ABSTRACT
Uncontrolled inflammation is a leading cause of various chronic diseases. Cinnamaldehyde (CA) is a major bioactive compound isolated from the essential oil of the leaves of Cinnamomum osmophloeum kaneh that exhibits anti-inflammatory activity; however, the use of CA is limited by its cytotoxicity. Here, we synthesized three CA derivatives and identified 4-hydroxycinnamaldehyde-galactosamine (HCAG) as a low toxicity anti-inflammatory compound in vitro (HCAG IC50 â« 1600 µM; CA IC50=40 µM) and in vivo. HCAG reduced pro-inflammatory mediator expression in LPS-activated macrophages by inhibiting MAPK and PKC-α/δ phosphorylation, decreasing ROS generation and reducing NF-κB activation. HCAG also reduced NLRP3 inflammasome-derived IL-1ß secretion by inhibiting the ATP-mediated phosphorylation of AKT and PKC-α/δ. In a mouse model of LPS-induced renal inflammation, we observed reduced albuminuria and a mild degree of glomerular proliferation, glomerular sclerosis and periglomerular inflammation in the HCAG-treated mice compared with the vehicle-treated mice. The underlying mechanisms for these renoprotective effects involved: (1) inhibited NLRP3 inflammasome activation; (2) decreased superoxide anion levels and apoptosis; and (3) suppressed activation of NF-κB and related downstream inflammatory mediators.
Subject(s)
Acrolein/analogs & derivatives , Anti-Inflammatory Agents/pharmacology , Galactosamine/analogs & derivatives , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Nephritis/drug therapy , Acrolein/pharmacology , Animals , Cell Survival/drug effects , Chemokine CCL2/metabolism , Drug Evaluation, Preclinical , Female , Galactosamine/pharmacology , Inflammasomes/antagonists & inhibitors , Interleukin-6/metabolism , Kidney/drug effects , Kidney/immunology , Kidney/pathology , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Nephritis/immunology , Nephritis/metabolism , RAW 264.7 Cells , Reactive Oxygen Species/metabolism , Signal Transduction , Toll-Like Receptor 4/metabolismABSTRACT
The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litseacubeba, a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model.