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Today, 12 Ιουλίου 2016, 3:55:13 μμ
The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Background & Objectives: Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. </p> <p> Conclusion: Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.
An Overview of Emerging Immunotargets of Genitourinary Tumors
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Emerging immunotherapies targeting immune checkpoints and tumor associated antigens are leading to important clinical advances and providing a new weapon in patients with prostate (PCa) and bladder cancer (BC) and, in particular, with renal cell carcinoma (RCC). The possibility to integrate these agents in the current therapeutic scenario or genitourinary tumors, both in sequential or combined approaches, relies on a more profound comprehension of the protumorigenic activity of the immune system and of the mechanisms of cancer-related immunosuppression. In this regards, neutrophils, T and B lymphocytes and tumor-associated macrophages (TAMs) are implicated in the pathogenesis, progression and development of drug resistance in genitourinary tumors. This review is an overview on the recent insights concerning the role of immune cells in this context.
Emerging Immunotargets in Bladder Cancer
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Bladder cancer treatment, namely systemic therapy, was dominated in the last three decades due to the absence of newer therapeutic options other than chemotherapy regimens. Chemotherapy, by itself, both in first and second-line seems to have achieved the modest plateau of its possibilities at the cost of non-negligible toxicity. Targeted therapies, which changed the therapy of many different tumors, seem rather ineffective in bladder cancer. More recently, a new generation of Immunotherapy based regimens represent the most promising avenue for the future systemic treatment of bladder cancer. Checkpoint inhibition, namely PD1/PD-L1 pathway inhibition, showed impressive results in many other tumor types and are expected to become a major player in the treatment of bladder cancer. Other immunotherapy strategies such as fusion proteins represent distant, although promising, options. A brief overview of the current status of bladder cancer immunotherapy is presented.
Editorial (Thematic Issue: Myokines and Exercise Training: More Shadows than Lights)
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Chemical Senses in Cancer Patients
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Background. Cancer and its treatment therapies, such as chemotherapy and radiotherapy, have negative effects on taste and smell functions. It is easy to explain smell and taste dysfunctions when a cancer involves the peripheric end organs or neurologic pathways of smell and taste. However, it is difficult to understand how distortion in sensory perception develops as cancer progresses and cancer therapies are applied, because few studies on this subject have described heterogeneous oncological patient populations who are receiving different treatment regimens. Methods. A literature review was performed about the chemical senses of the patients with various cancer types, and also about the possible mechanisms of taste and smell dysfunctions in cancer patients. Results. Chemotherapy and radiotherapy may cause taste and smell alterations by destroying taste and olfactory receptor cells, creating alterations on the surfaces of cells and receptors as well as interrupting neural coding. The prevalence of taste dysfunctions in cancer patients has been reported to be up to 77%. Unlike taste dysfunction, diminished sensitivity of smell in cancer patients is described infrequently and the available literature contains some conflicting results for smell dysfunction in cancer patients. Conclusion. Further studies are needed on the loss of appetite in cancer patients, and specific treatments should be identified according to the pathologic mechanism responsible for anorexia and particularly for taste and smell dysfunctions. Because sufficient nutrition and energy intake can help patients overcome the cancer and its treatment-related complications.
Anti-arthritic Effect and Underlying Mechanism of Ginsenoside Metabolite Compound K
Today, 12 Ιουλίου 2016, 3:55:14 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.
LPS Up-Regulates Cystathionine γ -Lyase Gene Expression in Primary Human Macrophages via NF-κB/ERK Pathway
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Hydrogen sulfide (H2S) is an endogenous inflammatory mediator produced by the activity of cystathionine γ–lyase (CSE) in mammals. Macrophages are a key element of the immune system and play a crucial role in inflammation. To determine the role of H<sub>2</sub>S and macrophages in inflammation, we investigated the expression of CSE in human primary macrophages. Our results show that H<sub>2</sub>S is produced by the activity of CSE in these cells. To investigate the role of common signalling pathway in biosynthesis of CSE in human primary macrophages, specific inhibitors were used to block NF-κB, ERK, p38 and JNK. Inhibition of NF-κB, ERK significantly reduced levels of CSE gene and protein expression in these cells but inhibition of JNK and p38 did not have an inhibitory effect on the expression of CSE gene in macrophages. Inhibition of NF-κB and ERK prevented the effect of LPS on H2S synthesizing activity in human primary macrophages. These data showed that H2S acts as an inflammatory mediator via NF-κB/ERK pathway in macrophages.
Increased Serum HMGB-1, ICAM-1 and Metalloproteinase-9 Levels in Buerger’s Patients
Today, 12 Ιουλίου 2016, 3:55:14 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>
Treatment for Cancer Patients with Oral Mucositis: Assessment Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and Proposal of Possible Novel Treatment with a Japanese Herbal Medicine
Today, 12 Ιουλίου 2016, 3:55:14 μμ
The cancer patients who received chemotherapy, radiotherapy, hematopoietic stem cell transplant and terminal care often have a wide range of stomatitis, which induces severe pain and limits fundamental life behaviors such as “eating, drinking and talking”. In addition, oral mucositis frequently leads to systemic infection through opportunistic microorganisms, which causes extension of hospitalization. Severe oral mucositis often causes cancer patients to partially or completely discontinue/modify cancer therapy regimen, which adversely affects the curative effects of cancer. Therefore, the control of oral mucositis is important and indispensable for improvement of quality of life and prognosis. In this review, we introduce recent trends of the oral mucositis management in cancer patients, according to the following sentences; 1) pathophysiological mechanisms of oral mucositis, 2) assessment, 3) risk factors, 4) prevention and treatment, and 5) development of novel therapy for oral mucositis.
