Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors.

With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.

Gegen Qinlian Decoction treatment of asymptomatic hyperuricemia by targeting circadian immune function.

BACKGROUND: The Gegen Qinlian Decoction (GGQLD) is a renowned traditional Chinese medicinal formula that has been used for centuries to effectively treat asymptomatic Hyperuricemia (HUA). This study aims to investigate the underlying mechanism of GGQLD's therapeutic effects on HUA. METHODS: The study enrolled a total of 25 healthy participants and 32 middle-aged and elderly individuals with asymptomatic HUA. All asymptomatic HUA participants were treated with GGQLD. Venous blood samples were collected from all participants to isolate peripheral blood mononuclear cells (PBMCs), which were then analyzed for biological profiles using flow cytometry. Network pharmacology analysis was utilized to identify the potential pathways involved in the therapeutic effects of GGQLD. Transcriptomic patterns of cultured proximal tubule epithelial cells (PTECs) were evaluated via bulk RNA-seq, and critical differentially expressed genes (DEGs) were identified and verified through ELISA. Molecular docking and molecular dynamics (MD) simulation were employed to investigate the potential compounds in GGQLD that may be involved in treating HUA. RESULTS: Network pharmacology analysis revealed that immune-related pathways might be involved in the therapeutic mechanism of GGQLD. RNA-seq analysis confirmed the involvement of innate lymphoid cell (ILC) development-related genes and clock genes. Polychromatic flow cytometric analysis demonstrated that GGQLD treatment reduced the proportion of ILC3s in total ILCs in asymptomatic HUA patients. ELISA results showed that GGQLD treatment reduced the levels of activating factors, such as ILC3-IL-18 and IL-1ß, in the plasma of HUA patients. GGQLD was also found to regulate circadian clock gene expression in PBMCs to treat asymptomatic HUA. Furthermore, the interaction between 40 compounds in GGQLD and HDAC3 (Histone Deacetylase 3), NLRP3 (NOD-like receptor protein 3), RORA (RAR-related orphan receptor A), and REV-ERBα (nuclear receptor subfamily 1) revealed that GGQLD may regulate ILCs and clock genes to treat asymptomatic HUA. CONCLUSIONS: The regulation of circadian clock gene expression and the proportion of ILC cells may be involved in the therapeutic effects of GGQLD on asymptomatic HUA patients.

Multidimensional virtual screening approaches combined with drug repurposing to identify potential covalent inhibitors of SARS-CoV-2 3CL protease.

The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused an unprecedented global pandemic, and new cases are still on the rise due to the absence of effective medicines. However, developing new drugs within a short time is extremely difficult. Repurposing the existing drugs provides a fast and effective strategy to identify promising inhibitors. Here we focus on the screening of drugs database for discovering potential covalent inhibitors that target 3-chymotrypsin-like protease (3CLpro), an essential enzyme mediating viral replication and transcription. Firstly, we constructed a receptor-ligand pharmacophore model and verified it through decoy set. The importance of pharmacophore features was evaluated by combining molecular dynamics simulation with interaction analyses. Then, covalent docking was used to perform further screening. According to docking score and Prime/Molecular Mechanics Generalized Born Surface Area (MM-GBSA) score, total ten compounds obtained good scores and successfully established covalent bonds with the catalytic Cys145 residue. They also formed favorable interactions with key residues in active sites and closely integrated with 3CLpro with binding modes similar to known 3CLpro inhibitor. Finally, the top four hits DB08732, DB04653, DB01871 and DB07299 were further subjected to 100 ns molecular dynamics (MD) simulation and MM-GBSA binding free energy calculations. The results suggest that the four candidates show good binding affinities for 3CLpro, which warrants further evaluation for their in-vitro/in-vivo activities. Overall, our research methods provide a valuable reference for discovering promising inhibitors against SARS-CoV-2 and help to fight against the epidemic.Communicated by Ramaswamy H. Sarma.

Research progress on vaccine efficacy against SARS-CoV-2 variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to circulate worldwide and a variety of variants have emerged. Variants of concern (VOC) designated by the World Health Organization (WHO) have triggered epidemic waves due to their strong infectivity or pathogenicity and potential immune escape, among other reasons. Although large-scale vaccination campaigns undertaken globally have contributed to the improved control of SARS-CoV-2, the efficacies of current vaccines against VOCs have declined to various degrees. In particular, the highly infectious Delta and Omicron variants have caused recent epidemics and prompted concerns about control measures. This review summarizes current VOCs, the protective efficacy of vaccines against VOCs, and the shortcomings in methods for evaluating vaccine efficacy. In addition, strategies for responding to variants are proposed for future epidemic prevention and control as well as for vaccine research and development.

Impact of the Delta variant on vaccine efficacy and response strategies.

INTRODUCTION: The Delta variant of SARS-CoV-2 has caused a new wave of the COVID-19 epidemic in many countries. It is the most infectious variant of SARS-CoV-2 to date, and its high infectivity means that a higher proportion of the population needs to be vaccinated to reduce the disease burden, which poses a substantial public health challenge. AREAS COVERED: The evolution of the Delta variant is reviewed, including an overview of the Delta Plus variant with a K417N mutation in the RBD, which may confer an improved immune evasion ability. Decreases in serum neutralizing antibody titers after vaccination against Delta were greater than those against Alpha but less than those against Beta. The protective efficacy of existing vaccines against the Delta variant have declined and is related to the number of doses and the time since vaccination. EXPERT OPINION: The currently used vaccines are effective against hospitalization/severe disease due to the Delta variant. Accelerating the popularization of vaccination, improving the coverage rate, and the implementation of intervention measures, such as wearing masks, are effective means to control the spread of the Delta variant and other variants. However, vaccination alone against SARS-CoV-2 without intervention measures may lead to continuous spread and the emergence of new variants.

Mechanistic Exploration of Methionine 274 Acting as a "Switch" of the Selective Pocket Involved in HDAC8 Inhibition: An in Silico Study.

The overexpression of histone deacetylase 8 (HDAC8) causes several diseases, and the selective inhibition of HDAC8 has been touted as a promising therapeutic strategy due to its fewer side effects. However, the mechanism of HDAC8 selective inhibition remains unclear. In this study, flexible docking and in silico mutation were used to explore the structural change of methionine (M274) during HDAC8 binding to inhibitors, along with the reason for this change. Meanwhile, steered and conventional molecular dynamics simulations were employed to explore the stability of the structural change. The findings suggest that M274 acts as a "switch" to control the exposure of the HDAC8-selective pocket. The structure of M274 changes from flipped-out to flipped-in only when L-shaped inhibitors bind to HDAC8. This structural change forms a groove that allows these inhibitors to enter the selective pocket. In other HDACs, a leucine residue replaces M274 in situ, and the same structural change is not observed. The findings reveal the mechanism of selective HDAC8 inhibition and provide guidance for the development of novel selective inhibitors.

[Research progress of anticarious Chinese herbal].

Caries is a chronicly infectious disease which happens to the hard tissue of the teeth and is the most common dental disease of human. Many scholars have devoted to research anticarigenics drugs and the Chinese herbal was considerably concerned. The paper briefly introduces kinds of anticarigenics Chinese herbals, such as Turkish galls, TFA and Magnolia.