A series of 3-oxo-C₁₂-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

In eukaryotic cells, the shortening and removal of the poly(A) tail of cytoplasmic mRNA by deadenylase enzymes is a critical step in post-transcriptional gene regulation. The ribonuclease activity of deadenylase enzymes is attributed to either a DEDD (Asp-Glu-Asp-Asp) or an endonuclease–exonuclease–phosphatase domain. Both domains require the presence of two Mg²⁺ ions in the active site. To facilitate the biochemical analysis of deadenylase enzymes, we have developed a fluorescence-based deadenylase assay. The assay is based on end-point measurement, suitable for quantitative analysis and can be adapted for 96- and 384-well microplate formats. We demonstrate the utility of the assay by screening a chemical compound library, resulting in the identification of non-nucleoside inhibitors of the Caf1/CNOT7 enzyme, a catalytic subunit of the Ccr4–Not deadenylase complex. These compounds may be useful tools for the biochemical analysis of the Caf1/CNOT7 deadenylase subunit of the Ccr4–Not complex and indicate the feasibility of developing selective inhibitors of deadenylase enzymes using the fluorescence-based assay.

Cardiovascular diseases (CVDs) are as menacing as ever and still continue to kill adults worldwide, notwithstanding tremendous efforts to decrease their consequent mortality and morbidity. Lately, a growing body of research indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptors expressed on myeloid cells-1 (TREM-1) was shown to induce and amplify the inflammation in both acute and chronic disease’ pathogenesis and progression, which hence makes it one of the most important complication factors of CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications, and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We critically analyzed and summarized our findings and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management, and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions, such as acute myocardial infarction (AMI) and atherosclerosis. Although most therapeutic approaches are yet to be elucidated, our present research outcome displays a promising future to utilizing the TREM-1 pathway as a potential target for understanding and managing CVDs.

β‐Blockers reduce mortality and improve symptoms in people with heart disease; however, current clinically available β‐blockers have poor selectivity for the cardiac β ₁ ‐adrenoceptor (AR) over the lung β ₂ ‐AR. Unwanted β ₂ blockade risks causing life‐threatening bronchospasm and reduced efficacy of β ₂ ‐agonist emergency rescue therapy. Thus, current life‐prolonging β‐blockers are contraindicated in patients with both heart disease and asthma. Here, we describe NDD‐713 and ‐825, novel highly β ₁ ‐selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed in Chinese hamster ovary cells demonstrate that NDD‐713 and ‐825 have nanomolar β ₁ ‐AR affinity >500‐fold β ₁ ‐AR vs. β ₂ ‐AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β ₁ ‐mediated reduction of heart rate while showing no effect on β ₂ ‐mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β‐blocker therapy for the large number of patients with heart and respiratory or peripheral vascular comorbidities.—Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective β ₁ ‐adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB J. 31, 3150–3166 (2017). www.fasebj.org

Triggering receptor expressed on myeloid cells-1 (TREM-1), a member of the immunoglobulin superfamily, plays a crucial role in amplifying inflammatory responses, thereby contributing to the pathogenesis and progression of various inflammatory diseases. This review presents a comprehensive analysis of the current understanding of TREM-1 signaling and its dysregulation in disease pathology. Additionally, it explores the prognostic significance of TREM-1 across a spectrum of conditions. Targeting TREM-1 signaling represents a promising therapeutic approach for managing a wide range of diseases, including cancer, neurodegenerative disorders, cardiovascular diseases, and other inflammation-driven conditions. Previous reviews on TREM-1 have largely focused on its immunological role across diverse disease conditions and selective peptide-based inhibitors targeting its signaling pathway. However, recent discoveries have identified small-molecule modulators of TREM-1 that offer new opportunities for therapeutic intervention. Incorporating these findings would provide a more comprehensive and updated perspective on TREM-1 biology, particularly regarding its molecular regulation, drug-target potential, and translational relevance in inflammatory and immune-mediated disorders. Advances in this field are expected to be driven by structure-based drug design, particularly in the development of TREM-1 inhibitors. However, further research is needed to elucidate the predictive value of TREM-1 alterations and to evaluate them in prospective human studies prior to clinical decision-making.