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Antisense oligomers have been shown to be effective tools for inhibiting gene expression in a highly specific manner. This technology has proven to be invaluable for determining gene function in conventional molecular and cellular studies. However, the promise of an antisense-based drug technology, suggested by antiviral efficacy shown nearly 25 years ago, is just now coming of age. Since then, numerous antisense approaches have been shown to be effective in animal models against numerous viruses and some tumors. Not surprisingly, antisense agents targeting these diseases are taking the lead in human clinical trials and FDA approval. Although comparatively smaller in scope, approaches for modulating immune responses to treat Crohn's disease, diabetes, multiple sclerosis and transplant rejection appear to be the next burgeoning phase of development in antisense therapy. 相似文献
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Recently, several decoy molecules belonging to tumor necrosis factor receptor superfamily (TNFRSF) have been identified, including decoy receptor 1 (DcR1), decoy receptor 2 (DcR2), and decoy receptor 3 (DcR3). One of the tumor necrosis factor superfamily (TNFSF) members, TNF-related apoptosis-inducing ligand (TRAIL), binds to DcR1 and DcR2, which are membranous receptors with a truncated cytoplasmic domain, thus unable to transduce TRAIL-mediated signaling. In contrast to DcR1 and DcR2, DcR3 is a soluble receptor capable of neutralizing the biological effects of three other TNFSF members: Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). Since FasL is a potent apoptosis- and inflammation-inducing factor, LIGHT is involved in apoptosis and inflammation, and TL1A is a T cell costimulator and is involved in gut inflammation, DcR3 can be defined as an immunomodulator on the basis of its neutralizing effects on FasL, LIGHT, and TL1A. Initial studies demonstrated that DcR3 expression is elevated in tumors cells; however, later work showed that DcR3 expression is also upregulated in inflammatory diseases, where serum DcR3 levels correlate with disease progression. In addition to its neutralizing effect, DcR3 also acts as an effector molecule to modulate cell function via ‘non-decoy’ activities. This review focuses on the immunomodulatory effects of DcR3 via ‘decoy’ and ‘non-decoy’ functions, and discusses the potential of DcR3 as a biomarker to predict cancer invasion and inflammation progression. We also discuss the possible utility of recombinant DcR3 as a therapeutic agent to control autoimmune diseases, as well as the potential to attenuate tumor progression by inhibiting DcR3 expression. 相似文献
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Transcription factors in autoimmune diseases 总被引:4,自引:0,他引:4
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Martocchia A Stefanelli M Cola S Falaschi P 《Current topics in medicinal chemistry》2011,11(13):1668-1683
A sexual dysmorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trials will help to find the best use of sex steroids in combination with current therapeutic drugs in autoimmune diseases. Sex steroid receptor modulating drugs will provide new therapeutic approaches in these pathologies. 相似文献
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Peptide-mediated immunotherapy has been studied in a number of experimental models of autoimmune diseases and has also been tested in human patients to a certain extent. Copolymer 1 is a synthetic amino acid copolymer that has been demonstrated to suppress experimental autoimmune encephalomyelitis (a model for multiple sclerosis) when administered parenterally. Some study results indicate that mucosal tolerance induced by appropriate recombinant peptide fragments of human AChR is effective in suppressing experimental autoimmune myasthenia gravis and might be considered as a therapeutic modality for patients with MG. A peptide of the heat-shock protein 60 molecule, designated peptide p277, was shown to be a target of T cells in autoimmune diabetes in NOD mice, and intraperitoneal injections of glutamic acid decarboxylase (GAD) peptide 524-543 delayed the onset of diabetes and significantly reduced its incidence. Experimental evidence has revealed that CDR-based peptides may be potential candidates for the therapy of systemic lupus erythematosus. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta 2GPI antibodies represents a possible new therapeutic approach to antiphospholipid syndrome. Studies in both acute and chronic-relapsing experimental autoimmune uveoretinitis have indicated that oral administration of S-Ag, S-Ag-derived peptides, inter-photoreceptor retinoid binding protein or HLA-derived peptides before immunization can protect animals from the disease. 相似文献
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Heat-shock proteins (HSPs) serve as both a valuable target as well as a potent tool in the therapy of melanoma and human papillomavirus infections. HSPs have been found to associate with key pathogenic antigens and, under different circumstances, activate or suppress both innate and adaptive immunity via several mechanisms. The dominant mechanism of HSP is as a chaperonin to upregulate antigens on antigen-presenting cell surfaces. While no HSP-based therapies are currently FDA approved, several are currently in phase III clinical trials. This study reviews the current literature on therapeutic studies of HSP and the significant role these proteins are likely to play in future therapeutic approaches to neoplasms, infections, and inflammatory diseases of the skin. 相似文献
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The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials. 相似文献
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Glinda S Cooper Frederick W Miller Dori R Germolec 《International immunopharmacology》2002,2(2-3):303-313
Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely. 相似文献
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M. C. Powanda 《Inflammopharmacology》1995,3(3):201-211
