SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat. The SARS-CoV-2 main protease (M^pro) is a critical target for the development of antiviral agents that can inhibit viral replication and transcription. In this study, we identified chebulagic acid (CHLA), isolated from Terminalia chebula Retz., as a potent non-peptidomimetic and non-covalent M^pro inhibitor. CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants, including the wild-type, Delta, Omicron BA.1.1, BA.2.3, BA.4, and BA.5, with EC₅₀ values below 2 μmol/L. Moreover, in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice. Notably, CHLA bound to a unique groove at the interface between M^pro domains I and II, which was revealed by the high-resolution crystal structure (1.4 Å) of the M^pro-CHLA complex, shrinking the substrate binding pocket of M^pro and inducing M^pro aggregation. CHLA was proposed to act as an allosteric inhibitor. Pharmacokinetic profiling and safety assessments underscore CHLA's potential as a promising broad-spectrum antiviral candidate. These findings report a novel binding site on M^pro and identify antiviral activity of CHLA, providing a robust framework for lead compounds discovery and elucidating the underlying molecular mechanisms of inhibition.

Cardiovascular diseases that develop from hypercholesterolemia-induced atherosclerosis have emerged as a significant threat to human health.Recently,probiotics exhibiting cholesterol-lowering properties have emerged as a prominent area of research.Numerous studies have demonstrated that Lactobacillus reuteri can effectively reduce endogenous cholesterol synthesis,regulate cholesterol transport,and promote cholesterol degradation by modulating the expression of key genes,such as sterol-regulatory element binding protein 2,3-hydroxy-3-methyl-glutaryl coenzyme A reductase,and cholesterol 7 alpha-hydroxylase,in both the liver and intestinal epithelial cells of the host.This leads to a notable decrease in total cholesterol and low-density lipoprotein cholesterol levels in the host serum.The present paper offers a comprehensive overview of the underlying mechanisms responsible for the cholesterol-lowering effects exerted by L.reuteri,aiming to provide valuable insights into the treatment of hypercholesterolemia and the development of probiotics with cholesterol-lowering properties.

Cardiovascular diseases that develop from hypercholesterolemia-induced atherosclerosis have emerged as a significant threat to human health.Recently,probiotics exhibiting cholesterol-lowering properties have emerged as a prominent area of research.Numerous studies have demonstrated that Lactobacillus reuteri can effectively reduce endogenous cholesterol synthesis,regulate cholesterol transport,and promote cholesterol degradation by modulating the expression of key genes,such as sterol-regulatory element binding protein 2,3-hydroxy-3-methyl-glutaryl coenzyme A reductase,and cholesterol 7 alpha-hydroxylase,in both the liver and intestinal epithelial cells of the host.This leads to a notable decrease in total cholesterol and low-density lipoprotein cholesterol levels in the host serum.The present paper offers a comprehensive overview of the underlying mechanisms responsible for the cholesterol-lowering effects exerted by L.reuteri,aiming to provide valuable insights into the treatment of hypercholesterolemia and the development of probiotics with cholesterol-lowering properties.

Purpose To study the status of EGFR mutations and the expression of excision repair cross-complementation group 1 ( ER-CC1) and Ki-67 protein in patients with non-small cell lung cancer (NSCLC) and to examine the relationship between their expression and clinicopathologic features. Methods EGFR mutations were analyzed with DNA sequencing, and the expression of ERCC1 and Ki-67 protein was examined by immunohistochemistry EnVision. The relationship of EGFR mutations with the expression of ERCC1and Ki-67 and the clinicopathological features were analyzed. Results EGFR mutations were detected in 143 (143/291, 49. 1%) of the 291 specimens. EGFR mutations were found more frequently in women, non-smokers and adenocarcinoma. The difference of EGFR muta-tion rate between the histological subtypes according to the IASLC/ATS/ERS classification of lung adenocarcinoma was significantly ( P=0. 008). The mean tumor diameter was smaller in patients with EGFR mutations than in those with wild-type EGFR (P=0. 020). EGFR mutations were not related to age, lymph node metastasis. However, EGFR mutations were not related to the expression of ER-CC1 and Ki-67 protein (P>0. 050). Conclusions EGFR mutation is closely linked to several clinicopathological factors, such as gender, differentiation, and histological subtype. There is heterogeneity of EGFR mutation in patients with NSCLC. EGFR mutations were not related to the expression of ERCC1 and Ki-67 protein.

Objective To investigate the expression of GFAP in rat hypothalamus after acute heat stress. Methods The rats were caged in a experimental incubator for 60 minutes,the temperature within the incubator was adjusted to 24℃,34℃,38.5℃ or 42℃,the humidity was 60%.Single anti-GFAP immunohistochemical(ABC) method and anti-Fos and GFAP double immunohistochemical method were used to observe the expression of GFAP in hypothalamus in different ambient temperatures after heat stress. Results The GFAP-positive cells were rare in hypothalamus at 24℃,however it was increased in many nuclei(anterior hypothalamic area,paraventricular nucleus,arcuate nucleus,suprachiasmatic nucleus and supraoptic nucleus)at 34℃ and peaked when ambient temperature was 38.5℃,and then decreased.However,Fos/GFAP-IR double labelled astrocytes were observed at 42℃.Conclusion Astrocytes participate in the pathophysiological process of heat stress.