Showing papers in "Current Pharmaceutical Design in 2013"

Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases

Abstract: Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.

Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence.

Abstract: Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.

Current Developments of Coumarin Compounds in Medicinal Chemistry

Abstract: Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented.

Tea and health: studies in humans.

Abstract: Tea, next to water is the cheapest beverage humans consume. Drinking the beverage tea has been considered a healthpromoting habit since ancient times. The modern medicinal research is providing a scientific basis for this belief. The evidence supporting the health benefits of tea drinking grows stronger with each new study that is published in the scientific literature. Tea plant Camellia sinensis has been cultivated for thousands of years and its leaves have been used for medicinal purposes. Tea is used as a popular beverage worldwide and its ingredients are now finding medicinal benefits. Encouraging data showing cancer-preventive effects of green tea from cell-culture, animal and human studies have emerged. Evidence is accumulating that black tea may have similar beneficial effects. Tea consumption has also been shown to be useful for prevention of many debilitating human diseases that include maintenance of cardiovascular and metabolic health. Various studies suggest that polyphenolic compounds present in green and black tea are associated with beneficial effects in prevention of cardiovascular diseases, particularly of atherosclerosis and coronary heart disease. In addition, anti-aging, antidiabetic and many other health beneficial effects associated with tea consumption are described. Evidence is accumulating that catechins and theaflavins, which are the main polyphenolic compounds of green and black tea, respectively, are responsible for most of the physiological effects of tea. This article describes the evidences from clinical and epidemiological studies in the prevention of chronic diseases like cancer and cardiovascular diseases and general health promotion associated with tea consumption.

The Smart Targeting of Nanoparticles

Abstract: One major challenge in nanomedicine is the selective delivery of nanoparticles to diseased tissues. Nanoparticle delivery systems require targeting for specific delivery to pathogenic sites when enhanced permeability and retention (EPR) is not suitable or inefficient. Nanoparticle functionalization is a widely-used technique for targeting ligand conjugation; these ligands possess inherent abilities to direct nanoparticle selective binding. This review illustrates methods of ligand-nanoparticle functionalization, provides a cross-section of various ligand classes, including small molecules, peptides, antibodies, engineered proteins, or nucleic acid aptamers, and discusses some unconventional approaches currently under investigation.

T Cell Replicative Senescence in Human Aging

Abstract: The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of proinflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has farreaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad.

Intrinsic disorder-based protein interactions and their modulators.

Abstract: It is clear now that proteins lacking ordered structure, generally known as intrinsically disordered proteins (IDPs), possess numerous biological functions that complement functional repertoires of ordered proteins. IDPs are common in nature, and abundantly found to be involved in the pathogenesis of various diseases. These proteins participate in various biological processes and play crucial roles in regulation of functions of their binding partners. Often, disorder-to-order transition induced by the IDP binding to a specific partner defines the low-affinity - high-specificity signaling interactions. Although many IDPs undergo a disorder-to-order transition upon binding, large fraction of IDPs can preserve significant amount of disorder even in their bound states. IDPs can participate in one-tomany and many-to-one interactions, where one intrinsically disordered protein region (IDPR) binds to multiple partners potentially gaining very different structures in the bound state, or where multiple unrelated IDPs/IDPRs bind to one partner. Binding functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the aspects of the intrinsic disorder-based protein interactions and modes of their regulation are considered in this review.

A review of therapeutic effects of curcumin.

Abstract: There is a growing interest in herbal medicine. Scientific studies have demonstrated the beneficial pharmacological effects of curcumin. Curcumin is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been proven that curcumin is a highly pleiotropic molecule which can be a modulator of intracellular signaling pathways that control cell growth, inflammation, and apoptosis. Curcumin might be a potential candidate for the prevention and/or treatment of some diseases due to its anti-oxidant, antiinflammatory activities and an excellent safety profile. We present an updated concise review of currently available animal and clinical studies demonstrating the therapeutic effect of curcumin.

Sleep loss and hypertension: a systematic review.

