Design, synthesis and structure-activity relationship of novel 1,2,4-triazolopyrimidin-5-one derivatives targeting GABA and Na1.2 with antiepileptic activity.

A novel class of 7-phenyl-[1,2,4]triazol-5(4H)-one derivatives was designed and synthesized, and their in vivo anticonvulsant activities were evaluated using subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock (MES) tests. Compounds 3u, 4f and 4k exhibited significant anticonvulsant activities in the Sc-PTZ model with ED values of 23.7, 17.

Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial.

Background: Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19).

Methods: This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021.

Apolipoprotein A-IV and its derived peptide, T55-121, improve glycemic control and increase energy expenditure.

It is crucial to understand the glucose control within our bodies. Bariatric/metabolic surgeries, including laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB), provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes (T2D). For the first time, a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics.

Draft Genome of Naganishia uzbekistanensis from a Clinical Pulmonary Infection.

This study presents the first high-quality assembled genome of Naganishia uzbekistanensis, derived from a clinical isolate CY11558 obtained from a patient with a postoperative pulmonary infection. This work provides an improved reference assembly for downstream research and diagnosis of infections caused by this species.

The History of Studies on Oxetane Ring Formation in Paclitaxel Biosynthesis.

There is no doubt that breakthroughs in the enzyme-mediated formation of the oxetane ring in paclitaxel biosynthesis constitute significant milestones in the biosynthesis of complex natural products. In this review, we summarize the understanding of the biosynthesis of the oxetane ring of paclitaxel from different viewpoints. Generally, it covers five aspects, (1) a different understanding of the mechanistic formation of the oxetane ring on the basis of sound chemical reasoning, (2) a reasonable speculation of the biosynthetic pathways and suitable surrogate substrates for oxetane ring formation based on the natural and chemical logical analysis, (3) Taxus genome-enabled enzymes identification, (4) the discovery of different enzymes that mediate oxetane ring formation, and (5) a mechanistic investigation involving the use of isotopic labelling experiments and quantum chemical calculations.

Discovery of Metabolic Reprogramming 2-Quinolones as Effective Antimicrobials for MRSA-Infected Wound Therapy.

To date, the abuse of antibiotics and a gradual decline in novel antibiotic discovery enlarge the threat of drug-resistant bacterial infections, especially methicillin-resistant (MRSA). Herein, inspired by the unique structures and antibacterial activities of 2-quinolones, a class of novel 2-quinolones with substituted pyridines was synthesized. Notably, compound , the derivative with a methylpyridine fragment, showed potent antibacterial and antibiofilm activities, especially for MRSA strains (MIC = 0.

Rationally designed highly amphipathic antimicrobial peptides demonstrating superior bacterial selectivity relative to the corresponding α-helix peptide.

De novo design of antimicrobial peptides is a pivotal strategy for developing new antibacterial agents, leveraging its rapid and efficient nature. (XXYY), where X represents cationic residues, Y denotes hydrophobic residues, and n varies from 2 to 4, is a classical α-helix template. Based on which, numerous antimicrobial peptides have been synthesized.

Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential.

The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals.

Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential.

Clarification of the biosynthetic gene cluster involved in the antifungal prodrug echinocandin B and its robust production in engineered Aspergillus pachycristatus.

Echinocandin antifungals exhibit high efficacy against drug-resistant strains due to their unique mechanism of action. The production of their semi-synthetic precursors relies solely on microbial metabolism, leading to elevated production costs. Anidulafungin, an excellent echinocandin drug, is derived from echinocandin B (ECB), which is industrially produced by Aspergillus pachycristatus.

Butyrolactone I blocks the transition of acute kidney injury to chronic kidney disease in mice by targeting JAK1.

Chronic kidney disease (CKD) is a disease that affects more than 850 million people. Acute kidney injury (AKI) is a common cause of CKD, and blocking the AKI-CKD transition shows promising therapeutic potential. Herein, we found that butyrolactone I (BLI), a natural product, exerts significant nephroprotective effects, including maintenance of kidney function, inhibition of inflammatory response, and prevention of fibrosis, in both folic acid- and ureteral obstruction-induced AKI-CKD transition mouse models.

Multiple Enzymes Expressed by the Gut Microbiota Can Transform Typhaneoside and Are Associated with Improving Hyperlipidemia.

The mechanism of multiple enzymes mediated drug metabolism in gut microbiota is still unclear. This study explores multiple enzyme interaction process of typhactyloside (TYP) with gut microbiota and its lipid-lowering pharmacological activity. TYP, with bioavailability of only 2.

Self-Immobilizing Fluorogenic Probe for In Situ Labeling of Granzyme B Activity in Host Immune Response to Bacterial Infections.

Bacterial infections, particularly those caused by drug-resistant bacteria, represent a pressing global health challenge. During the interaction between pathogen infection and host defense, bacterial infections initiate the host's immune response, which involves the activation of proteases that play a critical role in antibacterial defense. Granzyme B (GzmB), a key immune-related biomarker associated with cytotoxic T lymphocytes (CTLs), plays a pivotal role in this process.

