Current Drug Targets (v.18, #6)

Meet Our Editorial Board Member by Manuel S. Yepes (617-617).

Editorial: Natural Compounds and Their Derivatives as a Source of Promising Drugs for Diabetes and Insulin Resistance by Fatima Regina Mena Barreto Silva, Marisa Jadna Silva Frederico (618-618).

Obesity is a metabolic, multifactorial disease that is underpinned by factors such as genetics, epigenetics, as well as high-energy food intake and sedentarism. Obesity is often associated with, and exacerbated by, other metabolic disorders such as type 2 diabetes mellitus (T2DM). A hallmark of T2DM is failure of insulin secretion from pancreatic ?-cell to regulate blood glucose disposal into peripheral tissues, such as skeletal muscle, termed insulin resistance, as well as deregulation of pancreatic ?-cell function. It has been proposed that insulin resistance is, in part, a consequence of impaired signal transduction of insulin caused by several molecules released from adipose tissue that include (adipo)cytokines and fatty acids. However, not all fatty acids exert a negative impact on insulin sensitivity. In fact, it has been suggested that palmitoleic acid (16:1n-7) has hormone-like properties and improves some metabolic parameters that are impaired in obesity and T2DM. Moreover, in vitro approaches reveal that cis-16:1n-7 can influence pancreatic ?-cell survival, insulin secretion, and skeletal muscle insulin response and adipocyte metabolism. In vivo experiments using animal models show that the ingestion of cis-16:1n-7 or sources of it (e.g., macadamia oil) can partially prevent the metabolic alterations caused by high-fat/carbohydrate diets. In general, studies in humans found positive associations between higher trans-16:1n-7 proportion in plasma phospholipids and improved insulin sensitivity or decreased the onset of T2DM. However, plasma cis-16:1n-7 data are still controversial. In this brief review, we discuss the main studies on 16:1n-7 effects on obesity and T2DM and their potential for clinical application.

Possible Effects of Dietary Anthocyanins on Diabetes and Insulin Resistance by Eleonora Turrini, Lorenzo Ferruzzi, Carmela Fimognari (629-640).
Diabetes is reaching epidemic proportions worldwide. Many dietary compounds have been found to exert health beneficial effects against different pathologies including diabetes. Most bioactive compounds have been identified in fruits and vegetables and their mechanisms of action explored both in vitro and in vivo. In particular, great interest has been given to polyphenols and especially to a specific subset of molecules, i.e. anthocyanins. Several lines of evidence suggest that anthocyanins have positive effects on human health by inducing a number of biological activities. This review will give an overview on the influence of dietary anthocyanins on preventing and managing type 2 diabetes. In particular, in vitro and in vivo studies will be presented. The article also reviews the potential clinical impact of the antidiabetic activity of anthocyanins and outlines the major challenges of using anthocyanins for diabetes treatment.

Mechanism of Action of Novel Glibenclamide Derivatives on Potassium and Calcium Channels for Insulin Secretion by Marisa Jadna Silva Frederico, Allisson Jhonatan Gomes Castro, Danusa Menegaz, Cahue De Bernardis Murat, Camila Pires Mendes, Alessandra Mascarello, Ricardo Jose Nunes, Fatima Regina Mena Barreto Silva (641-650).
Glibenclamide is widely used and remains a cornerstone and an effective antihyperglycemic drug. After the casual discovery of its hypoglycemic potential, this compound was introduced for diabetes treatment. However, the long-term side effects reveal that glibenclamide should be replaced by new molecules able to maintain the health of β-cells, protecting them from hyperstimulation/hyperexcitability, hyperinsulinemia, functional failure and cell death. The aim of this review was to highlight the main mechanism of action of glibenclamide and the influence of its derivatives, such as acylhydrazones, sulfonamides and sulfonylthioureas on β-cells potassium and calcium channels for insulin secretion as well as the contribution of these new compounds to restore glucose homeostasis. Furthermore, the role of glibenclamide-based novel structures that promise less excitability of β-cell in a long-term treatment with effectiveness and safety for diabetes therapy was discussed.