Abstract: Hypertension and insomnia are very common and often coexist. There is evidence to suggest that the increasing prevalence of arterial hypertension in the past decade might be related both to an increased prevalence of insomnia and to the decline of sleep duration due to modern lifestyle. The aim of this paper is to reconsider both the clinical evidence of the relationship between conditions of sleep loss and of perceived impairment in sleep quality with hypertension and the potential pathophysiological mechanisms underlying the biological plausibility of their relationship. Through a systematic search from MEDLINE, EMBASE, PsychINFO we selected articles, which reported experimental sleep deprivation designs, or studied sleep duration or insomnia and their relationship with blood pressure or hypertension in participants over 18 years. This analysis shows that experimental sleep deprivation, short sleep duration, and persistent insomnia are associated with increased blood pressure and increased risk of hypertension, even after controlling for other risk factors. Pathophysiological mechanisms underlying this association might be related to inappropriate arousal ("hyperarousal") due to an overactivation of stress system functions. According this hypothesis, prolonged sleep loss or alterations of sleep quality might act as a neurobiological and physiologic stressor that impair brain functions and contribute to allostatic load, compromising stress resilience and somatic health.

Cullin-RING Ligases as Attractive Anti-cancer Targets

Abstract: The ubiquitin-proteasome system (UPS) promotes the timely degradation of short-lived proteins with key regulatory roles in a vast array of biological processes, such as cell cycle progression, oncogenesis and genome integrity Thus, abnormal regulation of UPS disrupts the protein homeostasis and causes many human diseases, particularly cancer Indeed, the FDA approval of bortezomib, the first class of general proteasome inhibitor, for the treatment of multiple myeloma, demonstrated that the UPS can be an attractive anti-cancer target However, normal cell toxicity associated with bortezomib, resulting from global inhibition of protein degradation, promotes the focus of drug discovery efforts on targeting enzymes upstream of the proteasome for better specificity E3 ubiquitin ligases, particularly those known to be activated in human cancer, become an attractive choice Cullin-RING Ligases (CRLs) with multiple components are the largest family of E3 ubiquitin ligases and are responsible for ubiquitination of ~20% of cellular proteins degraded through UPS Activity of CRLs is dynamically regulated and requires the RING component and cullin neddylation In this review, we will introduce the UPS and CRL E3s and discuss the biological processes regulated by each of eight CRLs through substrate degradation We will further discuss how cullin neddylation controls CRL activity, and how CRLs are being validated as the attractive cancer targets by abrogating the RING component through genetic means and by inhibiting cullin neddylation via MLN4924, a small molecule indirect inhibitor of CRLs, currently in several Phase I clinical trials Finally, we will discuss current efforts and future perspectives on the development of additional inhibitors of CRLs by targeting E2 and/or E3 of cullin neddylation and CRL-mediated ubiquitination as potential anti-cancer agents

Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment.

Abstract: Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.

Immune system, cell senescence, aging and longevity--inflamm-aging reappraised.

Abstract: Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm- aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

Perspectives on new synthetic curcumin analogs and their potential anticancer properties

Abstract: Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

Curcumin nanomedicine: a road to cancer therapeutics.

Abstract: Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemopreventive, chemo- and radio-sensitization properties. Curcumin's widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin's limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics.

Chronic Hyperuricemia, Uric Acid Deposit and Cardiovascular Risk

Abstract: Hyperuricemia is commonly associated with traditional risk factors such as dysglicemia, dyslipidemia, central obesity and abnormal blood pressure, i.e. the metabolic syndrome. Concordantly, recent studies have revived the controversy over the role of circulating uric acid, hyperuricemia, and gout as an independent prognostic factor for cardiovascular morbidity and mortality. In this regard, different studies also evaluated the possible role of xanthine inhibitors in inducing blood pressure reduction, increment in flow-mediated dilation, and improved cardiovascular prognosis in various patient settings. The vast majority of these studies have been conducted with either allopurinol or its active metabolite oxypurinol, i.e. two purine-like non-selective inhibitors of xanthine oxidase. More recently, the role of uric acid as a risk factor for cardiovascular disease and the possible protective role exerted by reduction of hyperuricemia to normal level have been evaluated by the use of febuxostat, a selective, non purine-like xanthine oxidase inhibitor. In this review, we will report current evidence on hyperuricemia in cardiovascular disease. The value of uric acid as a biomarker and as a potential therapeutic target for tailored old and novel “cardiometabolic” treatments will be also discussed.

