**11. Conclusions**

levels of apoB protein. ApoB is a molecule involved in the metabolism of cholesterol; the concentrations of this protein in human blood samples correlate with those of cholesterol. Higher levels of both compounds are associated with an increased risk of coronary heart disease. Intravenous injections of the siRNA-cholesterol conjugates in mice resulted in a lowering of the levels of blood cholesterol comparable to that in mice in which the apoB gene had been deleted. These results demonstrate that siRNA can be delivered systemically to target the liver and suggest that RNAi has the potential to become a new therapeutic for the treatment

For those molecular targets that have several different isoforms, the biggest challenge in the drug development is the specificity. A good example is ACAT inhibitors. To date, it has been demonstrated that there are two sioforms, ACAT1 and ACAT2. ACAT1 is ex‐ pressed universally while ACAT2 is expressed mainly in the liver and small intestine. Both isoforms can esterify cholesterol and other sterols. However, ACAT1 primarily works on the esterification of plant sterols and other sterol products, while ACAT2 main‐ ly converts cholesterol to its esters. Due to their different distribution and activities in the body, a universal inhibitor of both enzymes has been shown to be detrimental and recent humans trials are disappointing [104, 105]. The study of Bell et al. in 2006 breathes life back into the idea of ACAT2-specific inhibition [106]. In atherosclerosis-prone mice, ACAT2 was specifically ihibhied in the liver with antisense oligonucleotides. Biweekly intraperitoneal injections, which reduced ACAT2 expression by a remarkable 80%, de‐ creased diet-induced hypercholesterolemia and sharply reduced cholesterol ester deposi‐ tion in the aorta. The specific inhibition can be achieved from the antisense gene technology or small molecules that inhibit only ACAT2. There is no mature product in

It has been demonstrated by numerous studies that inhibition of cholesterol absorption is associated with much less side-effects than other approaches. It remains challenge but highly promising that a potent inhibitor of cholesterol absorption would sufficiently low‐ er blood cholesterol or keep blood cholesterol levels within the recommended healthy range. To achieve this goal, other approaches have to be take in addition to the specific inhibitor of cholesterol absorption, such as a combination of two or more products, in particular the combinations that work synergistically through one or multiple pathways of cholesterol homeostasis. Recent studies on the combination of the plant alkaloid ber‐ berine and plant sterols/stanols have shown an excellent example of this approach. The researchers have demonstrated consistently that plant sterols or stanols and berberine have a moderate effect to lower blood cholesterol levels in different animal models. However, when plant sterols/stanols were combined with berberine, a significant syner‐ gism was produced. They remarkably improved cholesterol-lowering efficacy by synerg‐

of metabolic diseases [102].

*10.2.3. Development of target-specific inhibitors or enhancers*

204 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

this category and lots more work needs to be done.

istically inhibiting cholesterol absorption [90,91].

Cardiovascular disease has long been the lead cause of mortality and morbidity in the developed countries and similar situation has arisen in recent years in the developing coun‐ tries. The increased prevalence of CVD is due to the significantly improved food supply and processing and rapid shift of lifestyle from active to sedentary nature, resulting increased incidence of obesity and overweight. Although the development and clinical use of statin drugs and other cholesterol-lowering drugs has been stabilize the mortality resulted from CVD since last decade, the incidence has been stably rising. According, the control of risk factors for atherosclerosis and CVD remains critical. The primary risk factor is hypercholesterolemia. There still exists a strong demand to develop novel products, especially from distinct choles‐ terol metabolic pathways or molecular targets and from different new approaches as men‐ tioned above. It is optimistic that in the near future, new cholesterol-lowering products, either drugs or natural products with higher efficacies, better specificity and better safe profiles will be developed.