Tools for Intersectional Optical and Chemical Tagging on Cell Surfaces.

We present versatile tools for intersectional optical and chemical tagging of live cells. Photocaged tetrazines serve as "photo-click" adapters between recognition groups on the cell surface and diverse chemical payloads. We describe two new functionalized photocaged tetrazine structures which add a light-gating step to three common cell-targeting chemical methods: HaloTag/chloroalkane labeling, nonspecific primary amine labeling, and antibody labeling.

Spatiotemporal transcriptome and metabolome landscapes of cotton fiber during initiation and early development.

Cotton fibers are single cells that develop from the epidermal cells in the outer integument of developing seeds. The processes regulating fiber cell development have been extensively studied; however, the spatiotemporal transcriptome and metabolome profiles during the early stages of fiber development remain largely unknown. In this study, we profile the dynamics of transcriptome and metabolome during the early stages of cotton fiber cell development using a combination of spatial transcriptomic, single-cell transcriptomic, and spatial metabolomic analyses.

The spatiotemporal changes of metabolites in Pinellia ternata at different development stages by MALDI-MSI.

Pinellia ternata is an herb species in the Pinellia genus with significant economic value due to its medicinal properties. Understanding the accumulation and spatial distribution characteristics of metabolites during the development of the medicinal part, the rhizome of P. ternata (PR), provides a basis for targeted metabolic regulation and quality evaluation.

Oral barriers to food-derived active peptides and nano-delivery strategies.

Food-derived bioactive peptides are a class of peptides from natural protein. It may have biological effects on the human body and play a significant role in protecting human physiological health and regulating physiological metabolism, such as lowering blood pressure, lowering cholesterol, antioxidant, antibacterial, regulating immune activity, and so on. However, most of the natural food-derived functional peptides need to overcome a variety of barriers in the body to enter the blood circulation system and target to specific tissues to generate physiological activity.

Selective Synthesis of Cyclopeptides with a 2-Oxindole or 3a-Hydroxy-hexahydropyrrolo-[2,3-]indole Structure by Cytochrome P450 Enzymes.

The structural groups of 2-oxindole and tricyclic 3a-hydroxy-hexahydropyrrolo-[2,3-]indole (HO-HPI) are important pharmacophores. Chemical synthesis of complex alkaloids containing a 2-oxindole or HO-HPI moiety, especially the latter one, has been a long-standing challenge. Herein, we characterized the P450 enzyme AfnD, and its homologue proteins, HmtT, ClpD, KtzM, and LtzR, as cyclopeptide 2-oxindole and HO-HPI monooxygenases (cpOPMOs) that could introduce a 2-oxindole or HO-HPI moiety into the tryptophan-containing cyclopeptides in a pH-dependent manner.

Neutrophil Elastase as A Potential Target in Ischemia-Reperfusion Injury.

Neutrophil elastase (NE), a major protease in neutrophils, is important in promoting inflammation and multiple pathological processes. While NE is released abundantly in ischemiareperfusion (I/R) injury, the intricate relationship between NE and I/R injury remains unclear. We examine several aspects of how NE is involved in I/R injury.

Discovery of Novel Pyrimidine Derivatives as Human Pin1 Covalent Inhibitors.

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of Pin1 with a covalent inhibitor is a potential strategy for developing anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward Pin1, which were validated for their covalent binding to Cys113 of Pin1 by X-ray cocrystal structures of compounds (IC = 11.55 μM) and (IC = 3.

Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.

Interleukin-1 receptor-related kinase (IRAK4) is a widely expressed serine/threonine kinase involved in the regulation of innate immunity. IRAK4 plays a pivotal role as a key kinase within the downstream signaling pathway cascades of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs). The signaling pathways orchestrated by IRAK4 are integral to inflammatory responses, and its overexpression is implicated in the pathogenesis of inflammatory diseases, autoimmune disorders, and cancer.

Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome.

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPAR and attenuated metabolic syndrome by stimulating thermogenesis.

Computational approaches for the identification of novel metal-binding pharmacophores: advances and challenges.

Metalloenzymes are important therapeutic targets for a variety of human diseases. Computational approaches have recently emerged as effective tools to understand metal-ligand interactions and expand the structural diversity of both metalloenzyme inhibitors (MIs) and metal-binding pharmacophores (MBPs). In this review, we highlight key advances in currently available fine-tuning modeling methods and data-driven cheminformatic approaches.

Sensitive characterization of complex chemical reactions in black garlic preparation based on on-line extraction electrospray ionization mass spectrometry.

Changes in chemical composition during food processing and handling are crucial for the alteration of food flavor and function, and accurate characterization of key chemical reaction pathways in complex food matrices is one of the core challenges in food chemistry research. Here, this study attempts to establish a strategy for sensitive characterization of chemical reactions during food processing based on on-line extraction electrospray ionization mass spectrometry (oEESI-MS). The process of making garlic into black garlic, a traditional global flavor food, was chosen as an exemplary research template.