Pathophysiology of NASH: perspectives for a targeted treatment.

Abstract: Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and this condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underlie NASH progression. Additional 'extrahepatic hits' include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition.

Mesenchymal stem/stromal cells: a new "cells as drugs" paradigm. Efficacy and critical aspects in cell therapy

Abstract: Mesenchymal stem cells (MSCs) were first isolated more than 50 years ago from the bone marrow. Currently MSCs may also be isolated from several alternative sources and they have been used in more than a hundred clinical trials worldwide to treat a wide variety of diseases. The MSCs mechanism of action is undefined and currently under investigation. For in vivo purposes MSCs must be produced in compliance with good manufacturing practices and this has stimulated research on MSCs characterization and safety. The objective of this review is to describe recent developments regarding MSCs properties, physiological effects, delivery, clinical applications and possible side effects.

Binding Site Detection and Druggability Prediction of Protein Targets for Structure- Based Drug Design

Abstract: Assessing whether a protein structure is a good target or not before actually doing structure-based drug design on it is an important step to speed up the ligand discovery process. This is known as the “druggability” or “ligandability” assessment problem that has attracted increasing interest in recent years. The assessment typically includes the detection of ligand-binding sites on the protein surface and the prediction of their abilities to bind drug-like small molecules. A brief summary of the established methods of binding sites detection and druggability(ligandability) prediction, as well as a detailed description of the CAVITY approach developed in the authors’ group was given. CAVITY showed good performance on ligand-binding site detection, and was successfully used to predict both the ligandabilities and druggabilities of the detected binding sites.

Chemical and Structural Features Influencing the Biological Activity of Curcumin

Abstract: Curcumin, a polyphenolic natural product, exhibits therapeutic activity against a number of diseases, attributed mainly to its chemical structure and unique physical, chemical, and biological properties. It is a diferuloyl methane molecule [1,7-bis (4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione)] containing two ferulic acid residues joined by a methylene bridge. It has three important functionalities: an aromatic o-methoxy phenolic group, α, β-unsaturated β-diketo moiety and a seven carbon linker. Extensive research in the last two decades has provided evidence for the role of these different functional groups in its crucial biological activities. A few highlights of chemical structural features associated with the biological activity of curcumin are: The o-methoxyphenol group and methylenic hydrogen are responsible for the antioxidant activity of curcumin, and curcumin donates an electron/ hydrogen atom to reactive oxygen species. Curcumin interacts with a number of biomolecules through non-covalent and covalent binding. The hydrogen bonding and hydrophobicity of curcumin, arising from the aromatic and tautomeric structures along with the flexibility of the linker group are responsible for the non-covalent interactions. The α, β-unsaturated β-diketone moiety covalently interacts with protein thiols, through Michael reaction. The β-diketo group forms chelates with transition metals, there by reducing the metal induced toxicity and some of the metal complexes exhibit improved antioxidant activity as enzyme mimics. New analogues with improved activity are being developed with modifications on specific functional groups of curcumin. The physico-chemical and structural features associated with some of the biological activities of curcumin and important analogues are summarized in this article.

The multifunctional mesencephalic locomotor region.

Abstract: In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR). Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey. In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms of patients with Parkinson's disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcu- neiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial de- scending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson's disease.

Antioxidant and Antiinflammatory Activities of Curcumin on Diabetes Mellitus and its Complications

Abstract: Diabetes mellitus (DM) has reached pandemic status and shows no signs of abatement. It can severely impair people’s quality of life and affects patients all over the world. Since it is a serious, chronic metabolic disease, it can bring about many kinds of complications, which can in turn increase mortality. In recent decades, more and more studies have shown that oxidative stress and inflammatory reactions play critical roles in the pathogenesis of DM. There is an increasing demand for natural antidiabetic medicines that do not have the same side effects as modern drugs. Curcumin, a phytochemical found in the spice turmeric, has been used in India for centuries, and it has no known side effects. It has been shown to have some beneficial effects against various chronic illnesses. Many of these therapeutic actions can be attributed to its potent anti-oxidant and anti-inflammatory activities. In view of the oxidative stress and inflammatory mechanisms of DM, curcumin can be considered suitable for the prevention and amelioration of diabetes. In this review, we summarize the nosogenesis of DM, giving primary focus to oxidative stress and inflammation. We discuss the anti-oxidant and anti-inflammatory activities of curcumin in DM and its ability to mitigate the effects on DM and its associated complications in detail.

