During the first year of life
During the first year of life, there was no interaction between cholesterol precursors and cholestanol, suggesting that cholesterol homeostasis was not yet developed. From the age of 1 year, cholesterol homeostasis could be considered intact. According to Fig. 1, cholesterol Cisatracurium Besylate prevailed cholesterol synthesis from the age of 1 to the age of 10 years. Thus, the lathosterol/cholestanol ratios shown in Fig. 1 increased from the low levels in the 1–10 year old (0.35–0.45) to 0.66 in the age group 11–15 years. In fact, a similar lathosterol/cholestanol ratio was observed earlier in 12-year old boys in The Cardiovascular Risk in Young Finns Study, and the ratio still increased up to about 0.80 in the 18-year-old boys . These previous results confirm our conclusion that in adolescence cholesterol synthesis prevails cholesterol absorption. Whether this childhood profile of cholesterol metabolism from 1 to 10 years of age with prevailing cholesterol absorption is proatherogenic warrants further investigation. However, the prevailing cholesterol absorption emphasizes to consider the importance of dietary cardiovascular risk factors even from early childhood.
Conflicts of interest
Introduction Atherosclerosis with excess lipid accumulation in the arterial intima is a chronic inflammatory disease and the major underlying cause for cardiovascular events. The formation of macrophage-derived foam cells in the plaque is the elementary feature of atherosclerotic lesion initiation and one of characteristics for the development of atherosclerosis. On the other hand, lipid homeostasis, especially cholesterol homeostasis, plays a vital role in the formation of macrophage-derived foam cells, indicating that inhibition of lipid accumulation could be an effective anti-atherosclerotic strategy. There are two main sources for cholesterol in the body: biosynthesis in liver and cholesterol absorption from the small intestine. Cholesterol absorption inhibitors can suppress the exogenous cholesterol absorption by targeting a polytopic transmembrane protein called the Niemann-Pick C1-like 1 (NPC1L1) protein. As the only approved cholesterol absorption inhibitor, ezetimibe (Zetia, 1) widely used in the therapy of patients with family hypercholesterolemia has been thoroughly studied in clinical trials to evaluate its effects on lipid profiles, cardiovascular outcomes or other surrogate endpoints. And in the clinical administration, the combination of ezetimibe and statin have been shown to lower LDL-C concentration and improve cardiovascular outcomes more effectively compared with statin therapy alone (Fig. 1).5, 6 Recently, some studies demonstrated that cholesterol absorption inhibitors have the same protective effect on the moderate atherosclerotic lesion as atorvastatin, and this function was associated with lowering serum cholesterol, decreasing circulatory inflammation cytokines and inhibiting macrophage accumulation in lesions.7, 8 In several animal models, cholesterol absorption inhibitors were also confirmed to have the beneficial effect on atherosclerosis by its reduction of atherosclerotic lesion. Udo Seedorf et al. reported that ezetimibe could inhibit the lipid accumulation of human macrophage and the formation of foam cells, which showed that cholesterol absorption inhibitors had potential effect on the prevention and treatment of atherosclerosis. Though ezetimibe is safe in clinic so far undoubtedly, Alsheikh-Ali and Karas reported that the combination of ezetimibe and simvastatin could increase the risk of cancer. So, there remains scant demand for developing new cholesterol absorption inhibitors that could improve therapeutic potency and provide patients with more choices. Earlier, we have reported the discovery and characterization of a series of 1H-pyrrole-2,5-dione derivatives 2 containing sulfonamide group as potent cholesterol absorption inhibitors, which indeed exhibited certain inhibitory activity. In this paper, we retained the substituents (p-fluoro, p-ethyl, p-trifluoromethyl and p-trifluoromethoxy) on the benzene ring at the terminal of side chain with best potency, shorten the length of side chain and completed the synthesis of eight 1H-pyrrole-2,5-dione derivatives 7a-h (Table 1).