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Today, 12 Ιουλίου 2016, 4:09:16 μμ
Prospects of Developing Medicinal Therapeutic Strategies and Pharmaceutical Design for Effective Gluten Intolerance Treatment
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Gluten intolerance is an umbrella term for gluten-related disorders manifested in health decline as a result of the gluten ingestion. The spectrum of gluten-related disorders includes three major groups: autoimmune (mainly, Celiac Disease, CD, also known as Celiac Sprue, dermatitis herpetiformis, or gluten-sensitive ataxia), allergic (wheat allergy, WA), and non-autoimmune non-allergic (non-celiac gluten sensitivity, NCGS, or gluten sensitivity, GS). Pathogenesis and diagnostics of CD and WA are well established in contrast to NCGS, pathogenicity of which is still poorly understood and its symptoms are frequently misdiagnosed since most of the NCGS cases are currently identified via the process of CD and WA exclusion. By now, the only one proven effective way for CD treatment is gluten-free diet (GFD). However, such an increasingly gaining popularity diet is apparently unsuitable for NCGS treatment because in this case gluten does not always arise as the major or exclusive culprit of gastrointestinal disorder. Furthermore, it is some physicians’ opinion that GFD can be deficient in fiber and in other vitamins and minerals. In many cases, GFD is commercially inaccessible for the most needy, whereas strict adherence to the diet is complicated by the presence of small amounts of the gluten components in some foods and even medicines. In this regard, a number of research groups and pharmaceutical companies are extensively developing alternative medicinal approaches to GFD for effective gluten intolerance treatment. This review summarizes our understanding of gluten-related disorders, possible mechanisms of gluten intolerance activation and advantages of gluten intolerance medicinal treatment using novel drug candidates obtained with a proper pharmaceutical design.
Immune-Regulatory Mechanisms of Classical and Experimental Multiple Sclerosis Drugs: A Special Focus on Helminth-Derived Treatments
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Multiple sclerosis (MS) is the most prevalent autoimmune disease affecting the central nervous system (CNS). Its pathophysiology is centered on neuron myelin sheath destruction in a manner largely dependent upon CD4+/CD8+ T-cell autoreactivity against myelin antigens, inducing Th1/Th17 pathogenic responses with the resulting production of free radicals and soluble mediators that exhibit the effector mechanisms of neurodegeneration. The immune response responsible for this disease is complex and challenges modern medicine. Consequently, many experimental therapies have been proposed in addition to the classical array of immunoregulatory/ immunosuppressive drugs that are normally used to treat MS. In this review, we will describe the effects and mechanisms of action of widely used disease-modifying MS drugs as well as those of select treatments that are currently in the experimental phase. Special emphasis is placed on helminth-derived immunoregulators, as some of them have shown promising results. Additionally, we will compare the mechanisms of action of both the MS drugs and the helminth-derived treatments to discuss the potential importance of some signaling pathways in the control of MS.
Sunscreening and Photosensitizing Properties of Coumarins and their Derivatives
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Coumarin and its derivatives belong to an important group of natural compounds with diverse biological properties. They are found in vegetables and plants and have been extensively investigated for various applications in pharmacology, medicine and cosmetics. The coumarins are lactones of hydroxycinnamic acids with photoprotective effect, the furanocoumarins (coumarins with furan ring) have photosensitizing properties and are often used for the treatment of skin diseases such as vitiligo and psoriasis. As cosmetic ingredients, coumarin derivatives are well known in fragrances, but have also been identified as UV absorbers, with photo-oxidation, antioxidant and photosensitizing properties also being reported. In this minireview we focused on photoprotective and photosensitizing effects of coumarins.
Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM). Cardiometabolic disorders (CMDs) remain the principal cause of death in both developed and developing countries, accounting for nearly 32% of all deaths worldwide per year. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs. Existing drugs are not efficient enough to reduce the disease burden as well as mortality. Therefore, there is an urgent demand for new drugs in this area to reduce the mortality and control the associated disability. Nonetheless, new drug discovery (NDD) in CMDs has become more challenging for last couple of decades due to increased expenses and decreased success rate. In such a scenario, drug repositioning in the CMDs appears promising for introducing existing drugs for new therapeutic indication. Repositioning is quite an old strategy dating back to 1960s and mainly followed by serendipitous observations during clinical use of drugs. A major advantage of repositioning is that the safety profile of the drug is well established thus reducing the chances of failure due to adverse toxic effects. In addition, repositioning requires less time and investment than NDD. Considering these facts, pharmaceutical companies are now becoming increasingly interested in drug repositioning. In this follow-up, we have talked about the concept of repositioning with important examples of repositioned drugs in cardiometabolic disorder.