Leuckart Synthesis and Pharmacological Assessment of Novel Acetamide Derivatives
Today, 12 Ιουλίου 2016, 3:55:14 μμ
A new concatenation of N-(1-(4-bromophenyl)ethyl)-2-phenoxyacetamide and N-(1-(4-methoxyphenyl) ethyl)-2-phenoxyacetamide derivatives having 2-phenoxy-N-(1-phenylethyl)acetamide nucleus as common in both the types was synthesized for the sake of achieve titled compounds as potential cytotoxic, anti-inflammatory, analgesic and antipyretic agents. All the novel derivatives have been synthesized through multi-step reaction sequence starting from Leuckart reaction. The structural assignments of the new compounds have been determined by virtue of their IR, 1H NMR, 13C NMR, elemental analysis and mass spectrum analysis. All the synthesized compounds were assessed for cytotoxicity and anti-inflammatory, analgesic and antipyretic effects. Among the series, compounds 3a, 3c, 3g and 3h possess cytotoxic, anti-inflammatory, analgesic and antipyretic activities comparable with standard drugs. The synthesized compounds were found to be active because of the presence of bromo, tert- butyl and nitro groups at position 4 of phenoxy nucleus.
Impact of Macrophages in Atherosclerosis
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Atherosclerosis is driven by inflammation, with a strong involvement of innate immunity, and involves an expansion of the arterial intima, a normally small area composed of several cell types including smooth muscle cells, lipids, monocytes, macrophages, dendritic cells, and extracellular matrix. Macrophages derived from recruited monocytes are predominant innate immune cells that play crucial roles in the formation of atherosclerotic lesions. Human atherosclerotic plaques have shown that macrophage subsets within a plaque might be more useful for explaining plaque phenotype than just simply giving the total number of macrophages. Therefore, recognizing the roles of macrophage subsets in atherosclerotic plaque formation, progression, and regression would be most helpful for identification of novel strategies to stabilize, or attenuate atherosclerotic lesions. This review discusses the impact of macrophage subsets and their roles in atherosclerosis.
An Update on Herbal Anti-inflammatory Agents in Periodontal Therapy
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Periodontal diseases are a group of disorders characterized by an inflammatory reaction of periodontium induced by bacterial challenge leading to gingival inflammation, periodontal tissue destruction and alveolar bone loss. The use of naturally derived agents is becoming more common. Many of these agents contain a mixture of active pharmaceutical ingredients combined based on their additive or synergistic properties. The aim of the present study is to review the literature about the use of herbal drugs and other natural products in the treatment of periodontal diseases and their antiinflammatory properties. A web search through Pubmed and hand search including several dental journals was performed up to December 2015, using the keywords (herbal anti-inflammatory agents OR herbal antioxidant) AND (periodontitis OR periodontal disease OR periodontosis). Three topics were investigated: 1) major herbal agents and their biological properties compared with chlorhexidine, the most used chemical agent in periodontal therapy 2) toothpaste, gel and mouthrinse formulations as principal vehicles for herbal products 3) In vitro and in vivo studies to test their ability in reducing periodontal inflammation. The search revealed numerous papers investigating herbal products in the treatment of periodontal diseases. As bacteria develop resistance to classical antibiotics, studies aim to formulate alternative options for controlling periodontal pathogens using plants with anti-inflammatory properties.
Application of Mesenchymal Stem Cells in the Targeted Gene Therapy for Gastric Cancer
Today, 12 Ιουλίου 2016, 3:55:14 μμ
The incidence of gastric cancer is third most prevalent among all malignant tumors in China. The conventional therapies for advanced gastric cancer are futile. Targeted gene therapy has become a promising alternative approach. Mesenchymal stem cells (MSCs) can be used as potential cellular vehicles for cancer therapy in vivo. This review will summarize the published data about the application of MSC-based targeted therapy for gastric cancer, and discuss some of the challenges associated with this method.
