Current Medicinal Chemistry - Volume 26, Issue 39, 2019

Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Cardiovascular Disease (CVD) is the major cause of death worldwide, especially in Western society. Flavonoids are a large group of polyphenolic compounds widely distributed in plants, present in a considerable amount in fruit and vegetable. Several epidemiological studies found an inverse association between flavonoids intake and mortality by CVD. The antioxidant effect of flavonoids was considered the main mechanism of action of flavonoids and other polyphenols. In recent years, the role of modulation of signaling pathways by direct interaction of flavonoids with multiple protein targets, namely kinases, has been increasingly recognized and involved in their cardiovascular protective effect. There are strong evidence, in in vitro and animal experimental models, that some flavonoids induce vasodilator effects, improve endothelial dysfunction and insulin resistance, exert platelet antiaggregant and atheroprotective effects, and reduce blood pressure. Despite interacting with multiple targets, flavonoids are surprisingly safe. This article reviews the recent evidence about cardiovascular effects that support a beneficial role of flavonoids on CVD and the potential molecular targets involved.

Thrombotic disorders are characterized by an increase in the probability of the formation of unnecessary thrombi that might be due to the activation of the coagulation cascade or the circulating platelets. Platelets or thrombocytes play an essential role in hemostasis but abnormal platelet function leads to the development of a number of cardiovascular complications, including thrombotic disorders. Under pathological conditions, platelets are associated with the development of different thrombotic disorders, including atherosclerosis, arterial thrombosis and stroke, deep venous thrombosis and pulmonary embolism; therefore, platelets are the target of a number of anti-thrombotic strategies. Flavonoids, a large group of polyphenols ubiquitously expressed in fruits and vegetables that have attracted considerable attention because of their benefits in human health, including the reduction of the risk of cardiovascular disease. Flavonoids have been reported to reduce platelet activity by attenuating agonist-induced GPIIb/IIIa receptor activation, mobilization of intracellular free Ca2+, granule exocytosis, as well as activation of different signaling molecules such as mitogen- activated protein kinases or phospholipases. This review summarizes the current studies concerning the modulation of platelet activation by flavonoids, giving especial attention to those events associated to thrombotic disorders.

Background: Chronic Obstructive Pulmonary Disease (COPD) and Cardiovascular Diseases (CV) Often Coexist. COPD and CVD are complex diseases characterized by a strict interaction between environment and genetic. The mechanisms linking these two diseases are complex, multifactorial and not entirely understood, influencing the therapeutic approach. COPD is characterized by several comorbidities, it hypothesized the treatment of cardiovascular co-morbidities that may reduce morbidity and mortality. Flavonoids are an important class of plant low molecular weight Secondary Metabolites (SMs). Convincing data from laboratory, epidemiological, and human clinical studies point the important effects on CVD risk prevention. Objective: This review aims to provide up-to-date information on the ability of Flavonoids to reduce the CVD risk. Conclusion: Current studies support the potential of Flavonoids to prevent the risk of CVD. Well-designed clinical studies are suggested to evaluate advantages and limits of Flavonoids for managing CVD comorbidity in COPD.

The efficacy of successful cancer therapies is frequently hindered by the development of drug resistance in the tumor. The term ‘drug resistance’ is used to illustrate the decreased effectiveness of a drug in curing a disease or alleviating the symptoms of the patient. This phenomenon helps tumors to survive the damage caused by a specific drug or group of drugs. In this context, studying the mechanisms of drug resistance and applying this information to design customized treatment regimens can improve therapeutic efficacy as well as the curative outcome. Over the years, numerous Multidrug Resistance (MDR) mechanisms have been recognized and tremendous effort has been put into developing agents to address them. The integration of data emerging from the elucidation of molecular and biochemical pathways and specific tumor-associated factors has shown tremendous promise within the oncology community for improving patient outcomes. In this review, we provide an overview of the utility of these molecular and biochemical signaling processes as well as tumor-associated factors associated with MDR, for the rational selection of cancer treatment strategies.

Background: Fatty Acid Synthase (FAS or FASN) is a vital enzyme which catalyzes the de novo synthesis of long chain fatty acids. A number of studies have recently been reported that FAS was combined targets for the discovery of anti-obesity and anti-cancer drugs. Great interest has been developed in finding novel FAS inhibitors, and result in more than 200 inhibitors being reported. Methods: The reported research literature about the FAS inhibitors was collected and analyzedsised through major databases including Web of Science, and PubMed. Then the chemical stractures, FAS inhibitory activities, and Structure-Activity Relationships (SAR) were summarized focused on all these reported FAS inhibitors. Results: The 248 FAS inhibitors, which were reported during the past 20 years, could be divided into thiolactone, butyrolactone and butyrolactam, polyphenols, alkaloids, terpenoids, and other structures, in view of their structure characteristics. And the SAR of high inhibitory structures of each type was proposed in this paper. Conclusion: A series of synthetic quinolinone derivatives show strongest inhibitory activity in the reported FAS inhibitors. Natural polyphenols, existing in food and herbs, show more adaptive in medicine exploration because of their safety and efficiency. Moreover, screening the FAS inhibitors from microorganism and marine natural products could be the hot research directions in the future.