DL-3-n-Butylphthalide Attenuates Myocardial Hypertrophy by Targeting Gasdermin D and Inhibiting Gasdermin D Mediated Inflammation.

Pressure overload leads to a hypertrophic milieu that produces deleterious cardiac dysfunction. Inflammation is a key pathophysiological mechanism underpinning myocardial hypertrophy. DL-3-n-butylphthalide (NBP), a neuroprotective agent, also has potent cardioprotective effects. In this study, the potential of NBP to antagonize myocardial hypertrophy was evaluated in C57BL/6 mice in vivo and in rat primary cardiomyocytes in vitro. In mice, NBP treatment reduced cardiac hypertrophy and dysfunction in a transverse aortic constriction (TAC)-induced pressure overload model. In angiotensin (Ang) II-challenged cardiomyocytes, NBP prevents cell size increases and inhibits gasdermin D (GSDMD)-mediated inflammation. Furthermore, overexpression of GSDMD-N reduced the protective effects of NBP against Ang II-induced changes. Using molecular docking and MD simulation, we found that the GSDMD-N protein may be a target of NBP. Our study shows that NBP attenuates myocardial hypertrophy by targeting GSDMD and inhibiting GSDMD-mediated inflammation.

AZD4547 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Inflammation: The Role of FGFR1 in Renal Tubular Epithelial Cells.

INTRODUCTION: Inflammation plays an important role in the pathogenesis of acute kidney injury (AKI). Fibroblast growth factor receptor 1 (FGFR1) signaling is implicated in kidney pathology. AZD4547 is a small molecule inhibitor of FGFR1. MATERIALS AND METHODS: Here, we investigated whether AZD4547 could mitigate inflammatory responses in AKI. C57BL/6 mice were injected with lipopolysaccharide (LPS) to induce AKI. FGFR1 was blocked using AZD4547 or CRISPR/Cas9 genome editing. After immunofluorescent double-staining of kidney tissues showing that P-FGFR1 was localized to renal tubular epithelial cells, a tubular epithelial cell line (NRK-52E) was used for in vitro analysis. RESULTS: AZD4547 significantly reduced renal inflammation, cell apoptosis, and kidney dysfunction in AKI mice. In vitro, treatment of NRK-52E cells with AZD4547 attenuated LPS-induced inflammatory responses and was associated with downregulated P-FGFR1 levels. These findings were further confirmed in NRK-52E cells by knocking down the expression of FGFR1. CONCLUSION: Our findings provide direct evidence that FGFR1 mediates LPS-induced inflammation leading to renal dysfunction. We also show that AZD4547 is a potential therapeutic agent to reduce inflammatory responses in AKI. Both FGFR1 and AZD4547 may interesting therapeutic options to combat AKI.

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II-challenged vascular endothelium.

Vascular endothelial dysfunction plays a crucial role in the pathogenesis of cardiovascular diseases. Oxidative stress is a key pathophysiological mechanism underpinning endothelial dysfunction. Schisandrin C (Sch C), a dibenzocyclooctadiene derivative of Schisandra chinensis, has antioxidative properties. Here, we report the use of Sch C as a novel therapeutic for the treatment of angiotensin II (Ang II)-induced endothelial deficits and explore the underlying mechanisms and the target of Sch C. Our results demonstrated that Sch C treatment prevents aorta oxidative stress and improves relaxation in mice, challenged with subcutaneous infusion of Ang II. In addition, Sch C significantly ameliorates Ang II-induced oxidative stress in rat aortic endothelial cells. We then discovered that these antioxidative effects of Sch C are mediated through the induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Using an expression plasmid and molecular docking, we identified that Kelch-like ECH-associated protein-1 (Keap1), a negative regulator of Nrf2, is a target of Sch C. These findings provide evidence for the potential use of Sch C as an antioxidative agent for treatment of vascular endothelial deficits.

Schisandrin B protects against angiotensin II-induced endotheliocyte deficits by targeting Keap1 and activating Nrf2 pathway.

INTRODUCTION: Schisandrin B (SchB), the main active constituent in Schisandra chinensis, has antioxidant activities. Endothelial dysfunction leads to various cardiovascular diseases. Oxidative stress is a crucial pathophysiological mechanism underpinning endothelial dysfunction. METHODS: We elucidated the role and underlying mechanisms of SchB in angiotensin II-induced rat aortic endothelial-cell deficits and explored targets of SchB through siRNA analysis and molecular docking. We measured apoptosis by TUNEL and oxidative stress by dihydroethidium (DHE) and 2',7' -dichlorofluorescin diacetate (DCF) staining. RESULTS: Our results demonstrated that SchB significantly ameliorated oxidative stress, mitochondrial membrane-potential depolarization and apoptosis in angiotensin II-challenged rat aortic endothelial cells. We further discovered that these antioxidative effects of SchB were mediated through induction of Nrf2. Importantly, using molecular docking and molecular dynamic simulation, we identified that Keap1, an adaptor for the degradation of Nrf2, was a target of SchB. CONCLUSION: These findings support the potential use of SchB as a Keap1 inhibitor for attenuating oxidative stress, and Keap1 might serve as a therapeutic target in the treatment of cardiovascular diseases.