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Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism. Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE−/− mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1β, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1β production in culturing primary macrophages of wild type and NLRP3−/− knockout mice were investigated for mechanism analyses. Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1β, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway. Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1β by macrophages via the ROS-NLRP3-caspase-1 pathway.

Blockade of excessive Toll-like receptor (TLR) signaling is a therapeutic approach being actively pursued for many inflammatory diseases. Here we report a Chinese herb-derived compound, sparstolonin B (SsnB), which selectively blocks TLR2-and TLR4-mediated inflammatory signaling. SsnB was isolated from a Chinese herb, Spaganium stoloniferum; its structure was determined by NMR spectroscopy and x-ray crystallography. SsnB effectively inhibited inflammatory cytokine expression in mouse macrophages induced by lipopolysaccharide (LPS, a TLR4 ligand), Pam3CSK4 (a TLR1/TLR2 ligand), and Fsl-1 (a TLR2/TLR6 ligand) but not that by poly(I:C) (a TLR3 ligand) or ODN1668 (a TLR9 ligand). It suppressed LPS-induced cytokine secretion from macrophages and diminished phosphorylation of Erk1/2, p38a, IB␣, and JNK in these cells. In THP-1 cells expressing a chimeric receptor CD4-TLR4, which triggers constitutive NF-B activation, SsnB effectively blunted the NF-B activity. Co-immunoprecipitation showed that SsnB reduced the association of MyD88 with TLR4 and TLR2, but not that with TLR9, in HEK293T cells and THP-1 cells overexpressing MyD88 and TLRs. Furthermore, administration of SsnB suppressed splenocyte inflammatory cytokine expression in mice challenged with LPS. These results demonstrate that SsnB acts as a selective TLR2 and TLR4 antagonist by blocking the early intracellular events in the TLR2 and TLR4 signaling. Thus, SssB may serve as a promising lead for the development of selective TLR antagonistic agents for inflammatory diseases. Toll-like receptors (TLRs)2 are key components of innate immunity (1) expressed by macrophages, dendritic cells, and many other cell types (2, 3). TLRs serve as the first line of defense against invading pathogens such as bacteria and viruses. Currently more than a dozen TLRs have been identified, with the first nine being well characterized. Some TLRs, including TLR1, -2, -4, -5, and -6, are mainly located on the plasma membrane and recognize bacterial, fungal, and protozoan pathogens, whereas others, including TLR3, -7, -8, and -9, are mainly located on endosomal/lysosomal membranes where they bind viral RNAs or DNAs (4 -6). All TLRs use leucine-rich repeats to sense the ligands and the Toll/IL-1 receptor homologue (TIR) domain to trigger downstream signaling by binding to adaptor proteins MyD88 (7-9), TIRAP/Mal (10, 11), or TRIF (12, 13). The signaling initiated by TLRs is a double-edged sword. On the one hand, it may lead to confining or eliminating the invading organisms (14, 15); on the other hand, a prolonged and exaggerated response can cause tissue and organ damage (16,17). Moreover, TLR signaling triggered by exogenous or endogenous ligands contributes to the pathogenesis of many chronic inflammatory diseases (18). For example, TLR2 and TLR4 are involved in atherosclerosis (19,20), autoimmune colitis (21), systemic lupus erythematosus (22, 23), diabetes (24, 25), and Alzheimer disease (26,27). Thus, blockade of excessive TLR signaling is a therapeutic approach being actively pursu...

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