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Today, 12 Ιουλίου 2016, 4:09:18 μμ
Editorial (Thematic Issue: Lipidic Nano-carrier Delivery of “Big” Molecules)
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Anti-arthritic Effect and Underlying Mechanism of Ginsenoside Metabolite Compound K
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Ginsenoside metabolite compound K (CK) is a degradation product of panaxadiol (Rb1, Rb2, Rc) in the intestine by bacteria and is the major form of ginsenoside absorbed in the body. Recently, the anti-arthritic effect of CK has been confirmed in adjuvant-induced arthritis rats and collagen- induced arthritis mice and also in in vitro experiments. CK can regulate the function of cells which are involved in rheumatoid arthritis including immune cells, endothelial cells and fibroblast synoviocytes resulting in the anti-arthritic effect. The mechanisms of these effects may be mediated by different signaling pathways including glucocorticoid receptors, Toll-like receptors, ion channels, NF-κB and MAPKs.
Progress in Research of KV1.1 and KV1.3 Channels as Therapeutic Targets
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Voltage-gated potassium channels (K<sub>V</sub>) mainly response in action potential repolarization in excitable cells and also participate in regulating resting potentials in non-excitable cells, involved in diverse physiological processes. This review focuses on potential drug developments targeting the K<sub>V</sub>1.1 and K<sub>V</sub>1.3 channels. K<sub>V</sub>1.1 mainly existing in the nervous system plays key roles in controlling neuronal excitability; while the distribution of K<sub>V</sub>1.3 in different types of cells contributes to a variety of cellular processes. This article seeks to review the distributions of two channels, their roles in diseases, phenotypes of knockout mice, human channelopathies and selective modulators.
Imaging Patterns of Cardiovascular Involvement in Mixed Connective Tissue Disease Evaluated by Cardiovascular Magnetic Resonance
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: To clarify the imaging patterns of cardiovascular lesions in patients with mixed connective tissue disease (MCTD) and cardiovascular symptoms with or/ without abnormal routine non-invasive evaluation. </p><p> Patients-Methods: Twenty-two MCTD patients (19F/3M), aged 38±4 yrs with cardiovascular symptoms were evaluated using a 1.5 T scanner. Of them, 8/22 had systemic lupus erythematosus (SLE), 5/22 rheumatoid arthritis (RA), 5/22 scleroderma (SSc) and 4/22 myositis (MY) overlap syndromes; 10/22 patients with MCTD presented with Raynaud phenomenon (RP) and all were positive for Anti-RNP antibodies. The cardiovascular magnetic resonance study (CMR) included evaluation of function, inflammation and fibrosis. Myocardial stress perfusion-fibrosis evaluation was performed only in MCTD patients with RP. </p><p> Results: A positive CMR study was identified in 4/8 with SLE, 1/5 with RA, 4/5 with SSc and in 1/4 with MY like MCTD. The CMR lesions were subendocardial or transmural LGE following the distribution of coronary arteries, intramyocardial LGE and diffuse subendocardial LGE in SLE-RA, MY and SSc like MCTD, respectively. Although no evidence of fibrosis was identified in patients with RP, adenosine stress myocardial perfusion revealed diffuse subendocardial perfusion defects. No correlation between disease duration and/or inflammatory indices and cardiac lesions was identified. </p><p> Conclusion: CMR can reveal myocardial lesions in MCTD patients with cardiac symptoms including myocardial infarction, inflammation, diffuse subendocardial fibrosis and diffuse perfusion defects, necessitating further cardiac investigation and/or treatment. </p><p>
Increased Serum HMGB-1, ICAM-1 and Metalloproteinase-9 Levels in Buerger’s Patients
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: Thromboangiitis obliterans (TAO), or Buerger’s disease, is an inflammatory occlusive disorder that affects the limb arteries of young smokers. In the aetiology of TAO the immune system appears to play a critical role; however, information on the aspects involved in the evolution of vascular tissue inflammation and of this disease are still limited. </p><p> Objective: This study was carried out to investigate HMGB-1 (high mobility group box-1), MMP (matrix metalloproteinase)- 2, MMP-9, MMP-11 and ICAM (intercellular adhesion molecule)-1 circulating levels in subjects with Buerger’s disease. </p><p> Methods: Between January 2010 and December 2012, eight patients underwent surgical revascularization of the lower limbs and a specimen of the affected arterial wall was obtained for histological confirmation of Buerger’s disease. A blood sample was collected on the same day for measuring HMGB-1, MMP-3, MMP-9 and ICAM-1 by western blot analysis. Controls (n=7) were healthy non-smokers. </p><p> Results: TAO subjects had a significant increase in HMGB-1, MMP-9 and ICAM-1 compared with controls (P<.0001), while no differences were observed in MMP-2 and MMP-11 levels. Histology confirmed a strong inflammatory infiltrate with signs of necrosis in the arterial wall. </p><p> Conclusion: These data suggest a role for HMGB -1 in the vascular lesions associated with TAO, unveiling HMGB-1 as a potential target for treating this rare disease. </p><p>
Non-cirrhotic Portal Hypertension Associated with Didanosine and Streptococcus agalactiae Infection: A Case Report
Today, 12 Ιουλίου 2016, 4:09:19 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>
Synthesis and Biological Evaluation of Scutellaria Flavone Cyclaneaminol Mannich Base Derivatives as Novel CDK1 Inhibitors
Today, 12 Ιουλίου 2016, 4:09:19 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.