HDL as a Target for Glycemic Control by Boris Waldman, Alicia J. Jenkins, David Sullivan, Martin K.C. Ng, Anthony C. Keech (651-673).
HDL has long been known for its role in reverse cholesterol transport, thought in part to explain the well-recognized links between low levels of HDL-C and cardiovascular disease. The past decade has seen increasing evidence from epidemiological, basic science and early human intervention studies that HDL biology is more complex and may influence the onset and progression of type 2 diabetes. Research has identified multiple potential pathways by which higher HDL particle concentrations or functional improvements may ameliorate the development and progression of the disease. These include promotion of insulin secretion and pancreatic islet beta-cell survival, promotion of peripheral glucose uptake, and suppression of inflammation. The relationships between HDL-C levels, commonly used in clinical practice, and HDL particle number, size and various HDL functions is complex, and is intimately linked with triglyceride metabolism. The complexity of these relationships is amplified in diabetes, which negatively impacts multiple aspects of lipoprotein biology. This article reviews the rationale for, and potential of, HDL-based anti-diabetic pharmacotherapy, with an emphasis on the particular challenges posed by diabetes-related HDL dysfunction, and on the difficulties of selecting appropriate targets and HDL-related biomarkers for research and for clinical practice. We discuss aspects of HDL metabolism that are known to be altered in type 2 diabetes, potentially useful measures of HDL-targeted therapy in diabetes, and review early intervention studies in humans. These areas provide a firm foundation for further research and knowledge expansion in this intriguing area of human health and disease.

The Role of Statins in the Activation of Heme Oxygenase-1 in Cardiovascular Diseases by Aleksandra Piechota-Polanczyk, Alicja Jozkowicz (674-686).
Cardiovascular diseases (CVD) are associated with the dysfunction of endothelium that regulates the contractile state of vascular walls and cellular composition. Recent large clinical trials indicated that lipid-modifying interventions decrease the risk of CVD in patients with hypercholesterolemia and in those with relatively normal levels of LDL cholesterol. They also highlighted lipid-independent role of well-established lipid-lowering drugs- statins- which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are used in the treatment of hypercholesterolemia and reduction of atherosclerosis. Novel therapeutic approaches of statins include their influence on heme oxygenase 1 (HO-1) and HO-1 related signaling pathways such as activator protein (AP)-1, protein kinase G (PKG), extracellular matrix-regulated kinase (ERK), p38 MAPK or NF?B in vascular wall cells. This review aimed to describe the molecular mechanisms involved in the induction of HO-1 under different statins in the most common CVD.

Bacterial respiratory infections are the main reason of morbidity and mortality among cystic fibrosis (CF) patients. In early childhood, the respiratory infections are due to Staphylococcus aureus and Haemophilus influenzae. In older CF patients, pathogenic Gram-negative bacteria like Achromobacter xylosoxidans, Burkholderia cepacia complex and especially Pseudomonas aeruginosa are more frequently seen. P. aeruginosa is a turning point in the respiratory disease in CF and its predominance increases with age. Bacteria use a variety of two-component systems (TCS) to differentially express virulence factors involved in both acute and chronic infections. Here, we review bacterial TCS as targets for antibacterial treatment for CF patients.

Therapeutic Drugs in Bone Loss-Associated Disorders: Clinical Outcomes and Challenges by Daniela M. Sousa, Ines S. Alencastre, Luís Leitao, Estrela Neto, Cecilia J. Alves, Meriem Lamghari (696-704).
Current therapeutic drugs for the treatment of bone loss-associated disorders such as osteoporosis and metastatic bone disease have limited clinical outcomes, namely in terms of efficiency and sustainability. Given the ageing of population in developed countries and the cumulative costs with treatment, bone loss-associated disorders represent a major socioeconomic burden worldwide. In this review, the therapeutic agents targeting bone loss tested in clinical and pre-clinical trials are summarized, as well as the challenges encountered by clinicians and patients. In an effort to attain costeffective clinical outcomes, potential cellular and signalling targets are disclosed.

Oxidative Stress and Antioxidants in Neurological Diseases: Is There Still Hope? by Andreia Neves Carvalho, Omidreza Firuzi, Maria Joao Gama, Jack van Horssen, Luciano Saso (705-718).
Oxidative stress is a pathological feature common to a multitude of neurological diseases. The production of reactive oxygen species (ROS) is the main mechanism underlying this cellular redox imbalance. Antioxidants protect biological targets against ROS, therefore, they have been considered as attractive potential therapeutic agents to counteract ROS-mediated neuronal damage. However, despite encouraging in vitro and preclinical in vivo data, the clinical efficacy of antioxidant treatment strategies is marginal and most clinical trials using antioxidants as therapeutic agents in neurodegenerative diseases have yielded disappointing outcomes. This might in part be due to the need of adjustment in concentrations and time parameters between preclinical studies and clinical settings. Moreover new efficient delivery methods need to be investigated, particularly taking into account that a successful therapeutic agent for neurological diseases should readily cross the blood-brain barrier (BBB). In that sense, the use of compounds that cross the BBB and boost the endogenous antioxidant defense machinery, by activating for instance the Nrf2 pathway, or compounds that are able to modulate ROS production, such as NOX enzyme inhibitors, seems to represent a more promising approach to combat oxidative stress in the central nervous system (CNS). Here we present a brief overview of the main players in oxidative stress and outline evidences of their involvement in Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis. Finally, we review and critically discuss the potential of antioxidants as therapeutics for central nervous system disorders with a special focus on emerging novel therapeutic strategies.

