Current Medicinal Chemistry (v.24, #4)

Meet Our Editorial Board Member by Sauro Vittori (331-331).

Editorial: Bioactive Substances from Medicinal Plants for Metabolic Disorders by Branca M. Silva, Pedro F. Oliveira, Marco G. Alves, Tania R. Dias (332-333).

Promising Potential of Dietary (Poly)Phenolic Compounds in the Prevention and Treatment of Diabetes Mellitus by Branca M. Silva, Pedro F. Oliveira, Susana Casal, Marco G. Alves, Tânia R. Dias (334-354).
Background: The incidence of diabetes mellitus (DM) is reaching alarming proportions worldwide, particularly because it is increasingly affecting younger people. This reflects the sedentary lifestyle and inappropriate dietary habits, especially due to the advent of processed foods in modern societies. Thus, unsurprisingly, the first medical recommendation to patients with clinically evident DM is the alteration in their eating behaviour, particularly regarding carbohydrates and total energy intake. Despite individual and cultural preferences, human diet makes available a large amount of phytochemicals with therapeutic potential. Phenolic compounds are the most abundant class of phytochemicals in edible plants, fruits and beverages. These compounds have strong antioxidant and anti-inflammatory activities that have been associated with specific features of their chemical structure. Among others, such properties make them promising antidiabetic agents and several mechanisms of action have already been proposed.

Objective: Herein, we discuss the recent findings on the potential of dietary phenolic compounds for the prevention and/or treatment of (pre)diabetes, and associated complications.

Conclusion: A broad range of studies supports the innate potential of phenolic compounds to protect against DM-associated deleterious effects. Their antidiabetic activity has been demonstrated by: i) regulation of carbohydrate metabolism; ii) improvement of glucose uptake; iii) protection of pancreatic β-cells; iv) enhancement of insulin action and v) regulation of crucial signalling pathways to cell homeostasis. Dietary phenolic compounds constitute an easy, safe and cost-effective way to combat the worrying scenario of DM. The interesting particularities of phenolic compounds reinforce the implementation of a (poly)phenolic-rich nutritional regime, not only for (pre)diabetic patients, but also for non-diabetic people.


The Antidiabetic Potential of Quercetin: Underlying Mechanisms by Pierre S. Haddad, Hoda M. Eid (355-364).
The dramatic increase in modern lifestyle diseases such as cancer, cardiovascular diseases and diabetes has renewed researchers' interest to explore nature as a source of novel therapeutic agents. Flavonoids are a large group of polyphenols that are widely present in the human diet. They have shown promising therapeutic activities against a wide variety of ailments. One of the most widely distributed and most extensively studied flavonoid is the flavonol quercetin. Its powerful antioxidant and anti-inflammatory activities are well documented and are thought to play a role in treating and protecting against diseases including diabetes, cancer, neurodegenerative and cardiovascular diseases. The purpose of this review is to shed light on quercetin therapeutic potential as an antidiabetic agent. Quercetin was reported to interact with many molecular targets in small intestine, pancreas, skeletal muscle, adipose tissue and liver to control whole-body glucose homeostasis. Mechanisms of action of quercetin are pleiotropic and involve the inhibition of intestinal glucose absorption, insulin secretory and insulin-sensitizing activities as well as improved glucose utilization in peripheral tissues. Initial studies suggested poor bioavailability of quercetin. However, recent reports have shown that quercetin was detected in the plasma after food or supplements consumption and has a long half-life in human body. Despite the wealth of in vitro and in vivo results supporting the antidiabetic potential of quercetin, its efficacy in diabetic human subjects is yet to be explored.

Daidzein and its Effects on Brain by Seyed Mohammad Nabavi, Seyed Fazel Nabavi, Maria Daglia, Grazia D'Onofrio, Barbara Budzy|ska, Ameema Tariq, Sana Javed, Touqeer Ahmed (365-375).
Among naturally occurring isoflavones, soy isoflavones are an important class with various biological activities. Due to their phytoestrogenic structure, their effects on the brain are profound thus making the neurobiological effects of these compounds an active area of research. One such compound is daidzein, which has been reported to affect various neurobiological regulatory mechanisms such as behavior, cognition, growth, development and reproduction. These effects are mainly elicited through the interaction of daidzein with different signaling molecules and receptors, thereby offering neuroprotection. In addition, daidzein has also been reported to possess activities against various neuropathological conditions mainly by its interaction with the cerebrovascular system. This review focuses on providing a comprehensive account on the bioavailability and metabolism of daidzein in vivo, and discusses its activities and mechanisms of action in detail, in both physiological and pathological conditions. In addition, the effects of daidzein on other disorders have also been examined briefly in this article.

Coffee: A Dietary Intervention on Type 2 Diabetes? by Irene Rebelo, Susana Casal (376-383).
Coffee beverages, prepared in a multitude of ways around the world, are increasingly part of our daily lives. Although considered an unhealthy beverage for decades, coffee is increasingly the headline of medical journals in association with a reduced risk for several diseases. What if this beverage could give us pleasure, while modulating mood and lowering the risk for several diseases of the modern society, including type 2 diabetes (T2D)? Based on the most recent epidemiological and research data, long-term consumption of coffee beverages is associated with a lower risk of developing T2D in healthy individuals, probably involving multiple mechanisms, with interventions on glucose homeostasis, antioxidant activity, and inflammatory biomarkers. Several coffee constituents potentially responsible for these effects are described, as well as the factors that make their presence highly variable, with interesting effects associated with chlorogenic acids, trigonelline and norharman. Due to the high number of compounds contained in coffee, we explore the potential synergic effect within the coffee matrix. Moreover, acute coffee consumption shows different health effects from those achieved on a long-term daily consumption, and not all coffee beverages are similar. Still, despite the huge amount or work developed in the last decade, the substances and mechanisms behind these protective effects on T2D are still to be fully elucidated, being therefore soon for dietary interventions based on coffee.

