bp-1-102 and Inflammation

The development of non-invasive pharmacological therapies to prevent the progression and rupture of intracranial aneurysms (IAs) is an important field of research. This study attempts to reveal the role of BP-1-102, an oral bioavailable signal transducer and activator of transcription 3 (STAT3) inhibitor, in IA. We first constructed an IA mouse model by injecting elastase into the cerebrospinal fluid with simultaneous induction of hypertension by deoxycorticosterone acetate (DOCA) implantation. The results showed that the proportion of IA rupture in mice after BP-1-102 administration was significantly reduced, and the survival time was significantly extended. Further research showed that compared with the vehicle group, the proportion of macrophages infiltrated at the aneurysm and the expression of pro-inflammatory cytokines in the BP-1-102 administration group were significantly reduced. The contractile phenotype vascular smooth muscle cell (VSMC) specific markers, SM22α and αSMA, were significantly upregulated in the BP-1-102 group. Furthermore, we found that BP-1-102 inhibited the expression of critical proteins in the nuclear factor kappa-B and Janus kinase 2/STAT3 signalling pathways. Our study shows that BP-1-102 significantly decreases the rupture of IA, reduces the inflammatory responses and modulates the phenotype of VSMCs, suggesting that BP-1-102 could be utilised as a potential intervention drug for IA.

Topics: Aminosalicylic Acids; Aneurysm, Ruptured; Animals; Cytokines; Disease Models, Animal; Inflammation; Intracranial Aneurysm; Macrophages; Male; Mice; Mice, Inbred C57BL; Signal Transduction; STAT3 Transcription Factor; Sulfonamides

Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis.. Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling.. Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition.. Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract.

Topics: Aminosalicylic Acids; Animals; Benzofurans; Blood Coagulation; Cecum; Cell Membrane Permeability; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Ligation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Molecular Targeted Therapy; Naphthoquinones; Phosphotyrosine; Punctures; RAW 264.7 Cells; Sepsis; STAT3 Transcription Factor; Sulfonamides; Suppression, Genetic; Survival Analysis; Thromboplastin; Toll-Like Receptor 4