Role of Osmolytes in Regulating Immune System
Today, 12 Ιουλίου 2016, 3:55:14 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>
Vascular Endothelial Growth Factor: A New Paradigm for Targeting Various Diseases
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Vascular endothelial growth factor is a signaling protein, which is responsible for the angiogenesis process. Variation in its expression leads to various disorders like cancer, diabetes, psoriasis and neuronal imbalance (depression) etc. The abundance of VEGF (VEGF-A, B, C) concentration is present in the kidney, heart, lung, ovary, thyroid gland, neurons, embryonic tissue etc. The regulation of VEGF expression is controlled by the hypoxia condition, hormonal regulation, inflammatory mediator cytokines and growth hormone. The VEGF binds to the VEGFR1, and VEGFR2 tyrosine kinase receptors causing conformational changes resulting in the endothelial cell proliferation, increased vascular permeability, and formation of new blood vessel. The high level of VEGF- A activity found in the synovial fluid leads to rheumatoid arthritis, whereas in the retinal cell it results in diabetic retinopathy. The tumor growth factor induced VEGF A expression in keratin cell lead to psoriasis. The higher level of VEGF activity increased neovascularization which is beneficial in cerebral ischemia, as well as in the growth of the neurons. VEGF is also considered to be an important factor in tumor invasion and metastasis. Various growth factors stimulate or participated in tumor angiogenesis. Therefore, the Anti-VEGF therapy can be a potential option for treatment of psoriasis, rheumatoid arthritis, diabetic retinopathy, and cancer. The (VEGF) gene expression modulation will lead to the new therapeutic possibilities in the future.
Commercially Available, FDA-approved Epigenetic Modifiers As Therapeutic Agents in Bacterial Infection
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Epigenetics represents a relatively new but burgeoning field with implications and applications in a wide variety of fields. Heritable post-translational epigenetic modifications (PTEMs) of chromatin can be induced by an ever-increasing list of biological factors, including those produced by bacteria. Of particular interest are the PTEMs induced by bacterial pathogens in host cells, in an attempt by the pathogen to promote survival and suppress host defence mechanisms. To date, a number of pharmacological agents have been used to reverse PTEMs, especially in cancer treatment. These Food and Drug Administration (FDA)-approved, commercially available epigenetic modifying agents (EMAs) include: 5- azacytidine (AZA), decitabine, suberoylanilide hydroxamic acid (SAHA) and romidepsin. AZA and decitabine have been used successfully to treat myeloblastic syndromes; likewise both SAHA and romidepsin have proven effective in the treatment of cutaneous T-cell lymphoma (CTL). There is accumulating evidence from rodent and in vitro studies, which point to the possibility that pathogen-induced PTEMs in host cells represent viable therapeutic opportunities for intervention with epigenetic drugs. However, the same commercially available EMAs used in cancer treatment remain untested in bacterial infection of humans. Here, we review current studies that have revealed PTEMs of host cells, induced by a number of pathogenic bacteria and discuss whether or not commercially available EMAs might represent realistic options in the treatment of these infections in humans.
Gene Electrotransfer in 3D Reconstructed Human Dermal Tissue
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Gene electrotransfer into the skin is of particular interest for the development of medical applications including DNA vaccination, cancer treatment, wound healing or treatment of local skin disorders. However, such clinical applications are currently limited due to poor understanding of the mechanisms governing DNA electrotransfer within human tissue. Nowadays, most studies are carried out in rodent models but rodent skin varies from human skin in terms of cell composition and architecture. We used a tissue-engineering approach to study gene electrotransfer mechanisms in a human tissue context. Primary human dermal fibroblasts were cultured according to the self-assembly method to produce 3D reconstructed human dermal tissue. In this study, we showed that cells of the reconstructed cutaneous tissue were efficiently electropermeabilized by applying millisecond electric pulses, without affecting their viability. A reporter gene was successfully electrotransferred into this human tissue and gene expression was detected for up to 48h. Interestingly, the transfected cells were solely located on the upper surface of the tissue, where they were in close contact with plasmid DNA solution. Furthermore, we report evidences that electrotransfection success depends on plasmid mobility within tissue- rich in collagens, but not on cell proliferation status. In conclusion, in addition to proposing a reliable alternative to animal experiments, tissue engineering produces valid biological tool for the in vitro study of gene electrotransfer mechanisms in human tissue.
Photodynamic Therapy and Periodontal Treatment
Today, 12 Ιουλίου 2016, 3:55:14 μμ
Periodontitis is an infectious and inflammatory disease where specific dental plaque pathogens are associated with the onset and severity of tissue destruction. Photodynamic therapy (PDT) has been proposed as a novel disinfection method, which may be a potential treatment for several infectious diseases by eradicating microorganisms. Due to the high antibacterial potential, PDT has been proposed as a beneficial tool in the treatment of chronic periodontitis and peri-implantitis, particularly in elimination of subgingival pathogens from areas such as deep pockets, root concavities, and furcations. Positive effects of adjunctive PDT have been reported on the clinical, biochemical and microbiologic parameters. However, the superiority of PDT in the treatment of periodontitis and periimplantitis compared to scaling and root planing alone or as an adjunct is still unclear. So far, there is no standard PDT protocol to be used in periodontal treatment. Larger scale randomized clinical studies with longer follow-up periods are required to better understand the potential of PDT in the treatment of periodontitis and peri-implantitis. Furthermore, possible role of various confounders such as smoking and diabetes mellitus or targeting the mechanically inaccessible areas such as deep pockets and furcations should be examined in future studies.
Prospects of Developing Medicinal Therapeutic Strategies and Pharmaceutical Design for Effective Gluten Intolerance Treatment
Today, 12 Ιουλίου 2016, 3:55:14 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.
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