Higher Expression of NOD1 and NOD2 is Associated with Vogt-Koyanagi-Harada (VKH) Syndrome But Not Behcet’s Disease (BD)
Today, 12 Ιουλίου 2016, 4:09:17 μμ
NOD1 and NOD2 have been found to play a significant regulatory role in autoimmune disease. To analyze the role of NOD1 and NOD2 in the pathogenesis of Vogt- Koyanagi-Harada (VKH) syndrome and Behcet's disease (BD). We analyzed the expression of NOD1 and NOD2 from PBMCs by RT-PCR and Western Blot. PBMCs and DCs were cultured with NOD receptor ligands iE-DAP (NOD1) or MDP (NOD2) and cells and supernatants were analyzed by flow cytometry (FCM) and enzyme-linked immunosorbent assay (ELISA). DCs and CD4+T cells were co-cultured with or without stimulation and cells and supernatants were analyzed by FCM and ELISA. A higher expression of NOD1 and NOD2 was observed in patients with active VKH syndrome as compared with controls. However, no significant differences were found between BD patients and controls. Activation of NOD1 and NOD2 with iE-DAP or MDP markedly increased the level of IL-6, TNF-α and IL-1β in PBMCs and DCs and induced the expression of CD40, CD80, CD83, CD86 and HLA-DR on DCs. Activation of NOD1 and NOD2 in DCs promoted the differentiation and proliferation of CD4<sup+</sup>T cells. In conclusion, activation of NOD1 or NOD2 increased the production of pro-inflammatory cytokines in PBMCs and promoted the maturation and activation of human DCs in association with stimulation of Th1 and Th17 cells. Our results suggest that over-expression of NOD1 and NOD2 may be involved in the pathogenesis of VKH syndrome.
Non-cirrhotic Portal Hypertension Associated with Didanosine and Streptococcus agalactiae Infection: A Case Report
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Background: Non-Cirrhotic Portal Hypertension (NCPH) is a rare but potentially fatal liver disorder described in patients treated with anti-retroviral therapy for Human Immunodeficiency Virus (HIV). In particular, the most important predisposing factor to its development has been identified as prolonged exposure to Didanosine (ddI). The clinical entity of NCPH is characterized by an increase in portal pressure due to pre- or intra-hepatic causes, in absence of liver cirrhosis. However, the exact pathogenesis remains poorly understood, and due to its rarity, the diagnosis is often delayed. </p><p> Objective: We herein report a case in which ddI administration, with concomitant spontaneous bacterial peritonitis by Streptococcus agalactiae, has induced NCPH in a HIV male patient. </p><p> Conclusion: NPCH should be suspected when HIV patient with an history of ddI treatment presents liver decompensation. </p><p>
Novel Strategies in the Treatment of Pulmonary Arterial Hypertension
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Pulmonary arterial hypertension (PAH) is a pathophysiological condition characterized by increased pulmonary vascular resistance (PVR), initially due to abnormal pulmonary vasoconstriction in response to endothelial injury. Recent studies confirmed the key role of endothelin (ET)-1 in the vasoconstriction and remodeling of pulmonary microcirculation during PAH. In responders patients, classical treatments for PAH are prostanoids, phosphodiesterase (PDE)-5 inhibitors and endothelin receptor antagonists (ERAs), which target prostaglandin I2, nitric oxide and endothelin pathways, respectively. Randomised, placebo-controlled trials have shown that ERAs improves haemodynamic parameters of the pulmonary circulation, functional capacity and clinical outcome in patients affected by PAH. Here, we will review the definition, classification and pathophysiology of PH. Furthermore, we will provide an up-to-date overview of currently recommended diagnostic and therapeutic work-up in PAH.
Synthesis and Biological Evaluation of Scutellaria Flavone Cyclaneaminol Mannich Base Derivatives as Novel CDK1 Inhibitors
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. Natural flavones are selective CDK1 inhibitors which can suppress the proliferation of cancer cells. However, their bioavailability is poor. To solve these problems, 6 Scutellaria flavones were isolated from hydrolyzed products of Scutellaria baicalensis and used as lead compounds, 18 Scutellaria flavones cyclane-aminol Mannich base derivatives were semi-synthesized and their biological activity as novel CDK1 inhibitors was evaluated. Results indicated that the biological activity of 8-Hydroxypiperidinemethyl-baicalein (BA-j) is the highest among these compounds. BA-j is a selective CDK1 inhibitor, and has broad-spectrum anti-proliferative activity in human cancer cells (IC<sub>50</sub> 12.3μM). BA-j can capture oxygen free radicals (.O<sub>2</sub><sup>-</sup>) and selectively increase intracellular H<sub>2</sub>O<sub>2</sub> level in cancer cells and activated lymphocytes, thus inducing their apoptosis rather than in normal cells. These findings suggest that BA-j selectively induces apoptosis in cancer and activated lymphocyte by controlling intracellular H<sub>2</sub>O<sub>2</sub> level, and can be developed into a novel anti-proliferative agent for the treatment of cancer, AIDS, and some immune diseases.
