Atherosclerotic cardiovascular disease is one of the most common causes of morbidity and mortality worldwide 1 . Atherosclerosis is considered a chronic inflammatory disease, initiated by the retention of plasma apolipoprotein B (apoB)-containing lipoproteins in focal areas of the arterial tree 2,3 . The cholesterol and oxidized phospholipids in these lipoproteins induce the activation of endothelial cells, which subsequently recruit monocytes into the subendothelial space 4,5 . In the arterial intima, monocytes differentiate into pro-inflammatory macrophages that locally amplify the inflammatory response 6 . In addition, macrophages engulf lipoproteins in the intima to form lipid-laden foam cells, giving rise to early atherosclerotic lesions. If the pro-inflammatory state persists, the atherosclerotic lesions progress to an advanced stage characterized by increased macrophage apoptosis and defective clearance of apoptotic cells 7-9 . This catastrophic combination promotes plaque necrosis, a key feature of 'vulnerable' plaques that can trigger occlusive luminal thrombosis and its consequences, namely, myocardial infarction, stroke and sudden cardiac death 1,10 . The risk of these cardiovascular events remains fairly high in the general population despite treatment with lipid-lowering therapies, notably statins but also PCSK9 inhibitors 11,12 . In theory, cardiovascular disease could be eliminated if apoB-containing lipoproteins could be decreased to very low levels early in life. However, this strategy is currently not practical for widespread application mainly because of low compliance and adverse effects in certain individuals. Moreover, the safety concerns of using cholesterol-lowering drugs in childhood have not yet been fully evaluated. For this reason, novel anti-inflammatory therapies are being developed to further reduce the risk of cardiovascular disease; however, these efforts are hampered by the low bioavailability, poor target specificity and high toxicity of conventional anti-inflammatory drugs. Furthermore, identifying which individuals are at risk of developing clinically dangerous vulnerable plaques remains a challenge.Nanotechnology is particularly advantageous for addressing these challenges. Specifically, extensive Apolipoprotein B (apoB)-containing lipoproteinsCholesterol-rich lipoproteins, such as LDL and chylomicron remnants, that have a crucial role in atherogenesis. 'Vulnerable' plaquesA type of atherosclerotic plaque composed of a lipid-rich necrotic core and thin overlying fibrous cap. These plaques are highly unstable and their rupture can trigger acute thrombosis and its consequences, namely myocardial infarction and stroke.

We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist TUG‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3‐Leiden.CETP mice to either regular light‐dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light‐dark cycles (12 hours shifts), as a well‐established model for shift work. We found that mice exposed to 15 weeks of alternating light‐dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light‐dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light‐dark cycles directly aggravates atherosclerosis development.