Editorial (Mini Thematic Issue: Immunotherapy – A Pivotal Mechanism in the Fight of Cancer)
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Mechanisms Explaining the Influence of Subclinical Hypothyroidism on the Onset and Progression of Chronic Heart Failure
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: Subclinical hypothyroidism can be associated with the onset and progression of chronic heart failure. </p><p> Methods: We undertook a careful search of the literature aiming to review the possible pathogenetic mechanisms explaining the influence of subclinical hypothyroidism on the onset and progression of chronic heart failure. </p><p> Results: Thyroid hormones can influence the expression of genes involved in calcium handling and contractile properties of myocardiocytes. Subclinical hypothyroidism, therefore, can alter both cardiovascular morphology and function leading to changes in myocardiocytes shape and structure, and to alterations of both contractile and relaxing properties, impairing systolic as well as diastolic functions. Furthermore, it can favour dyslipidemia, endothelial dysfunction and diastolic hypertension, favouring atherogenesis and coronary heart disease, possibly evolving into chronic heart failure. Beside an influence on the onset of chronic heart failure, subclinical hypothyroidism can represent a risk factor for its progression, in particular hospitalization and mortality but the mechanisms involved need to be fully elucidated. </p><p> Conclusions: Subclinical hypothyroidism can be associated with the onset of chronic heart failure, because it can favour two frequent conditions that can evolve in heart failure: coronary heart disease and hypertension; it can also alter both cardiovascular morphology and function leading to heart failure progression in patients already affected through mechanisms still not completely understood. </p><p>
Polymer-Based Drug Delivery Systems, Development and Pre-Clinical Status
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: The nanomedicine is considered as the application of nanotechnology in the medical field where nanoparticles are sized in the nanoscale range. Drug delivery technologies are becoming increasingly important as a scientific area of investigation. Controlled-release systems and drug-targeting systems represents an alternative to traditional delivery nanoparticles, and the use of polymers is increasing nowadays. Although polymers could be classified as excipients, they are capable of modifying the biopharmaceutical and biokinetic behaviour of the transported active molecule increasing its efficacy and stability, and reduced cytotoxicity on healthy peripheral tissues. Methods: The goal of this work is to collect and analyse the most current polymeric nanoparticles development as controlledrelease and drug-targeting systems in cancer, infectious diseases and immunomodulation areas, as alternatives to conventional therapies. Results: This review provides an update on the polymeric nanoparticles development analysing the trend of polymeric-based drug delivery systems, future opportunities and challenges of this fast-growing area. Conclusion: With the thorough comprehension of biological effects depending on structure, it is possible to design specific systems for specific diseases, treatments and patients. The ability of polymer- based nanoparticles to modify and improve pharmacokinetics and pharmacodynamics, associated to techniques for enhancement of the therapeutic efficiency with minimal side effects, demonstrate the advantages of these systems.