Personalized Treatment of Obsessive-Compulsive Disorder: Radiology, EEG, Pharmacogenetics and Biochemistry
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. </p><p> Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. </p><p> Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. </p><p> Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree. </p><p>
Neglected Tropical Protozoan Diseases: Drug Repositioning as a Rational Option
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Neglected tropical diseases represent a major sanitary problem and a huge economic burden to endemic countries, and are currently expanding to non-endemic countries owing to migration currents. Though long abandoned in the past, recent research on novel therapeutics has already started to show results. Drug repositioning is one of the prominent, more successful strategies to approach the development of new treatments for these diseases. Here we present an overview on the limitations of the current available medications to treat African trypanosomiasis, Chagas disease and Leishmaniasis, along with a review on drug candidates presently undergoing clinical trials and drug candidates identified through drug repositioning initiatives.
Psychosocial Risk Factors Related to Ischemic Heart Disease in Women
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Background: Psychosocial risk factors such as stress and psychiatric disorders are known to have negative impacts on health outcomes, but their effects on ischemic heart disease, particularly in women, remain to be fully understood despite contributing to one-third of the population attributable risk in acute myocardial infarction. Methods: The impact of stress, social isolation, low socioeconomic status, hostility and anger, and stress-related psychiatric disorders on cardiovascular outcomes and the potential mechanisms that underlie their association with ischemic heart disease, with a focus on women, is evaluated. Online search of relevant terms, including the aforementioned risk factors, women, and ischemic heart disease, was utilized to find recent and pertinent trials. Results: Psychosocial risk factors increase cardiovascular risk in both women and men. However, current literature points to a greater degree of adverse cardiovascular events in women who experience these risk factors than in men, but the literature is not as well-defined as the data regarding traditional risk factors and cardiovascular disease. Conclusion: Dedicated study of the sex differences in ischemic heart disease incidence and recurrence, including the impact of psychosocial risk factors, is warranted for the development of appropriate gender-specific diagnostic testing and treatment options in heart disease.
Management of Inflammation by Natural Polyphenols: A Comprehensive Mechanistic Update
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Inflammation generates a systemic response against injury or infection from bacteria, viruses, and other pathogens. The welfare of host is the primary target of this process. However, uncontrolled or inadequate regulation of the inflammatory response produces detrimental effects leading to the generation of various chronic disorders including atherosclerosis, type-2 diabetes, neurodegenerative disease, cancer and Alzheimer’s disease with severe tissue damage. The exact identity of the inflammatory stimuli is still elusive as they function in multiple pathways; therefore targeting a particular pathway does not resolve the problem. Existing therapeutics targeting the inflammatory responses include steroidal antiinflammatory drugs (SAIDs) and nonsteroidal antiinflammatory drugs (NSAIDs). In spite of their numerous beneficial effects, both SAIDs as well as NSAIDs have their independent, unavoidable side effects, which discourage their prolonged therapeutic applications. Since the management of uncontrolled inflammation is critical for the general wellbeing, therefore an alternative source of multi-targeted non-toxic therapeutic intervention is mandatory. Plant-derived phenols constitute such a group of molecules that can be utilised to manage inflammation. They synergistically modulate several important components involved in multiple signalling pathways that regulate uncontrolled inflammation to exhibit their beneficial health effects. This review discusses the recent advances in structure-function activity of some antiinflammatory polyphenols, their bioavailability enhancement, clinical/ preclinical findings with a view to provide knowledge for developing novel antiinflammatory drugs by following system biology of proinflammatory responses with minimal side effects.
Editorial (Thematic Issue: Drug Reprofiling: An Alternative Path to Drug Discovery)
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Nutraceuticals against Neurodegeneration: A Mechanistic Insight
Today, 12 Ιουλίου 2016, 4:09:17 μμ
The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca<sup>2+</sup> overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.
Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.
Exploring Polypharmacology in Drug Discovery and Repurposing Using the CANDO Platform
Today, 12 Ιουλίου 2016, 4:09:17 μμ
Background: Traditional drug discovery approaches focus on a limited set of target molecules for treatment against specific indications/diseases. However, drug absorption, dispersion, metabolism, and excretion (ADME) involve interactions with multiple protein systems. Drugs approved for particular indication(s) may be repurposed as novel therapeutics for others. The severely declining rate of discovery and increasing costs of new drugs illustrate the limitations of the traditional reductionist paradigm in drug discovery. Methods: We developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform based on a hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for therapeutic repurposing and discovery. We compiled a library of compounds that are human ingestible with minimal side effects, followed by an ‘all-compounds’ vs ‘all-proteins’ fragment-based multitarget docking with dynamics screen to construct compound-proteome interaction matrices that were then analyzed to determine similarity of drug behavior. The proteomic signature similarity of drugs is then ranked to make putative drug predictions for all indications in a shotgun manner. Results: We have previously applied this platform with success in both retrospective benchmarking and prospective validation, and to understand the effect of druggable protein classes on repurposing accuracy. Here we use the CANDO platform to analyze and determine the contribution of multitargeting (polypharmacology) to drug repurposing benchmarking accuracy. Taken together with the previous work, our results indicate that a large number of protein structures with diverse fold space and a specific polypharmacological interactome is necessary for accurate drug predictions using our proteomic and evolutionary drug discovery and repurposing platform. Conclusion: These results have implications for future drug development and repurposing in the context of polypharmacology.
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