Current Medicinal Chemistry - Volume 26, Issue 37, 2019

Plant sterols and stanols (PS) are natural, non-nutritive molecules that play a structural role in plant membranes similar to that of cholesterol in animal membranes and abound in seeds and derived oils. PS exert their physical effect of interference with micellar solubilization of cholesterol within the intestinal lumen and are marginally absorbed by enterocytes, with negiglible increases in circulating levels. The physiological role of PS in plants and their natural origin and non-systemic action, together with their cholesterol-lowering effect, make them an attractive option as non-pharmacological agents for the management of hypercholesterolemia. Recent meta-analyses have summarized the results of >100 controlled clinical trials and have firmly established that the consumption of PS-supplemented foods in different formats at doses of 2-3 g per day results in LDL-cholesterol reductions of 9-12%. PS are both effective and safe cholesterol-lowering agents and have many clinical applications: adjuncts to a healthy diet, treatment of common hypercholesterolemia, combination therapy with statins and other lipid-lowering drugs, and treatment of metabolic syndrome and diabetes. The cholesterol-lowering efficacy is similar in all clinical situations. PS are also useful agents for treatment of hypercholesterolemic children who are not yet candidates to statins or receive low-doses of these agents. In the setting of statin treatment, the average LDL-cholesterol reduction obtained with PS is equivalent to up- titrating twice the statin dose. However, information is still scarce on the efficacy of PS as an add-on therapy to ezetimibe, fibrates, omega- 3 fatty acids, or bile acid binding resins. The consistent scientific evidence on the cholesterollowering efficacy and safety of functional foods supplemented with PS has led several national and international scientific societies to endorse their use for the non-pharmacologic treatment of hypercholesterolemia as adjuncts to a healthy diet. There is, however, a lack of clinical trials of PS with outcomes on cardiovascular events.

Dietary phytosterols, which comprise plant sterols and stanols, reduce plasma Low-Density Lipoprotein-Cholesterol (LDL-C) levels when given 2 g/day. Since this dose has not been reported to cause health-related side effects in long-term human studies, food products containing these plant compounds are used as potential therapeutic dietary options to reduce LDL-C and cardiovascular disease risk. Several mechanisms have been proposed to explain the cholesterol-lowering action of phytosterols. They may compete with dietary and biliary cholesterol for micellar solubilization in the intestinal lumen, impairing intestinal cholesterol absorption. Recent evidence indicates that phytosterols may also regulate other pathways. Impaired intestinal cholesterol absorption is usually associated with reduced cholesterol transport to the liver, which may reduce the incorporation of cholesterol into Very-Low- Density Lipoprotein (VLDL) particles, thereby lowering the rate of VLDL assembly and secretion. Impaired liver VLDL production may reduce the rate of LDL production. On the other hand, significant evidence supports a role for plant sterols in the Transintestinal Cholesterol Excretion (TICE) pathway, although the exact mechanisms by which they promote the flow of cholesterol from the blood to enterocytes and the intestinal lumen remains unknown. Dietary phytosterols may also alter the conversion of bile acids into secondary bile acids, and may lower the bile acid hydrophobic/hydrophilic ratio, thereby reducing intestinal cholesterol absorption. This article reviews the progress to date in research on the molecular mechanisms underlying the cholesterol-lowering effects of phytosterols.

Besides the well-characterized effect of foods and supplements enriched with plant sterols/stanols on serum LDL-C concentrations, evidence is now emerging that phytosterols exert beneficial effects on non-lipid variables such as inflammatory and oxidative stress markers, coagulation parameters and endothelial function. This makes sterols and stanols an attractive alternative for dietary interventions in cardiovascular disease prevention, particularly in populations at low or medium risk. This review aims to summarize the current knowledge derived from experimental studies and human data on the anti-inflammatory effects of phytosterols/stanols and their relevance in promoting atheroprotection and preventing cardiovascular disease. The anti-inflammatory effects induced by plant sterols/stanols have been demonstrated in in vitro studies and in experimental animal models. However, not all the beneficial effects seen at an experimental level have translated into clinical benefit. Indeed, clinical studies that evaluate the association between phytosterols consumption and inflammatory variables (CRP and cytokines) are inconsistent and have not yet provided a solid answer. Plant sterols have been proposed as useful adjuncts to statin therapy to further reduce the risk of cardiovascular disease. However, there is limited available data and more research needs to be done.

Cancer is the second leading cause of death worldwide. Compelling evidence supports the hypothesis that the manipulation of dietary components, including plant compounds termed as phytochemicals, demonstrates certain important health benefits in humans, including those in cancer. In fact, beyond their well-known cardiovascular applications, phytosterols may also possess anticancer properties, as has been demonstrated by several studies. Although the mechanism of action by which phytosterols (and derivatives) may prevent cancer development is still under investigation, data from multiple experimental studies support the hypothesis that they may modulate proliferation and apoptosis of tumor cells. Phytosterols are generally considered safe for human consumption and may also be added to a broad spectrum of food matrices; further, they could be used in primary and secondary prevention. However, few interventional studies have evaluated the relationship between the efficacy of different types and forms of phytosterols in cancer prevention. In this context, the purpose of this review was to revisit and update the current knowledge on the molecular mechanisms involved in the anticancer action of phytosterols and their potential in cancer prevention or treatment.

The central nervous system (CNS) is the most cholesterol-rich organ in mammals. Cholesterol homeostasis is essential for proper brain functioning and dysregulation of cholesterol metabolism can lead to neurological problems. Multiple sclerosis (MS) and Alzheimer’s disease (AD) are examples of neurological diseases that are characterized by a disturbed cholesterol metabolism. Phytosterols (PS) are plant-derived components that structurally and functionally resemble cholesterol. PS are known for their cholesterol-lowering properties. Due to their ability to reach the brain, researchers have started to investigate the physiological role of PS in the CNS. In this review, the metabolism and function of PS in the diseased and healthy CNS are discussed.

Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis. These characteristics are shared with familial hypercholesterolemia (FH), making it possible for sitosterolemia to be misdiagnosed as homozygous FH, especially in pediatric patients. In such cases, a specific chromatography-based laboratory method is essential to differentiate sitosterol and cholesterol. Hematological abnormalities (hemolytic anemia and macrothrombocytopenia) may be present in 25-35% of patients, in whom it is usually associated with the main clinical features, as occurs in the 70% of the cases. In this context, the peripheral blood smear is essential and reveals giant platelets and stomatocytes. Only 21 causative variants in ABCG5/ABCG8 are associated with macrothrombocytopenia. Most physicians still do not recognize these hematological abnormalities or relate them to sitosterolemia. Patients may suffer long-term misdiagnosis of immune thrombocytopenia and be at high risk of receiving harmful therapies or of not benefitting from a low-cholesterol diet and/or from the gold standard treatment with ezetimibe. This drug reduces the levels of plasma plant sterols, provokes regression of xanthomas, and can alleviate hematological abnormalities. Finally, to identify genetic defects, recent advances in high-throughput sequencing, especially in the use of targeted sequencing of pre-specified genes, have begun to be incorporated in the first-line approach in the field of genetic disorders.

Phytosterol measurement has gained a lot of interest during the last two decades after foods and supplements with added 4-desmethyl phytosterols were recognized and used as effective and safe non-pharmacologic hypocholesterolemic agents, and also after the mechanisms of intestinal absorption and hepatic excretion of sterols were unraveled. In addition, the wide use of serum phytosterols as biomarkers of cholesterol absorption has increased the interest in their measurement. In this review, the basic methods are discussed without going into details of the practical operations. The analysis includes first lipid extraction and saponification from various biologic matrices such as serum/plasma, feces, or tissues, after which the individual sterols are separated by adsorption chromatography (gas-liquid or liquid or high performance liquid chromatography) based on the polarity of the various sterols. We also deal with some specific aspects of phytosterol measurements in biological samples such as the need of harmonization of their analysis in biological samples, the discrepancies in the results of sitosterol and campesterol concentrations between different studies, and what is known about their biological day-to-day fluctuation. Phytosterols have a remarkable role in human health, so that their complicated and time consuming measurements call attention to routine ways of standardization between the sterol research laboratories.

Isoliquiritigenin (2’,4’,4-trihydroxychalcone, ISL) is one of the most important chalcone compounds which is mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti-diabetic activities, etc. Numerous research teams have demonstrated that ISL posseses the ability to carry out antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL that inhibit cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limit its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinics over the past 20 years.

Background: Phenylboronic acid-polymers (PBA-polymers) have attracted tremendous attention as potential stimuli-responsive materials with applications in drug-delivery depots, scaffolds for tissue engineering, HIV barriers, and biomolecule-detecting/sensing platforms. The unique aspect of PBA-polymers is their interactions with diols, which result in reversible, covalent bond formation. This very nature of reversible bonding between boronic acids and diols has been fundamental to their applications in the biomedical area. Methods: We have searched peer-reviewed articles including reviews from Scopus, PubMed, and Google Scholar with a focus on the 1) chemistry of PBA, 2) synthesis of PBA-polymers, and 3) their biomedical applications. Results: We have summarized approximately 179 papers in this review. Most of the applications described in this review are focused on the unique ability of PBA molecules to interact with diol molecules and the dynamic nature of the resulting boronate esters. The strong sensitivity of boronate ester groups towards the surrounding pH also makes these molecules stimuli-responsive. In addition, we also discuss how the re-arrangement of the dynamic boronate ester bonds renders PBA-based materials with other unique features such as self-healing and shear thinning. Conclusion: The presence of PBA in the polymer chain can render it with diverse functions/ relativities without changing their intrinsic properties. In this review, we discuss the development of PBA polymers with diverse functions and their biomedical applications with a specific focus on the dynamic nature of boronate ester groups.

Glycogen synthase kinase-3 (GSK-3) is a highly evolutionarily conserved and ubiquitously expressed serine/threonine kinase, an enzyme protein profoundly specific for glycogen synthase (GS). GSK-3 is involved in various cellular functions and physiological processes, including cell proliferation, differentiation, motility, and survival as well as glycogen metabolism, protein synthesis, and apoptosis. There are two isoforms of human GSK-3 (named GSK-3α and GSK-3β) encoded by two distinct genes. Recently, GSK-3β has been reported to function as a powerful regulator of various transport processes across the cell membrane. This kinase, GSK-3β, either directly or indirectly, may stimulate or inhibit many different types of transporter proteins, including ion channel and cellular carriers. More specifically, GSK-3β-sensitive cellular transport regulation involves various calcium, chloride, sodium, and potassium ion channels, as well as a number of Na+-coupled cellular carriers including excitatory amino acid transporters EAAT2, 3 and 4, high-affinity Na+ coupled glucose carriers SGLT1, creatine transporter 1 CreaT1, and the type II sodium/phosphate cotransporter NaPi-IIa. The GSK-3β-dependent cellular transport regulations are a part of the kinase functions in numerous physiological and pathophysiological processes. Clearly, additional studies are required to examine the role of GSK-3β in many other types of cellular transporters as well as further elucidating the underlying mechanisms of GSK-3β-mediated cellular transport regulation.