Role of Osmolytes in Regulating Immune System
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: The immune system has evolved to protect the host organism from diverse range of pathogenic microbes that are themselves constantly evolving. It is a complex network of cells, humoral factors, chemokines and cytokines. Dysregulation of immune system results in various kinds of immunological disorders. There are several external agents which govern the regulation of immune system. Recent studies have indicated the role of osmolytes in regulation of various immunological processes such as Ag-Ab interaction, Ig assembly, Ag presentation etc. </p><p> Scope of Review: In this present review, we have systematically discussed the role of osmolytes involved in regulation of several key immunological processes. </p><p> Major Conclusion: Osmolytes are involved in the regulation of several key immunological processes such as immunoglobulin assembly and folding, immune cells proliferation, regulation of immune cells function, Ag-Ab interaction, antigen presentation, inflammatory response and protection against photo-immunosuppression. Hence, osmolytes and their transporters might be used as potential drug and drug targets respectively. </p><p> General Significance: This review is therefore designed to help clinicians in development of osmolyte based therapeutic strategies in the treatment of various immunological disorders. Appropriate future perspectives have also been included. </p><p>
Recent Advances Using Phosphodiesterase 4 (PDE4) Inhibitors to Treat Inflammatory Disorders: Animal and Clinical Studies
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.
The Role of α7 Nicotinic Acetylcholine Receptors and α7-Specific Antibodies in Neuroinflammation Related to Alzheimer Disease
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: Alzheimer disease (AD) is a neurodegenerative disorder occurring in elderly people and leading to the loss of memory, practical and speaking habits. In spite of extensive efforts undertaken during the last decades, there is still no generally recognized explanation of the origin and primary pathological changes leading to AD development. Consequently, the suggested pharmacological approaches to treat the AD patients are mostly symptomatic and do not stop the disease progression. Neuroinflammation and cholinergic deficit usually accompany AD development. However, their impact in AD progression still waits for being properly recognized. </p> <p> Objective: The present review aims at analysis of the role of inflammation and nicotinic acetylcholine receptors, primarily of α7 subtype (α7 nAChRs), in the development of AD in humans and AD-like symptoms in experimental animals. </p> <p> Results: The reviewed data describe the involvement of α7 nAChRs in the AD pathogenesis, in particular, through their interaction with amyloid-β, maintenance of brain cell viability and regulation of neuroinflammation. They also delineate the role of α7-specific (auto)antibodies in stimulating neuroinflammation, memory impairment in mice and AD progression in humans. </p> <p> Conclusion: Neuroinflammation is suggested as a primary stimulus sufficient to trigger accumulation of pathologically processed amyloid-β, degeneration of cholinergic neurons and memory impairment. The level of α7 nAChR expression in the brain is critical for supporting the resistance to inflammatory and apoptogenic agents. The data presented may be a basis to create a new strategy for preventing and, possibly, slowing AD development in humans.
Predictive Efficacy Biomarkers of Programmed Cell Death 1/Programmed Cell Death 1 Ligand Blockade Therapy
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Inhibitors of immune check-point molecule, programmed cell death 1 (PD-1) and its ligand, programmed cell death ligand 1 (PD-L1) have attracted much attention in cancer immunotherapy recently due to their durable antitumor effects in various malignances, especially the advanced ones. Unfortunately, only a fraction of patients with advanced tumors could benefit from anti-PD-1/PD-L1 therapy, while others still worsened. The key to this point is that there are no efficient biomarkers for screening anti-PD-1/PD-L1-sensitive patients. In this review, we aim at summarizing the latest advances of anti-PD-1/PDL1 immunotherapy and the potential predictive efficacy biomarkers to provide evidences for identifying anti-PD-1/PDL1- sensitive patients. The present article also includes the patent review coverage on this topic.
