Urolithin A Hijacks ERK1/2-ULK1 Cascade to Improve CD8+ T Cell Fitness for Antitumor Immunity.

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell-mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA-mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA-ERK1/2-ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA-treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs.

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models.

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.

Safety and Efficacy of Antiviral Drugs for the Treatment of COVID-19: A Systematic Review.

Objective: To investigate the efficacy and safety of antiviral drugs in the treatment of coronavirus disease 2019 (COVID-19). Methods: All clinical trials of antiviral drug treatment for COVID-19 from December 2019 to December 2021 in CNKI, PubMed, Embase, Wanfang and VIP databases were searched by computer, and the results were systematically reviewed. Results: A total of 21 studies were included, including 5 randomized controlled studies, 5 non-randomized controlled studies, 3 retrospective cohort studies, 6 retrospective case series studies, and 2 observational studies, with a total of 2118 patients. The evaluated drugs included Ridzevir, Lopinavir/Ritonavir, Jingluwa, Fapiravi, Abidor, Danorivir, and interferon α. The evaluated antiviral drugs did not show superior efficacy for COVID-19 in clinical trials. In terms of safety, particular attention needs to be paid to the gastrointestinal side effects of lopinavir/ritonavir and the serious side effects of redsivir. Conclusion: There is no specific drug. Antiviral drugs have a greater therapeutic benefit for mild and usual patients, and in severe patients, lopinavir/ritonavir may not be effective. For critically ill patients, adefovir or more than two antiviral drugs can be used early. Antiviral drugs combined with traditional Chinese medicine treatment is effective. In view of the safety of the drug, it is necessary to consider the increase of serum uric acid caused by fapravi, the increase of bilirubin caused by abidol, and the gastrointestinal reactions of pitavir. In addition, other adverse reactions should also be noted.

Improved reproductive growth of euhalophyte Suaeda salsa under salinity is correlated with altered phytohormone biosynthesis and signal transduction.

Phytohormones are essential for plant reproductive growth. Salinity limits crop reproductive growth and yield, but improves reproductive growth of euhalophytes. However, little is known about the mechanisms underlying salinity's effects on plant reproductive growth. To elucidate the role of plant hormones in flower development of the euhalophyte Suaeda salsa under saline conditions, we analysed endogenous gibberellic acid (GA3,4), indoleacetic acid (IAA), zeatin riboside (ZR), abscisic acid (ABA), and brassinosteroids (BRs) during flowering in control (0 mM) and NaCl-treated (200 mM) plants. At the end of vegetative growth, endogenous GA3, GA4, ABA and BR contents in stems of NaCl-treated plants were significantly higher than those in controls. During flowering, GA3, GA4, IAA and ZR contents showed the most significant enhancement in flower organs of plants treated with NaCl when compared with controls. Additionally, genes related to ZR, IAA, GA, BR and ABA biosynthesis and plant hormone signal transduction, such as those encoding CYP735A, CYP85A, GID1, NCED, PIF4, AHP, TCH4, SnRK2 and ABF, were upregulated in S. salsa flowers from NaCl-treated plants. These results suggest that coordinated upregulation of genes involved in phytohormone biosynthesis and signal transduction contributes to the enhanced reproductive growth of S. salsa under salinity.