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Autoimmune diseases affect about 3% of the world population, more frequently women than men, and their incidence is attributed to an immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate immuno-regulatory mechanisms. Advances in understanding the cellular activity pathways and cytokine expression profiles have led to new therapeutic regiments, like soluble receptors, monoclonal antibodies and molecular mimetics that have been employed to enhance or replace conventional immunosuppressive therapies. Among new biologicals that have been developed to target defined pathways of the adaptive immune response are TNF-alpha inhibitors. TNF-alpha is a proinflammatory cytokine elevated in many autoimmune lesions, and its deregulation characterizes many autoimmune diseases. TNF-alpha seems to exhibit an immunoregulatory role that can alter the balance of T regulatory cells and orchestrate acute immunological responses. More than half a million autoimmune patients have received therapy with anti-TNF-alpha antibodies, usually because they were refractory to conventional treatments. This review offers an update on TNF-alpha-targeted therapies used in patients suffering from various autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on the efficacy and safety that clinical trials have shown until now. 相似文献
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Hantavirus diseases pathophysiology,their diagnostic strategies and therapeutic approaches: A review
Naveed Munir Muhammad Jahangeer Shoukat Hussain Zahed Mahmood Mehvish Ashiq Fatima Ehsan Muhammad Akram Syed Muhammad Ali Shah Muhammad Riaz Aneezah Sana 《Clinical and experimental pharmacology & physiology》2021,48(1):20-34
Hantaviruses are enveloped negative (?) single‐stranded RNA viruses belongs to Hantaviridae family, hosted by small rodents and entering into the human body through inhalation, causing haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) also known as hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses infect approximately more than 200 000 people annually all around the world and its mortality rate is about 35%–40%. Hantaviruses play significant role in affecting the target cells as these inhibit the apoptotic factor in these cells. These viruses impair the integrity of endothelial barrier due to an excessive innate immune response that is proposed to be central in the pathogenesis and is a hallmark of hantavirus disease. A wide range of different diagnostic tools including polymerase chain reaction (PCR), focus reduction neutralization test (FRNT), enzyme‐linked immunosorbent assay (ELISA), immunoblot assay (IBA), immunofluorescence assay (IFA), and other molecular techniques are used as detection tools for hantavirus in the human body. Now the availability of therapeutic modalities is the major challenge to control this deadly virus because still no FDA approved drug or vaccine is available. Antiviral agents, DNA‐based vaccines, polyclonal and monoclonal antibodies neutralized the viruses so these techniques are considered as the hope for the treatment of hantavirus disease. This review has been compiled to provide a comprehensive overview of hantaviruses disease, its pathophysiology, diagnostic tools and the treatment approaches to control the hantavirus infection. 相似文献
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T-bet对免疫细胞分化的调节及其与自身免疫病的关系 总被引:1,自引:0,他引:1
T盒转录因子T-bet是Th1型免疫的关键调节因子,在T淋巴细胞、B淋巴细胞、树突状细胞、NK细胞效应细胞的建立和维持中发挥着极其重要的作用,一些自身免疫病,特别是典型的与Th1免疫相关的疾病,其发病需要T-bet参与,这些在动物模型中得到证实。在此,就T-het在免疫细胞分化和自身免疫病发病机制中的作用及其在干预治疗中的可行性做一综述。 相似文献
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D S Carson 《Drug intelligence & clinical pharmacy》1987,21(9):694-701
Child day care is used increasingly by both single-parent and two-parent families. With the growth in numbers of children receiving day care outside the home comes a greater awareness of the potential for disease transmission. Epidemiologic patterns of spread of such diseases as Hemophilus influenzae type b, hepatitis A, diarrheal diseases, and cytomegalovirus are changing with respect to attendance at a day-care center. Not only is this a problem for the staff and children who attend a center, but it also may be a public health concern as these diseases could spread to households and the community at large. This review will identify those transmissible infectious agents frequently found in children who attend day-care centers with an emphasis on approaches to prevention and methods for decreasing secondary spread. 相似文献
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Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches 总被引:3,自引:0,他引:3
Camins A Pallas M Silvestre JS 《Methods and findings in experimental and clinical pharmacology》2008,30(1):43-65
Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most significant neurodegenerative disorders in the developed world. However, although these diseases were described almost a century ago, the molecular mechanisms that lead to the neuronal cell death associated with these diseases are not yet clear, and vigorous research efforts have failed to identify effective treatment options. In the present review, we evaluate the potential mechanisms underlying apoptosis and neuronal death in neurodegenerative disorders. A role for mitochondria in the release of proapoptotic proteins, such as cytochrome c and apoptosis-inducing factor (AIF) etc., is discussed along with key processes involving oxidative stress and activation of glutamate receptors. We also deliberate the implication of DNA damage, primarily p53 induction and reentry in the cell cycle. Finally, we postulate that multitargeting therapies comprising antioxidants, cell cycle inhibitors and modulating agents of COX-2 or c-JUN kinase pathways could be suitable strategies to prevent or delay the process of neuronal cell death in neurodegenerative disorders. Thus, the aim of this review is to discuss the pathways involved in the pathogenesis of neurodegenerative diseases such as AD, PD and Huntington's disease (HD). Furthermore, current and future pharmacotherapeutics will be considered. 相似文献
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Suresh KK Bhosale SD Thulasiram HV Kulkarni MJ 《The Journal of toxicological sciences》2011,36(6):787-796
Gatifloxacin has been associated with increased risks of hypoglycemic and hyperglycemic side effects. In order to understand the molecular mechanism of gatifloxacin induced deregulation of glucose metabolism, a combination of comparative and chemical proteomic approaches were employed using yeast as a model system. Differential protein expression studies using two dimensional electrophoresis and mass spectrometry reveal that gatifloxacin deregulates the expression of key enzymes involved in glucose metabolism. Furthermore, affinity chromatography and LC-MS(E) analysis led to identification of enolase, as one of the key gatifloxacin binding proteins. Fluorescence spectrometric studies confirmed that the gatifloxacin indeed binds to enolase. Role of enolase in regulation of gatifloxacin induced dysglycemic effect is discussed. 相似文献