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De novo discovery of cyclic peptide inhibitors of IL-11 signaling.
Bioorg Med Chem
November 2024
Takeda Development Center Americas, Inc., 9625 Towne Centre Drive, San Diego, CA 92121, USA.
Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited.
View Article and Find Full Text PDFImpaired coagulation parameters in early RA are restored by effective antirheumatic therapy: a prospective pilot study.
RMD Open
December 2024
Rheumatology, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
Objectives: To assess the effect of treatment on haemostatic parameters in patients with early rheumatoid arthritis (RA).
Methods: Patients with newly diagnosed RA started methotrexate and were randomised to additional conventional treatment, certolizumab pegol, abatacept or tocilizumab. Several biomarkers for haemostasis were analysed including parameters of the two global haemostatic assays-overall haemostatic potential (OHP) and endogenous thrombin potential (ETP), as well as single haemostatic factors-fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, thrombin activatable fibrinolysis inhibitor (TAFI) and clot lysis time (CLT) in 24 patients at baseline, 12 and 24 weeks after the start of the treatment.
Vascular Endothelial Dysfunction and Immunothrombosis in the Pathogenesis of Atrial Fibrillation.
Clin Appl Thromb Hemost
December 2024
Department of Medicine, Division of Cardiology, Loyola University Medical Center, Maywood, IL, USA.
Atrial Fibrillation (AF) induces proinflammatory processes which incite vascular endothelial activation and dysfunction. This study seeks to examine the potential relationship between various endothelial, inflammatory, thrombotic, and renin-angiotensin-system (RAS) biomarkers in AF patients.Blood samples were from AF patients (n = 110) prospectively enrolled in this study prior to their first AF ablation.
View Article and Find Full Text PDFNovel Deep Sea Isoindole Alkaloid FGFC1 Exhibits Its Fibrinolytic Effects by Inhibiting Thrombin-Activatable Fibrinolysis Inhibitor.
Pharmaceuticals (Basel)
October 2024
Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
Background: The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM).
Methods: In this study, the investigation focused on the unique target TAFI of fungi fibrinolytic compound 1 (FGFC1), a novel fibrinolytic compound sourced from the deep sea. In this sense, the regulation of TAFI by FGFC1, in comparison to established TAFI inhibitors such as DS-1040 and PCTI in hPPP, was investigated, which was validated through the molecular docking of FGFC1 to TAFI.
High-dose atorvastatin and rosuvastatin reduce the levels of neutrophil extracellular trap-related proteins in coronary artery disease: association with prothrombotic state.
Pol Arch Intern Med
October 2024
Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland; Krakow Center for Medical Research and Technologies, St. John Paul II Hospital, Kraków, Poland.
Article Synopsis
- The study aimed to investigate how high-dose statins impact the formation of neutrophil extracellular traps (NETs) in patients with coronary artery disease (CAD).
- A group of 130 patients was monitored before and after starting statin therapy, revealing significant reductions in proteins linked to NETs, such as citrullinated histone H3, myeloperoxidase, and neutrophil elastase.
- These reductions correlated with decreased inflammation markers and changes that suggest improved clot formation properties, indicating that statins may have beneficial effects beyond just lowering LDL cholesterol.
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