Avocado (Persea americana) seed as a source of bioactive phytochemicals.

Abstract: The pulp of avocado (Persea americana, Lauraceae) has been reported to have beneficial cardiovascular health effects. Avocado oil is used for dermatological applications and its unsaponifiable portion is reported to have beneficial effects against osteoarthritis. Although the seed represents a considerable percentage of the total fruit, scientific research on the phytochemistry and biological effects of avocado seeds is in the nascent stages,. Currently, the seed represents an under-utilized resource and a waste issue for avocado processors. There is ethno-pharmacological information on the use of seeds for the treatment of health-related conditions, especially in South American countries where avocados are endemic and currently grown on a large scale. Current research has shown that avocado seeds may improve hypercholesterolemia, and be useful in the treatment of hypertension, inflammatory conditions and diabetes. Seeds have also been found to possess insecticidal, fungicidal, and anti-microbial activities. The avocado seeds and rich in phenolic compounds, and these may play a role in the putative health effects. Historically, extracts of avocado seeds were also used as ink for writing and research in our laboratory has explored the potential colorant properties of a polyphenol oxidase-produced colored avocado seed extract. Here, we review the currently-available data on the bioactivity and other functional properties of avocado seeds. We discuss the strength of the available data, the putative active compounds, and potential directions for future studies.

Lysine Acetyltransferases CBP and p300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders

Abstract: Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

Epidemiology and natural history of patients with NAFLD.

Abstract: Non-alcoholic fatty liver disease (NAFLD) currently represents the most common liver disease in Western countries, being found in 25-30% of the general population. NAFLD embraces a wide range of metabolic hepatic damage characterised by steatosis and, in some cases, associated non-alcoholic steatohepatitis (NASH). The long-term hepatic prognosis of NAFLD patients depends on the histological stage at diagnosis: simple steatosis has a favourable outcome, whereas patients with NASH can develop cirrhosis and other liver-related complications, including hepatocellular carcinoma. Progression of fibrosis is thought to develop in up to one third of NASH patients, including the development of cirrhosis, but regression is also possible in pre-cirrhotic stages. Independent predictors of fibrosis are older age, diabetes, obesity, hypertension, and the degree of insulin resistance. Patients with NAFLD, particularly those with NASH, have a higher prevalence and incidence of clinically manifested cardiovascular disease, independently of classical cardiometabolic risk factors. Hepatocellular carcinoma (HCC) is usually diagnosed at a late stage, but it may also occur in non-cirrhotic NASH, as obesity and diabetes both independently increases the risk of developing HCC. Liver-related mortality is increased up to ten-fold in patients with NASH.

Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review.

Abstract: Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail.

From Bortezomib to other Inhibitors of the Proteasome and Beyond

Abstract: The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.

Cardiovascular and systemic risk in nonalcoholic fatty liver disease - atherosclerosis as a major player in the natural course of NAFLD.

Abstract: Non-alcoholic fatty liver disease (NAFLD) encompasses pure steatosis through nonalcoholic steatohepatitis (NASH) and is the most common cause of chronic liver disease in Western countries. NASH is a progressive liver disease that increases the risk of cirrhosis and end-stage liver disease. Interestingly, the global health risk of NAFLD is not confined to the liver. Compared with those without NAFLD, patients with NAFLD exhibit not only increased liver-related complications and liver-related mortality but also increased risk of developing type 2 diabetes, cardiovascular disease (CVD) and chronic kidney disease, increased risk of post-operative complications after major liver surgery, and increased risk of developing certain malignancies, including primary liver cancer and colorectal cancer. In this review, we discuss the current evidence linking NAFLD with the risk of CVD in the setting of the more complex scenario of other hepatic and extra-hepatic complications that may occur during the natural course of NAFLD. Moreover, we provide a brief description of the putative biological mechanisms underlying such complications, particular emphasis being given to CVD. We conclude that NAFLD is a complex health problem with implications far beyond the liver. Hence, it may cause a significant global health burden and the assistance of patients with NAFLD impacts on the work of physicians from many different medical specialties.