Modelling Chemotherapy-induced Cardiotoxicity by Human Pluripotent Stem Cells by Rosalinda Madonna, Christian Cadeddu, Martino Deidda, Paolo Spallarossa, Concetta Zito, Giuseppe Mercuro (719-723).
Novel antineoplastic therapies have greatly improved cancer survival; nevertheless they are bringing in new forms of cardiomyopathy, that can often limit proper cancer treatments. Novel cardioprotective therapies are therefore needed, for improving clinical outcomes in cancer patients. In order to test novel therapeutic strategies, there is an increasing need for appropriate experimental models of chemotherapy-induced cardiomyopathy. Induced pluripotent stem (iPS) cell- and human embryonic stem cell (hESC )-derived cardiomyocytes may be used as alternative in vitro models for studying mechanisms that underly chemotherapy-induced cardiomyopathy. In this review we discuss the use of iPS- and hESC-derived cardiomyocytes for evaluating additional pharmacological targets and for predicting chemotherapy-induced cardiotoxicity.

Graphene: A Comprehensive Review by Aditya D. Ghuge, Abhay R. Shirode, Vilasrao J. Kadam (724-733).
Graphene, a one-atom thick, two-dimensional sheets of sp2hybridized carbon atoms packed in a hexagonal lattice with a Caron-Carbon distance of about 0.142 nm. Its extended honeycomb network forms the basic building block of other important allotropes; it can be stacked to form 3-Dgraphite, rolled to form 1-D-nanotubes and wrapped to form 0-D-fullerenes. Long-range π conjugation in graphene results in its extraordinary thermal, mechanical and electrical properties, which have been the interest of many theoretical studies and recently became an exciting area for scientists. Graphene is impermeable to gas and liquids, has excellent thermal conductivity and higher current density in comparison to other most effective materials. All of its exceptional properties have opened up new avenues for the use of graphene in nano-devices and nano-systems, which initiated its prominent use as a material for drug targeting. In addition, several fabrication techniques are outlined, starting from the mechanical exfoliation of high-quality graphene to the direct growth on silicon carbide or metal substrates and from the chemical routes utilizing graphene oxide to the newly developed approach at the molecular level. By this article reviewers intend to emphasize on unique properties, fabrication techniques and updated applications of graphene. In addition, we discuss about the potential of graphene in drug targeting in fields of nanotechnology, biomedical engineering and technology and its use for innovations in various fields such as electronics and photonics.

Is Metformin a Therapeutic Paradigm for Colorectal Cancer: Insight into the Molecular Pathway? by Zar Chi Thent, Nurul Hannim Zaidun, Muhammad Fairuz Azmi, Mu`izuddin Senin, Haszianaliza Haslan, Ruzain Salehuddin (734-750).
Colorectal cancer (CRC) remains one of the major leading causes of cancer related morbidity and mortality. Apart from the conventional anti-neoplastic agents, metformin, a biguanide anti-diabetic agent, has recently found to have anti-cancer property. Several studies observed the effect of metformin towards its anti-cancer effect on colon or colorectal cancer in diabetic patients. However, only a few studies showed its effect on colorectal cancer in relation to the non-diabetic status. The present review aimed to highlight the insight into the molecular pathway of metformin towards colorectal cancer in the absence of diabetes mellitus. In CRC-independent of diabetes mellitus, highly deregulation of PI3K/AKT pathway is found which activates the downstream mammalian target of rapamycin (mTOR). Metformin inhibits cancer growth in colon by suppressing the colonic epithelial proliferation by inhibiting the mTOR pathway. Metformin exerts its anti-neoplastic effects by acting on tumour suppressor pathway via activating the adenosine monophosphateactivated protein kinase (AMPK) signaling pathway. Metformin interrupts the glucose metabolism by activating the AMPK. Metformin reduces tumour cell growth and metastasis by activating the p53 tumour suppressor gene. In addition to its therapeutic benefits, metformin is easily accessible, cost effective with better tolerance to the patients compared to the chemotherapeutic agents. This review summarised modern findings on the therapeutic applications of metformin on the colorectal cancer with no evidences of diabetes mellitus.