Survivin Modulators: An Updated Patent Review (2011 - 2015)
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: Survivin is widely overexpressed in many forms of cancer and studies have related high survivin expression with poor survival rates. Although, there have been several attempts to target survivin, most therapeutics haven’t shown substantial success in clinical trials therefore, authors wish to attract the focus towards many recent therapeutic innovations to target survivin. </p><p> Objective: Survivin plays an essential role in the cell cycle progression, apoptosis, cell stress response, drug resistance and angiogenesis therefore the prognostic and targeting benefits of survivin have been underestimated. An update on the current and existing therapeutic strategies implemented to target survivin is provided. Therefore, the reader will gain an insight into the recent patents targeting survivin. The review has emphasised on patents for quantification of survivin, survivin peptides as immunotherapeutics, application of survivin promoters, RNA interference of survivin, small molecules inhibitors of survivin and nanoparticles targeting survivin. The review also encompasses the survivin targeted therapeutics being implemented at clinical stages which include survivin targeted immunotherapeutics, peptide-based vaccines, antisense oligonucleotides and chemical inhibitors. </p><p> Conclusion: We reviewed recent patents based on preclinical anti-survivin therapies reported to date and it was concluded that gataparsen has been most widely used for anti-survivin therapy in clinical trials. It was also concluded that most therapeutic patents were focussed on development of natural anti-survivin therapeutics such as anti-survivin peptides or survivin anti-sense oligonucleotides in the recent years therefore, proving that natural proteins and nucleic acids has an upper hand over chemicals and synthetic drugs. </p><p>
Risk Factors for Myocardial Infarction in Women and Men: A Review of the Current Literature
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Background: Cardiovascular disease has been the leading cause of death in both sexes in developed countries for decades. In general, men and women share the same cardiovascular risk factors. However, in recent trials including both men and women sexspecific analyses have raised awareness of sex differences in cardiovascular risk factors due to both biological and cultural differences. </p><p> Results: Women experience their first myocardial infarction (MI) 6-10 years later than men and a protective effect of their natural estrogen status prior to menopause has been suggested. Female sex hormones have been associated with a less atherogenic lipid profile and a more healthy fat distribution. These differences are attenuated following menopause. Regarding life style the prevalence of smoking is highest in men but female smokers have a relatively higher cardiovascular risk than male smokers. Men are more physically active than women while women have healthier dietary habits. Genetic factors also affect cardiovascular risk but no sex differences have been seen. Increased cardiovascular risk attributed to psychosocial distress is similar in men and women, but since women are more prone to psychosocial distress their burden of disease is greater. Compared with a healthy population the relative risk of MI in a diabetic population is higher in women than in men. No sex difference exists in the prevalence of hypertension but it has an earlier onset in men. </p><p> Conclusion: Sex differences in cardiovascular risk are becoming more apparent and paying attention to this is pivotal when addressing risk factors in preventive efforts. </p><p>
Leflunomide, a Reversible Monoamine Oxidase Inhibitor
Today, 12 Ιουλίου 2016, 4:09:19 μμ
A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC<sub>50</sub> values of 19.1 μM and 13.7 μM, respectively. The corresponding K<sub>i</sub> values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson’s disease, and are under investigation as therapy for certain types of cancer, Alzheimer’s disease and age-related impairment of cardiac function.
Endoplasmic Reticulum Stress, Calcium Dysregulation and Altered Protein Translation: Intersection of Processes That Contribute to Cancer Cachexia Induced Skeletal Muscle Wasting
Today, 12 Ιουλίου 2016, 4:09:19 μμ
Cancer cachexia is a debilitating paraneoplastic wasting syndrome characterized by skeletal muscle depletion and unintentional weight loss. It affects up to 50-80% of patients with cancer and directly accounts for one-quarter of cancer-related deaths due to cardio-respiratory failure. Muscle weakness, one of the hallmarks of this syndrome, has been postulated to be due to a combination of muscle breakdown, dysfunction and decrease in the ability to repair, with effective treatment strategies presently limited. Excessive inflammatory cytokine levels due to the host-tumor interaction, such as Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α, are hypothesised to drive this pathological process but the specific mechanisms by which these cytokines produce skeletal muscle dysfunction in cancer cachexia remain undefined. Endoplasmic Reticulum (ER) stress and the associated disruptions in calcium signaling have been implicated in cytokine-mediated disruptions in skeletal muscle and function. Disrupted ER stress-related processes such as the Unfolded Protein Response (UPR), calcium homeostasis and altered muscle protein synthesis have been reported in clinical and experimental cachexia and other inflammation-driven muscle diseases such as myositis, potentially suggesting a link between increased IL-6 and TNF-α and ER stress in skeletal muscle cells. As the concept of upregulated ER stress in skeletal muscle cells due to elevated cytokines is novel and potentially very relevant to our understanding of cancer cachexia, this review aims to examine the potential relationship between inflammatory cytokine mediated muscle breakdown and ER stress, in the context of cancer cachexia, and to discuss the molecular signaling pathways underpinning this pathology.
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