Discovery of a 2'-α-Fluoro-2'-β--(fluoromethyl) Purine Nucleotide Prodrug as a Potential Oral Anti-SARS-CoV-2 Agent.

A novel 2'-α-fluoro-2'-β--(fluoromethyl) purine nucleoside phosphoramidate prodrug has been designed and synthesized to treat SARS-CoV-2 infection. The SARS-CoV-2 central replication transcription complex (C-RTC, nsp12-nsp7-nsp8) catalyzed in vitro RNA synthesis was effectively inhibited by the corresponding bioactive nucleoside triphosphate (). The cryo-electron microscopy structure of the C-RTC: complex was also determined.

Rbfox3 Promotes Transformation of MDSC-Like Tumor Cells to Shape Immunosuppressive Microenvironment.

Myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) contribute to the malignant progression of tumors by exerting immunosuppressive effects. Bacterial lipopolysaccharides (LPS) have been widely demonstrated in various types of solid tumors. LPS can promote the malignant progression of tumors, which mechanism has not yet been fully elucidated.

Discovery of Spirosnuolides A-D, Type I/III Hybrid Polyketide Spiro-Macrolides for a Chemotherapeutic Lead against Lung Cancer.

Four new macrolides, spirosnuolides A-D (-, respectively), were discovered from the termite nest-derived sp. INHA29. Spirosnuolides A-D are 18-membered macrolides sharing an embedded [6,6]-spiroketal functionality inside the macrocycle and are conjugated with structurally uncommon side chains featuring cyclopentenone, 1,4-benzoquinone, hydroxyfuroic acid, or butenolide moieties.

Capture of Totipotency in Mouse Embryonic Stem Cells in the Absence of Pdzk1.

Totipotent cells can differentiate into three lineages: the epiblast, primitive endoderm, and trophectoderm. Naturally, only early fertilized embryos possess totipotency, and they lose this ability as they develop. The expansion of stem cell differentiation potential has been a hot topic in developmental biology for years, particularly with respect to the generation totipotent-like stem cells.

Dream of the Endless: Special Considerations in Procedural Sedation.

Procedural sedation and analgesia (PSAA) is integral to facilitating painful and anxiety-inducing medical procedures in the emergency department (ED). Optimal PSAA enhances procedural success and improves both patient and provider satisfaction. The selection of appropriate sedative and analgesic agents, routes, and dosages, which depend on various patient- and procedure-specific factors is a complex process.

Perturbation of mammary epithelial cell apicobasal polarity by RHBDF1-facilitated nuclear translocation of PKCζ.

Background: The establishment of apicobasal polarity in epithelial cells is of critical importance in morphogenesis of mammary gland and other secretive gland tissues. The demise of the polarity is a critical step in early stages of tumorigenesis such as in breast ductal carcinoma in situ. The underlying molecular mechanism thus warrants in-depth investigations.

Screening Inhibitors of α-Amylase in Polygala Radix Based on an Online Targeted Detection System and Molecular Docking.

Introduction: Targeted screening of inhibitors of key enzymes in the progression of diabetes from natural products is one of the effective methods for the treatment of diabetes. Polygala has been proved to reduce glucose levels; however, the bioactive compounds in Polygalae Radix (PR) that have anti-diabetic properties are unknown.

Objective: The purpose of this study was to explore the material basis of the anti-diabetic effect of PR by inhibiting α-amylase through an online detection system and molecular docking.

Enantioselective 1,4-Borylamination via Copper-Catalyzed Cascade Hydroborylation and Hydroamination of Arylidenecyclopropanes.

Compounds bearing both boryl and amino groups at distal positions are invaluable synthons for synthesizing pharmaceuticals, drug candidates, and natural products, but their catalytic enantioselective synthesis remains rarely explored. We report the first enantioselective 1,4-borylamination reaction through a copper-catalyzed cascade hydroborylation and hydroamination of arylidenecyclopropanes. This reaction combines four readily available components in a highly chemo-, site-, and enantioselective fashion (>20:1 r.

Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids.

Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6-10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a-c to 17a-c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines.

RHBDF1 promotes PERK expression through the JNK/FoxO3 pathway in breast cancer cells.

Human rhomboid family-1 ( ) gene is recognized as an oncogene involved in breast cancer development. Previous studies have indicated that RHBDF1 contributes significantly to endoplasmic reticulum (ER) protein homeostasis by stabilizing the binding immunoglobulin protein (BiP) and promoting the unfolded protein response (UPR). Here, we report a relationship between RHBDF1 and the ER stress sensors PERK, IRE1, and ATF6.

Metabolomic analysis of the impact of red ginseng on equine physiology.

Introduction: Red ginseng (RG), a traditional herbal remedy, has garnered attention owing to its diverse health benefits resulting from its complex composition. However, extensive research is needed to substantiate the efficacy of RG and understand the underlying mechanisms supporting these benefits. This study aimed to identify potential biomarkers and investigate the impact of RG on related metabolic pathways in horse plasma using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics.

Translation Initiation Factor-2S2 (eIF2S2) Contributes to Cervical Carcinogenesis by Inhibiting the TGF-β/SMAD4 Signaling Pathway.

The deregulation of protein translational machinery and the oncogenic role of several translation initiation factors have been extensively investigated. This study aimed to investigate the role of eukaryotic translation initiation factor 2S2 (eIF2S2, also known as eIF2β) in cervical carcinogenesis. Immunohistochemical analysis of human cervical carcinoma tissues revealed a stage-specific increase in eIF2S2 expression.

Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies.

Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems.

Nonclinical Pharmacokinetics Study of OLX702A-075-16, -Acetylgalactosamine Conjugated Asymmetric Small Interfering RNA (GalNAc-asiRNA).

In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel -acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy.

Molecular basis of facilitated target search and sequence discrimination of TALE homeodomain transcription factor Meis1.

Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode).

Enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins using cinchona-derived bifunctional organocatalysts.

Despite the extensive use of N-heteroarenes in pharmaceuticals and natural products, efficient methods for selective alkylation at the C-4 position of 2-pyridone are scarce. We developed an enantioselective Michael addition of 3-hydroxy-2-pyridone to nitroolefins at the C-4 position using cinchona-derived bifunctional squaramide organocatalysts, achieving up to 95% yield and >99% ee. This selectivity is driven by the bifunctional organocatalysts' hydrogen bonding interactions with 3-hydroxy-2-pyridone and nitroolefins under mild conditions.

CPD Success With Technagogy in Health Professions: Determinants and Merits.

Introduction: Continuing professional development (CPD) has become a common strategy to address the gaps in knowledge and competencies during the pandemic. Given the drastic changes in the learning environment, this study explored "technagogy" or teaching with technology in CPD in the health professions.

Methods: A mixed-methods study was used to ascertain the determinants and merits of CPD success from the participants' perspectives ( n = 237).

PTGES2 and RNASET2 identified as novel potential biomarkers and therapeutic targets for basal cell carcinoma: insights from proteome-wide mendelian randomization, colocalization, and MR-PheWAS analyses.

Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC.