卵巢纤维化是多种妇科疾病的共同病理表现之一,卵巢早衰、子宫内膜异位囊肿、多囊卵巢综合征等均会造成卵巢纤维化;主要形成原因是卵巢组织细胞受损超过了周围实质细胞的修复能力,为了维持组织结构的完整性,细胞外基质大量产生并过度沉积,导致卵巢组织内结缔组织增多,实质细胞减少,最终造成卵巢不可逆修复而发生纤维化.卵巢纤维化的形成与许多细胞因子有关,本文将就卵巢纤维化相关疾病的影响因子、临床表现及其治疗方法的研究进展作简要介绍.

目的:探讨小檗碱对流感病毒感染小鼠肺与结肠损伤的保护作用.方法:以流感病毒H1N1亚型感染BALB/c小鼠建立流感模型,注射给予小檗碱或利巴韦林治疗.观察小鼠生存及肺、结肠炎症损伤情况;ELISA检测血清细胞因子IL-6、IL-17A和IFN-γ水平;RT-qPCR检测肺脏IFN-γ、IL-10和CCL25 mRNA转录水平;16S rRNA测序分析粪便肠道菌群.结果:H1N1病毒感染的模型小鼠出现明显肺脏和结肠病变,且体重下降.小檗碱可有效维持病毒感染小鼠的存活率和体重,显著减轻肺部水肿,抑制肺指数升高;显著降低血清中细胞因子IFN-γ水平,抑制肺脏细胞因子IFN-γ、IL-10和CCL25 mRNA转录.小檗碱可维持感染小鼠结肠长度和重量,并影响肠道菌群基本结构和优势菌群.结论:小檗碱可抑制血清IFN-γ及肺部IFN-γ、IL-10和CCL25过度产生,并调控肠道菌群,从而对流感病毒感染导致的小鼠肺与结肠损伤起保护作用.

This study was designed to investigate the mechanism by which MMDD improves lung function, and observe the effect of MMDD on endoplasmic reticulum stress(ERS) in alveolar type II epithelial cells (AECIIs) of pulmonary fibrosis rats. pulmonary fibrosis animal model was established by intratracheal injection of BLM at a dose of 6mg/kg body weight. Overall, Thirty male SPF Sprague-Dawley rats were randomly divided into control group, BLM group and BLM+MMDD group. BLM+MMDD group rats were fed 24 g/kg over three weeks for twice a day on the fourteenth day after model establishment. MMDD improves pulmonary function of fibrotic rats and reduces the occurrence of endoplasmic reticulum stress in AECIIs. MMDD could significantly improve the forced vital capacity (FVC) of bleomycin-induced pulmonary fibrosis in rats. MMDD reduced the expression of GRP78 and CHOP in AECIIs, increased the secretion of surfactant protein C (SPC) by AECIIs. Moreover, the apoptosis of the fibrosis zone in the lung tissue was remarkably mitigated by administration of MMDD. The finding of this study revealed that MMDD can improve lung function in rats with pulmonary fibrosis by reducing the occurrence of ERS and cell apoptosis of AECIIs. It may provide a new method for the treatment of pulmonary fibrosis.

