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Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)-one of the most studied DNA sensors-recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P P –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P P –/– Apoe –/– mice promoted atherogenesis ( P P -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.

Aims Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. Methods and results Apolipoprotein E-deficient (Apoe−/−) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe−/− mice. Genetic deletion of Sting in Apoe−/− mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe−/− mice. In contrast, bone marrow-specific STING expression in Apoe−/− mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. Conclusion Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

The development of nanomaterials in the field of biomedical has attracted much attention in the past decades. New mesoporous nanosilica (MNS) generation, called multi functionalized MNS, presents the promising applications for efficient encapsulation, controlled release, and intracellular delivery of therapeutic agents due to their unique physiochemical properties, such as large surface area and pore volume, tunable particle size, biocompatibility, and high loading capacity. In this review, we intensively discussed the multi functionalized MNSs that respond to the demand of physical stimuli (thermo, light, magnetic field, ultrasound, and electricity), chemical stimuli (pH, redox, H2O2), and biological stimuli (enzyme, glucose, ATP), individual or in combination. Moreover, the recent applications of multi functionalized MNSs, focusing on drug and other therapeutic agents delivery, diagnostic imaging, and catalysis are also summarized in order to promote the further development of MNSs as a universal platform in the bright upcoming future.

In this chapter, the authors aim for a discussion on what has been learned from using liposome technology for the delivery of phytoconstituents including the overview of liposomal nanosystems, formulation and delivery aspects, and the current applications of liposomal nanocarrier systems for phytoconstituents. Liposomes have been considered novel nanocarriers for phytochemicals due to their remarkable advantages such as biocompatibility, biodegradability, less toxicity, the capability to encapsulate both hydrophilic and lipophilic drugs, and targeted drug delivery to tumor sites. Liposomes can protect the encapsulated molecules from the outer environment, ensuring their stability and structure. The food industry, especially the food processing industry, can benefit from liposomes as well, since liposomes and their advantages offer a way to increase solubility of some compounds with demanding solubility properties, and protect compounds from the outer environment and ensure their activities. The encapsulation of active compounds, especially phytoconstituents, in liposomes has remarkably improved the performance of them in comparison to free compounds.

An emerging approach in development of nanocarriers for the delivery of hydrophobic anticancer drugs has recently been paid much attention. In this study, a redox-sensitive Heparin-ss-Pluronic F127 (Hep-ss-Plu127) nanogel was fabricated for paclitaxel (PTX) delivery. In the synthetic process, Plu127 was mono-activated by 4-Nitrophenyl chloroformate (NPC) and conjugated with Hep via redox-sensitive disulfide bond of cystamine. The chemical structure of the resulting product was characterized by fourier transform infrared (FTIR) and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The PTX-loaded Hep-ss-Plu127 nanogels were formed by solvent dialysis method and showed the hydrodynamic diameter of 91.4 ± 0.3 nm, determined by dynamic light scattering (DLS) instrument. Size and morphology of PTX-loaded Hep-ss-Plu127 nanogels were shown to be 104 nm and spherical in shape by transmission electron microscopy (TEM). In addition, PTX was effectively encapsulated into Hep-ss-Plu127 nanogels, which was around 66.2 ± 4.7% for drug loading efficiency and 13.2 ± 0.9% for drug loading content, determined by high performance liquid chromatography (HPLC). Overall, the redox-sensitive Pluronic F127-based nanogel was successfully synthesized and could be an effective nanocarrier that holds a great potential to enhance the redox responsiveness and efficacy for the delivery of PTX in cancer treatment.

Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P P Ser1177 phosphorylation in the aorta (P −/−) mice did not affect endothelial function and eNOSSer1177 phosphorylation in the aorta compared with non-diabetic PAR2−/− mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2−/− mice. FXa promoted JNK phosphorylation (P Ser1177 phosphorylation (P P Ser1177 phosphorylation (P