Phytogenic Polyphenols as Glycogen Phosphorylase Inhibitors: The Potential of Triterpenes and Flavonoids for Glycaemic Control in Type 2 Diabetes by Demetres D. Leonidas, Joseph M. Hayes, Atsushi Kato, Vassiliki T. Skamnaki, Demetra S.M. Chatzileontiadou, Anastassia L. Kantsadi, Efthimios Kyriakis, Ben A. Chetter, George A. Stravodimos (384-403).
Glycogen phosphorylase (GP) is a validated pharmaceutical target for the development of antihyperglycaemic agents. Phytogenic polyphenols, mainly flavonoids and pentacyclic triterpenes, have been found to be potent inhibitors of GP. These compounds have both pharmaceutical and nutraceutical potential for glycemic control in diabetes type 2. This review focuses mainly on the most successful (potent) of these compounds discovered to date. The protein-ligand interactions that form the structural basis of their potencies are discussed, highlighting the potential for exploitation of their scaffolds in the future design of new GP inhibitors.

Medicinal Plants for Diabetes Treatment During Pregnancy by Debora Cristina Damasceno, Thais Leal-Silva, Thaigra Sousa Soares, Rafaianne Queiroz Moraes-Souza, Gustavo Tadeu Volpato (404-410).
Diabetes mellitus is a syndrome of great importance that affects an increasing number of people every day. In particular, diabetes is a common and important disease during pregnancy and is marked by complications, both fetal and maternal, that increase the risks of morbidity and mortality for diabetic pregnant women and their offspring. Drugs such as insulin and hypoglycemic drugs are given to treat diabetes, but regular exercise and adequate diet have also been indicated. Furthermore, coadjutant therapies such as medicinal plants are popularly used to reduce diabetes-induced hyperglycemia, either within or outside the context of pregnancy. However, studies examining plant use for diabetes treatment are necessary to confirm its possible effects and its safety for the mother and fetus. The objective of this literature review was to conduct a survey of plant species that are utilized worldwide and their stated therapeutic uses. A literature search was performed using the terms “diabetes and pregnancy”, which resulted in the identification of 31,272 articles. Of these studies, only 12 (0.0038%) were related to medicinal plants, demonstrating that there has been little investigation into this issue. Of the papers analyzed in this review, half evaluated plant leaves, indicating that these scientific studies attempted to reproduce the preparations commonly used by various populations, i.e., in the form of tea. Additionally, more than 90% of studies utilized experimental animals to evaluate the maternal-fetal safety of medicinal plant substances that may potentially be dangerous for humans. Thus, once confidence levels for plant-derived substances are established based on toxicological analyses and safety is confirmed, it is possible that plants will be used to complement conventional diabetes therapies.

Advances in Medicinal Plants with Effects on Anxiety Behavior Associated to Mental and Health Conditions by George E. Barreto, Marco Avila-Rodriguez, Madeline Foitzick, Gjumrakch Aliev, Valentina Echeverria (411-423).
Background: Many mental health conditions including psychiatric disorders and neurodegenerative conditions are poorly responsive for actual medications or have low patient adherence to treatment due to the side effects or costs associated with these treatments.

Objective: The main goal of this review is to provide clinical providers and patients with actualized information about the efficacy of selected herbal medicines for anxiety disorders derived from mental and/or health conditions, and their associated side effects.

Methods: In this review, actual scientific advances about the use of medicinal plants for anxiety disorders are presented.

Results: In recent years, the herbal therapies have reemerged as a source of efficacious natural treatments, at a lower cost and most of the time reduced side effects than currently prescribed pharmaceutical drugs. The herbs described mainly correspond to plants of traditional medicine from the American continent and near islands and Asia.

Conclusion: Current evidence confirms the therapeutic effects of traditional medicine. Further clinical investigation is required to confirm these findings. The current understanding of the molecular mechanisms involved in psychiatric disorders, as well as the new advances in brain imaging permit a rapid and serious evaluation of anxiolytic compounds.


Magnesium in Pain Research: State of the Art by Milica Prostran, Katarina Savic Vujovic, Jovan Kosutic, Aleksandar Milovanovic, Sonja Vuckovic, Dragana Srebro (424-434).
Magnesium has been shown to produce an antinociceptive effect on animal models of neuropathic and inflammatory pain. It has also been shown to exert an analgesic effect on humans in conditions presenting acute (postoperative pain) and chronic (neuropathic) pain. As it is known that magnesium is a physiological antagonist of the N-methyl-Daspartate (NMDA) receptor ion channel, and that the NMDA receptor plays a key role in central sensitization, the primary mechanism through which magnesium produces its analgesic effect is believed to be blockade of the NMDA receptor in the spinal cord. In addition, magnesium blocks calcium channels and modulates potassium channels. The activation of the nitric oxide (NO) pathway could have an important role in the antinociceptive effects of systemic magnesium sulfate in the somatic, but not in the visceral model of inflammatory pain. Although it is known for some time that intramuscular, intravenous and subcutaneous injections of magnesium sulfate in humans, and intraperitoneal injection in rodents produce local pain sensation, the mechanism of this action was elucidated only recently. It was demonstrated that subcutaneous injection of an isotonic, pHadjusted (7.4) solution of magnesium sulfate (6.2%) to rats produces local peripheral pain via activation of peripheral TRPA1, TRPV1, TRPV4 and NMDA receptors and peripheral production of NO. In animal models of pain, magnesium has been shown to exert both antinociceptive and pronociceptive effects by acting on different ion channels and NO pathways, however, the precise mechanisms remain to be elucidated.