Discovery of Fluorescent Probe ABDS-2 for Farnesoid X Receptor Modulator Characterization and Cell-Based Imaging.

The farnesoid X receptor (FXR) regulates key physiological processes, such as bile acid homeostasis and lipid metabolism, making it an important target for drug discovery. However, the overactivation of FXR often leads to adverse effects. This study presents the development of a novel fluorescent probe utilizing the computer-aided drug design (CADD) approach to optimize linkers between more potent warhead and FITC fluorescent groups.

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19.

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CL), and papain-like protease (PL) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CL inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CL from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms.

SMARCA4 mutations and expression in lung adenocarcinoma: prognostic significance and impact on the immunotherapy response.

The switch/sucrose non-fermenting (SWI/SNF) complex family includes important chromatin-remodeling factors that are frequently mutated in lung adenocarcinoma (LUAD). However, the role of one family member, SMARCA4, in LUAD prognosis and immunotherapy sensitivity remains unclear. In the present study, 6745 LUAD samples from the cBioPortal database were used to analyze the relationships between SMARCA4 mutations and patient prognoses and clinical characteristics.

Fine-tuning pH sensor H98 by remote essential residues in the hydrogen-bond network of mTASK-3.

TASK-3 generates a background K conductance which when inhibited by acidification depolarizes membrane potential and increases cell excitability. These channels sense pH by protonation of histidine residue H98, but recent evidence revealed that several other amino acid residues also contribute to TASK-3 pH sensitivity, suggesting that the pH sensitivity is determined by an intermolecular network. Here we use electrophysiology and molecular modeling to characterize the nature and requisite role(s) of multiple amino acids in pH sensing by TASK-3.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process.

Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets.

TWIK-related acid-sensitive K (TASK) channels, including TASK-1, TASK-3, and TASK-5, are important members of the two-pore domain potassium (K) channel family. TASK-5 is not functionally expressed in the recombinant system. TASK channels are very sensitive to changes in extracellular pH and are active during all membrane potential periods.

A small-molecule Skp1 inhibitor elicits cell death by p53-dependent mechanism.

Skp1 overexpression promotes tumor growth, whereas reduced Skp1 activity is also linked with genomic instability and neoplastic transformation. This highlights the need to gain better understanding of Skp1 biology in cancer settings. To this context, potent and cellularly active small-molecule Skp1 inhibitors may be of great value.

Research on the Application Value of Intelligent Heating Box in Newborn Nursing.

The aim of this study was to explore the application effect of intelligent incubator in neonatal care. We selected the period from January 1, 2018, to December 31, 2020, where there were 100 full-term and premature babies born in a hospital and transferred to the neonatal intensive care unit (NICU) within 1 hour after birth. Before the improved heat preservation, 100 full-term infants in the control group and 100 full-term infants in the intervention group of the intelligent warming box were formed into a full-term infant group for a comparative study.

Phytochemical library screening reveals betulinic acid as a novel Skp2-SCF E3 ligase inhibitor in non-small cell lung cancer.

Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome-dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant-derived Skp2 inhibitor, betulinic acid (BA), via high-throughput structure-based virtual screening of a phytochemical library.

Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma.

Aberrant activation of the Hedgehog (Hh) pathway is implicated in the pathogenesis and development of multiple cancers, especially Hh-driven medulloblastoma (MB). Smoothened (SMO) is a promising therapeutic target of the Hh pathway in clinical cancer treatment. However, SMO mutations frequently occur, which leads to drug resistance and tumor relapse.

Isolation, expression, and biochemical characterization: nitrite reductase from LJ01.

Biological remediation of toxic oxygen-containing anions such as nitrate that are common in the environment is of great significance. Therefore, it is necessary to understand the specific role of nitrate and nitrite reductase in the bioremediation process. LJ01, which was isolated from traditional Chinese soybean paste, effectively degraded nitrite (such as NaNO) at 0-15 mmol L in LB medium.

Suppression of Musashi‑2 by the small compound largazole exerts inhibitory effects on malignant cells.

