Current Medicinal Chemistry - Volume 20, Issue 21, 2013

Obesity and metabolic syndrome represent major public health problems, and are the biggest preventable causes of death worldwide. Obesity is the leading risk factor for type 2 diabetes mellitus (T2DM), cardiovascular diseases and non-alcoholic fatty liver disease. Obesity-associated insulin resistance, which is characterized by reduced uptake and utilization of glucose in muscle, adipose and liver tissues, is a key predictor of metabolic syndrome and T2DM. With increasing prevalence of obesity in adults and children, the need to identify and characterize potential targets for treating metabolic syndrome is imminent. Emerging evidence from animal models, clinical studies and cell lines studies suggest that protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin signaling, is likely to be involved in the pathways leading to insulin resistance. PTP1B is tethered to the cytosolic surface of endoplasmic reticulum (ER), an organelle that is responsible for folding, modification, and trafficking of proteins. Recent evidence links the disruption of ER homeostasis, referred to as ER stress, to the pathogenesis of obesity and T2DM. PTP1B has been recognized as an important player linking ER stress and insulin resistance in obese subjects. This review highlights recent advances in the research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of obesity and type 2 diabetes, and focuses on the potential therapeutic exploitation of PTP1B inhibitors for the management of these conditions.

The definition of the Metabolic Syndrome (MS) has encountered difficulty in reaching a universal consensus although there exists an agreement of its main pathologies which are hypertension, obesity, dyslipidemia, insulin resistance, inflammation and renal damage. The prevalent opinion is that three of those alterations may define the syndrome. The incidence of the MS has increased globally, particularly in the last few years, to the point of being regarded as an epidemic. The treatment of the MS can be approached from different angles, since it may be a multifaceted health problem. A healthy lifestyle, which means the practice of regular exercise is suggested to MS patients. Increasing physical activity has anti-inflammatory effects since there is an inverse association of physical activity and inflammatory biomarker concentrations. An adequate diet is recommended, such as the Mediterranean, which contains fish, tomatoes, garlic, red peppers, olive oil and includes red wine, that is, antioxidants and non-saturated oils. There are also the traditional herbal preparations, used in the alternative medicine. Several therapeutic tools can be used; the most common are the pharmaceutical products to deal with obesity, hypertension, dyslipidemias, diabetes and inflammation. In addition several pharmacological therapies such as non steroidal anti-inflammatory drugs are recommended. Recently new mechanisms of action of statins, fibrates, metformin and thiazolidinediones have demonstrated their anti-inflammatory effect and potential use to treat MS.

Polyphenols are composed of a wide variety of molecules that are classified into several categories, according to their chemical type such as phenolic acids, flavonoids, stilbenes, and lignans. Many studies have proven the beneficial effects of flavonoids in atherosclerosis progression and cardiovascular disease. Dietary flavonoids reduce oxidative stress and exert anti-inflammatory actions. Moreover, flavonoids have the ability to avoid the thrombus formation, improve endothelial function, modify lipid levels and regulate glucose metabolism. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids in atherosclerosis progression.

Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structureactivity relationship of capsaicinoids.

According to World Health Organization (WHO), trypanosomiasis and leishmaniasis are the most challenging among the neglected tropical diseases. Comparative studies between Leishmania spp and Trypanosoma cruzi have been conducted aiming to find a broad spectrum antiprotozoal agent acting against both parasites. Among the potential molecular target, Trypanothione reductase (TR) is considered an ideal enzyme since it is involved in the unique thiol-based metabolism observed in the Trypanosomatidae family and is a validated target for the search of antitrypanosomatidae drugs. In this review we intend to describe the currently available therapy to treat trypanosomatidae diseases and to highlight important aspects of trypanothione reductase as a target for the search of new and selective inhibitors, such as tricyclic, diphenylsulfide, bicyclic and heterocyclic, polyamine, natural product, N-oxide and nitroheterocyclic, aryl β- aminocarbonyl and α,β-unsaturated carbonyl derivatives.

Anemia, one of the most common blood disorders, globally affecting ˜1.62 billion people, occurs when the level of healthy red blood cells (RBCs) or/and hemoglobin in the body becomes too low. It can cause a variety of complications to human body, some of which are potentially very serious and carry significant risk factors, thus representing a big burden for social and economic development. Current therapeutic methods are efficient in controlling this disease but associated with many problematic issues. One way to circumvent these issues is by targeting HIF-PH (Hypoxia inducible factor prolyl hydroxylases) pathway. HIF is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Experimental and clinical studies have demonstrated that stabilization of HIF can up-regulate erythropoietin (EPO) expression and in turn increase count of RBCs potentially without causing drug resistance and cardiovascular diseases commonly seen with other therapies, rendering HIF stabilization a promising way to treat anemia. In this review, we highlight the biology of HIF-PH pathway, as well as the recent advances of HIF stabilizers of a natural or synthetic origin and concerns regarding drug development in this field.

The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment of onco-hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed, based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3 loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB). NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3 in promoting both induction of apoptosis and cell cycle arrest in p53 wild-type JVM-2 cells, but not in p53 mutated BJAB cells. Moreover, injection of NP-Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural characteristics of the NP-Nutlin-3, as well as their biological activity in vitro and in vivo, made them promising for further preclinical evaluations as potentially useful anti-leukemic carriers.

Chymase stored in mast cells activates matrix metalloproteinase (MMP)-9, which may relate to the progression of sinusoidal obstruction syndrome (SOS). We investigated the preventive effect of a chymase inhibitor, TY-51469, on monocrotaline-induced SOS in hamsters. Hamsters were orally administrated with a single dose of monocrotaline (120 mg/kg) to induce SOS. Treatment with TY-51469 (1 mg/kg per day) or placebo had started 3 days before the monocrotaline administration. Two days after the monocrotaline administration, significant increases in aspartate aminotransferase, alanine aminotransferase and total bilirubin and a significant reduction of albumin were observed in plasma, but their changes were significantly attenuated by treatment with TY-51469. The numerous hepatic necrosis areas were observed in the placebo-treated group, but the ratio of necrotic area to total area in liver had been significantly reduced by treatment with TY-51469. Both chymase activity and MMP-9 level in liver were significantly augmented in the placebo-treated group. Furthermore, tumor necrosis factor (TNF)-α level in liver was also augmented in the placebo-treated group. However, the chymase activity and levels of MMP-9 and TNF-α were significantly attenuated in the TY-51469-treated group. Until 14 days after monocrotaline administration, survival rates in the placebo- and TY-51469-treated groups were % and %, respectively, and a significant difference was observed. In conclusion, chymase inhibition by TY-51469 may prevent the accelerating of severity in monocrotaline-induced SOS in hamsters.