Objective To investigate the role of the PGE2 and EP2/EP3 receptor on improving lung function of rats with pulmonary fibrosis treated with Youguiyin Decoction. Methods 32 SPF SD male rats were divided into normal group, model group, Youguiyin low dose group and Youguiyin high dose group, according to the random number table method. The normal group (8 rats) was given no intervention and was given normal feeding. The other 3 groups were established by intravenous injection of Bleomycin (6 mg/kg) via tracheal intubation. Youguiyin low dose group (8 rats) and Youguiyin high dose group (8 rats) were given 5 g/kg and 10 g/kg of Youguiyin Decoction at specific time from the 14 th day after model establishment. The model group (8 rats) was given the same dose of drinking water once a day for 20 days. The lung weight and body weight were recorded, and the lung coefficient was calculated. The concentration of PGE2 in serum and lung tissue was measured with ELISA. The expression of EP2 and EP3 in lung tissue and tissue localization were analyzed by immunohistochemical staining, and the number of positive cells was counted. Results Compared with the normal group, the lung weight (3. 1 ± 0. 44 g, P ＜ 0. 05) and lung coefficient (0. 69 ± 0. 13％, P ＜0. 05) of the model group increased pathologically, and the level of PGE2 increased in both serum (45. 49 ± 7. 38 pg/ml, P ＜ 0. 05) and lung tissue (113. 64 ± 16. 78 pg/ml, P ＜ 0. 05). Abnormal proliferation of AEC IIs associated with strong EP2-positive in the consolidation of lung tissues, and the macrophages accumulated in the alveolar ducts and alveolar spaces were EP3-positive. The positive cells in the two groups increased significantly (P ＜ 0. 05). Compared with the model group, the lung weight (2. 63 ± 0. 24 g, P ＜ 0. 05) and lung coefficient (0. 57 ± 0. 08％, P＜ 0. 05) of Youguiyin low dose group decreased, and the level of PGE2 decreased in both serum (23. 01 ± 8. 61 pg/ml, P ＜ 0. 05) and lung tissue (89. 84 ± 20. 54 pg/ml, P ＜ 0. 05). The expression of EP2 in the AEC IIs with strong EP2-positive decreased, and the number of cell reduced (P ＜ 0. 05). The number of macrophages with EP3-positive increased (P ＜ 0. 05). In the Youguiyin high dose group, there was no statistical difference except the decreased level of PGE2 in serum (P ＜ 0. 05). Conclusion Youguiyin can significantly improve pulmonary fibrosis induced by Bleomycin in rats, which may be associated with lowing PGE2 level in the consolidation of lung tissues, inhibiting the expression of EP2 in the consolidation area, reduction of AECIIs with EP2-positive, and increase of macrophages with EP3-positive.

Objective To investigate the relative mechanism of Maimendong Tang (Ophiopogon Decoction) in amelioration of lung function and endoplasmic reticulum stress (ERS) in rats with bleomycin-induced pulmonary fibrosis.Methods Male healthy SD rats were randomly divided into normal group, model group, Maimendong Tang group 1 and Maimendong Tang group 2.The rat model of pulmonary fibrosis was established by bleomycin pulverization via tracheal intubation.On the 14 t h d after modeling, Maimendong Tang was intragastrically given to Maimendong Tang group1 and Maimendong Tang group 2 twice a day for 20 d continuously.The general conditions were observed, and pathological changes of lung tissue were observed after HE and Masson staining.The forced vital capacity (FVC) , 0.4 second rate (FEV0.4/FVC) , mass FVC, inspiratory resistance (Ri) , expiratory resistance (Re) and dynamic pulmonary compliance (Cydn) were detected by using spirometer.The expressions of glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) protein in lung tissue were analyzed by using Western blotting assay and immunohistochemistry staining technique.Results Compared with normal group, FVC, FVC/lung mass and Cydn decreased, and 0.4 second rate increased in model group.Compared with model group, FVC increased and 0.4 second rate decreased and Cydn increased in Maimendong Tang group 1 and Maimendong Tang group 2, and mass FVC increased in Maimendong Tang group 2.Pathological sections showed that there were chronic inflammatory cell infiltration in consolidation zone of lung tissue and massive collagen deposition, GRP78 and CHOP with high expressions were mainly positioned in vesicular type Ⅱ alveolar epithelial cells (AECⅡs).The inflammation was relieved, collagen deposition was decreased, protein expressions of GRP78 and CHOP were reduced and in Maimendong Tang group 2.Conclusion Maimendong Tang can significantly improve lung function and reduce lung interstitial collagen deposition, which may be related to regulation of protein expressions of GRP78 and CHOP in AECⅡs in consolidation zone of lung tissue, relief of ERS, and recovery of normal AECⅡs function.