RNA‑binding protein Musashi‑2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non‑small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients.

Silencing Of MAGI1 Promotes The Proliferation And Inhibits Apoptosis Of Glioma Cells Via The Wnt/β-Catenin And PTEN/AKT Signaling Pathways.

Background: Membrane-associated guanylate kinase (MAGUK) with inverted orientation protein 1 (MAGI1) is a novel member of the MAGUK family with a vital role in tumor progression related to invasion and metastasis. However, the function of MAGI1 in glioma is currently unknown. We therefore analyzed the expression of MAGI1 protein in human glioma samples, glioma cell lines and glioma stem cells (GSCs), and explored its effects on glioma cell proliferation and apoptosis.

Phloretin ameliorates hyperuricemia-induced chronic renal dysfunction through inhibiting NLRP3 inflammasome and uric acid reabsorption.

Background: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown.

4-Aryl Pyrrolidines as Novel Orally Efficacious Antimalarial Agents. Part 2: 2-Aryl--(4-arylpyrrolidin-3-yl)acetamides.

Malaria is caused by infection from the parasite and kills hundreds of thousands of people every year. Emergence of new drug resistant strains of demands identification of new drugs with novel chemotypes and mechanisms of action. As a follow up to our evaluation of 4-aryl--benzylpyrrolidine-3-carboxamides as novel pyrrolidine-based antimalarial agents, we describe herein the structure-activity relationships of the reversed amide homologues 2-aryl--(4-arylpyrrolidin-3-yl)acetamides.

CXCL13/CXCR5 signaling axis in cancer.

The tumor microenvironment comprises stromal and tumor cells which interact with each other through complex cross-talks that are mediated by a variety of growth factors, cytokines, and chemokines. The chemokine ligand 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are among the key chemotactic factors which play crucial roles in deriving cancer cell biology. CXCL13/CXCR5 signaling axis makes pivotal contributions to the development and progression of several human cancers.

4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides.

Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases.

Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a K value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC value of 100 nM.

Enantioselective Synthesis of Planar Chiral Pyridoferrocenes via Palladium-Catalyzed Imidoylative Cyclization Reactions.

A highly efficient synthesis of planar chiral pyrido[3,4- b] ferrocenes by a palladium-catalyzed enantioselective isocyanide insertion/desymmetric C(sp)-H bond activation reaction was developed. Various planar chiral pyridoferrocenes were obtained in high yields with good to excellent enantioselectivity under mild conditions (up to 99% yield, 99% ee), enabled by a unique SPINOL-derived phosphoramidite ligand.

Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.

SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV).

Pentafluorosulfanyl-Substituted Benzopyran Analogues As New Cyclooxygenase-2 Inhibitors with Excellent Pharmacokinetics and Efficacy in Blocking Inflammation.

In this report, we disclose the design and synthesis of a series of pentafluorosulfanyl (SF) benzopyran derivatives as novel COX-2 inhibitors with improved pharmacokinetic and pharmacodynamic properties. The pentafluorosulfanyl compounds showed both potency and selectivity for COX-2 and demonstrated efficacy in several murine models of inflammation and pain. More interestingly, one of the compounds, R,S-3a, revealed exceptional efficacy in the adjuvant induced arthritis (AIA) model, achieving an ED as low as 0.

Proteomic identification of the oncoprotein STAT3 as a target of a novel Skp1 inhibitor.

The S phase kinase-associated protein 1 (Skp1), an adaptor protein of the Skp1-Cul1-F-box protein complex, binds the ubiquitin E3 ligase Skp2 and is critical to its biological functions. Targeting of Skp1 by a small compound 6-O-angeloylplenolin (6-OAP) results in dissociation and degradation of Skp2 and mitotic arrest of lung cancer cells. Here, by using a proteome microarray containing 16,368 proteins and a biotinylated 6-OAP, we identified 99 proteins that could bind 6-OAP, with Skp1 and STAT3 sitting at the central position of the 6-OAP interactome.

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists.

Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design.