Commercial aspects of pharmaceutical protein production in plants.

Abstract: Many different plant-based systems have been used to produce recombinant pharmaceutical proteins but only a small number have made the leap from an experimental platform to a viable commercial process. This reflects a combination of factors, principally the technical issues that must be addressed to achieve competitive performance, the economic principles that need to be satisfied to ensure manufacturing processes are financially viable and sustainable, and the regulatory demands that must be met to ensure that pharmaceuticals manufactured in plants are safe, efficacious and meet the quality standards demanded by the regulators. With the recent approval of the first plant-derived recombinant pharmaceutical protein designated for human use, we are now entering a new era in which plants not only meet all the demands of a commercial pharmaceutical manufacturing process but also provide unique benefits that allow the displacement of established platform technologies in niche markets. In this article, we consider the commercial aspects of molecular farming, specifically those required to make plants more competitive and attractive to industry.

Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the progressive destruction of joint causes morbidity. It is also associated with an increased risk of atherosclerosis, which can result in cardiovascular disease and mortality. The therapeutic goal is to control the systemic inflammation to obtain not only the remission of symptoms, but also improve general state of health. Although recent biologic immunosuppressive therapies targeting pro-inflammatory cytokines have spawned a paradigm shift regarding the prognosis of RA, these therapies possess inherent side effects. Also, early diagnosis of the disease remains confounded by uncertainty. While the mechanisms responsible for the onset of RA remain unclear, reactive oxygen species (ROS) play a significant role in the pathogenesis of RA. ROS play a central role both upstream and downstream of NF-κB and TNFα pathways, which are located at the center of the inflammatory response. Among the ROS, the hydroxyl radical is the most harmful, and molecular hydrogen (H2) is a selective scavenger for this species. Recently, it has been shown that H2 is useful when administered along with the conventional therapy in RA as it acts to reduce oxidative stress in the patients. Especially in the early stage, H2 showed significant therapeutic potential, which also seemed to assist diagnosis and treatment decisions of RA. The possible expectations regarding the potential benefits of H2 by reducing the oxidative stress, resulting from inflammatory factors, are raised and discussed here. They include prevention of RA and related atherosclerosis, as well as therapeutic validity for RA

Cardiac dysfunction and oxidative stress in the metabolic syndrome: an update on antioxidant therapies.

Abstract: The metabolic syndrome (MetS) is a cluster of risk factors including obesity, insulin resistance, dyslipidemia, elevated blood pressure and glucose intolerance. The MetS increases the risk for cardiovascular disease (CVD) and type 2 diabetes. Each component of the MetS causes cardiac dysfunction and their combination carries additional risk. The mechanisms underlying cardiac dysfunction in the MetS are complex and might include lipid accumulation, increased fibrosis and stiffness, altered calcium homeostasis, abnormal autophagy, altered substrate utilization, mitochondrial dysfunction and increased oxidative stress. Mitochondrial and extra-mitochondrial sources of reactive oxygen species (ROS) and reduced antioxidant defense mechanisms characterize the myocardium of humans and animals with the MetS. The mechanisms for increased cardiac oxidative stress in the MetS are not fully understood but include increased fatty acid oxidation, mitochondrial dysfunction and enhanced NADPH oxidase activity. Therapies aimed to reduce oxidative stress and enhance antioxidant defense have been employed to reduce cardiac dysfunction in the MetS in animals. In contrast, large scale clinical trials using antioxidants therapies for the treatment of CVD have been disappointing because of the lack of efficacy and undesired side effects. The focus of this review is to summarize the current knowledge about the mechanisms underlying cardiac dysfunction in the MetS with a special interest in the role of oxidative stress. Finally, we will update the reader on the results obtained with natural antioxidant and mitochondria-targeted antioxidant therapies for the treatment of CVD in the MetS.