Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination.

BACKGROUND: Sepsis and its associated heart failure are among the leading causes of death. Gramine, a natural indole alkaloid, can be extracted from a wide variety of raw plants, and it exhibits therapeutic potential in pathological cardiac hypertrophy. However, the effect of gramine on inflammatory cardiomyopathy, particularly sepsis-induced myocardial injury, remains an unexplored area. PURPOSE: To determine the role of gramine in sepsis-induced myocardial dysfunction and explore its underlying mechanism. STUDY DESIGN AND METHODS: In mice, sepsis was established by intraperitoneally injecting lipopolysaccharide (LPS, 10 mg/kg). Subsequently, the effects of gramine administration (50 or 100 mg/kg) on LPS-triggered cardiac dysfunction in mice were investigated. For in vitro studies, isolated primary cardiomyocytes were used to assess the effect of gramine (25 or 50 µM) on LPS-induced apoptosis and inflammation. Additionally, molecular docking, co-immunoprecipitation and ubiquitination analyzes were conducted to explore the underlying mechanisms. RESULTS: Gramine visibly ameliorated sepsis-induced cardiac dysfunction, inflammatory response, and mortality in vivo. Moreover, it significantly alleviated LPS-induced apoptotic and inflammatory responses in vitro. Furthermore, target prediction for gramine using the SuperPred website indicated that the nuclear factor NF-κB p105 subunit was one of the molecules ranked in priority order with a high model accuracy and a high probability score. Molecular docking studies demonstrated that gramine effectively docked to the death domain of NF-κB p105. Mechanistic studies revealed that gramine suppressed the processing of NF-κB p105 to p50 by inhibiting NF-κB p105 ubiquitination. Additionally, the protective effect of gramine on cardiac injury was almost abolished by overexpressing NF-κB p105. CONCLUSION: Gramine is a promising bioactive small molecule for treating sepsis-induced myocardial dysfunction, which acts by docking to NF-κB p105 and inhibiting NF-κB p105 ubiquitination, thus preventing its processing to NF-κB p50. Therefore, gramine holds potential as a clinical drug for treating myocardial depression during sepsis.

Vitamin D protects against diabetic nephropathy: Evidence-based effectiveness and mechanism.

Vitamin D has been suggested to harbor multiple biological activities, among them the potential of vitamin D in the protection of diabetic nephropathy (DN) has attracted special attention. Both animal studies and clinical trials have documented an inverse correlation between low vitamin D levels and DN risk, and supplementation with vitamin D or its active derivatives has been demonstrated to improve endothelial cell injury, reduce proteinuria, attenuate renal fibrosis, and resultantly retard DN progression. Vitamin D exerts its pharmacological effects primarily via vitamin D receptor, whose activation inhibits the renin-angiotensin system, a key culprit for DN under hyperglycemia. The anti-DN benefit of vitamin D can be enhanced when administrated in combination with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Mechanistic studies reveal that pathways relevant to inflammation participate in the pathogenesis of DN, however, consumption of vitamin D-related products negatively regulates inflammatory response at multiple levels, indicated by inhibiting macrophage infiltration, nuclear factor-kappa B (NF-κB) activation, and production of such inflammatory mediators as transforming growth factor-ß(TGF-ß), monocyte chemoattractant protein 1(MCP-1), and regulated upon activation normal T cell expressed and secreted protein(RANTES). The robust anti-inflammatory property of vitamin D-related products allows them with a promising renoprotective therapeutic option for DN. This review summarizes new advances in our understanding of vitamin D-related products in the DN management.