Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the peroxisome proliferator activated receptor (PPAR) family of transcription factors are under investigation as molecular targets for the treatment of numerous diseases including Alzheimer's, asthma, atherosclerosis, inflammation, multiple sclerosis, cancer, and diabetes. We employed the X-ray crystal structure of the PPARgamma subtype complexed with the potent small molecule agonist GI262570 (farglitazar) to design and synthesize a novel fluorescent and high-affinity probe for homogeneous and high-throughput fluorescent polarization (FP) assays. Examination of this X-ray structure revealed that the phenyl carbon atom meta to the oxazole moiety of GI262570 is exposed to solvent at the bottom of a narrow protein cavity. A derivative of GI262570 was synthesized bearing a linear phenylacetylene-derived side chain comprising propargylamine coupled to fluorescein. This fluorescent analogue was designed to project the fluorophore into the adjacent protein cavity with minimal effects on receptor affinity and maximal effects on fluorescence polarization properties. The recombinant PPARgamma ligand binding domain protein bound tightly and specifically to this probe with Kd=61+/-14 nM as determined by FP measurements. Competition binding assays with known PPARgamma ligands provided Ki values that were highly correlated with analogous values obtained by scintillation proximity (SP) assays. This fluorescent PPARgamma probe enables high-throughput and homogenous FP assays for the identification of novel endogenous and exogenous PPARgamma ligands, and this rational ligand design approach may be applied to other therapeutically important members of the nuclear hormone receptor superfamily.
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PMID:Synthesis of a high-affinity fluorescent PPARgamma ligand for high-throughput fluorescence polarization assays. 1312 68

Inflammation is a fundamental response to tissue injury and invasion of pathogens, but it is detrimental in clinically important inflammatory disorders. Leukocytes are key players in the inflammatory response because of their antimicrobial, secretory and phagocytic activities. They are recruited to the inflamed tissue by sequential adhesive interactions between leukocytes and the endothelium that are mediated by cell-adhesion molecules (CAMs) on the surface of the interacting cells. The effects of many anti-inflammatory drugs can be ascribed, in part, to inhibition of the expression of CAMs. However, in the search for more selective and potent drugs for clinically important diseases such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, allergies and atherosclerosis, direct inhibition of the function of CAMs has attracted increasing interest. In recent years, the development of synthetic antagonists has provided better opportunities for drug targeting. Future advances in this field hold new prospects for therapeutic intervention in human inflammatory disorders.
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PMID:Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. 1465 5

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.
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PMID:Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases beyond diabetes: quo vadis? 1501 41

The apolipoprotein genetic polymorphism (APO E) is part of a broader paradigm, highlighting the role of gene-environment interactions as risk factors for human diseases such as cardiovascular disease, Alzheimer's disease, dementia, atherosclerosis, multiple sclerosis, peripheral artery disease, diabetes, stroke, and most recently, cancer. APO E, a normal constituent of very-low-density lipoproteins and high-density lipoproteins, is involved in many functions, including lipid metabolism, cholesterol transport, tissue repair, immune response and regulation, as well as cell growth and differentiation. The location, frequency and functional effects of this gene have been reviewed elsewhere in terms of cardiovascular disease, Alzheimer's disease, neuromuscular disease, multiple sclerosis, stroke and diabetes. However, while the majority of studies have examined the significance of APO E as a molecular marker for a variety of diseases in multiethnic populations, few evaluate its role as a putative marker of cancer susceptibility. Fewer explore the importance of APO E on the risk of breast cancer, although some report an association. None have been designed to study its relevance as a marker of breast cancer risk in multiethnic populations. The purpose of this review was to evaluate the association between APO E and the risk for breast cancer in non-Hispanic white and African-American women.
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PMID:Apolipoprotein E and the risk of breast cancer in African-American and non-Hispanic white women. A review. 1513 59

CD1d-restricted natural killer T (NKT) cells are innate lymphocytes that play a regulatory role during an immune response. The identification of alpha-galactosylceramide (alpha-GalCer), a marine sponge-derived glycosphingolipid, as a potent stimulator of NKT cells led many laboratories to investigate the effects of NKT cell activation on the regulation of immune responses. These studies revealed that alpha-GalCer induces rapid and robust cytokine production by NKT cells, secondary activation of a variety of innate and adaptive immune cells, and modulation of Th cell responses. Further, alpha-GalCer influences disease progression in a variety of experimental models of autoimmunity and inflammation in mice, including models for type 1 diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and atherosclerosis. While these studies have raised significant enthusiasm for manipulation of NKT cells as a means of preventing autoimmunity in the clinical setting, there are significant concerns regarding the safety of repeated alpha-GalCer injections in human subjects.
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PMID:Natural killer T cells as targets for immunotherapy of autoimmune diseases. 1518 63

Members of the genus Chlamydia cause a plethora of ocular, genital and respiratory diseases, with severe complications, such as blinding trachoma, pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility, interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult-onset asthma and Alzheimer's disease. The current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. There are three essential and mutually inclusive areas of challenge confronting researchers developing Chlamydia vaccines. These are to define the elements of protective immunity and the basis of vaccine evaluation, the judicious selection of an immunogenic and safe antigen(s) to form the basis of a subunit vaccine, and to develop effective delivery systems that boost the immune response to achieve long-lasting protective immunity. The development of delivery vehicles and adjuvants to boost protective long-term immunity against chlamydiae currently poses the greatest challenge in vaccine research. However, enormous progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, and living and non-living bacterial delivery systems, and the use of chemical adjuvants. In addition, there is increasing effort being made in designing delivery strategies involving specific immunomodulatory procedures that modify the cytokine and chemokine environment, upregulate co-stimulatory molecules and target vaccines to specific mucosal sites. These efforts will likely culminate in an efficacious chlamydial vaccine in the near future.
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PMID:Developing effective delivery systems for Chlamydia vaccines. 1519 31

The present paper proposes a new therapy using Trypanosoma cruzi trans-sialidase to treat diseases with unclear pathogenesis that present in common chronic inflammation and fibrosis. This hypothesis is based on recent findings that co-infection with mycoplasma and chlamydia is present in many of these diseases and that this enzyme was capable to eliminate or decrease the co-infection from the host. We identified that mycoplasmas and chlamydias are present in atherosclerosis, aortic valve stenosis, dilated cardiomyopathy, chronic chagasic myocarditis and cancer. We hypothetized that mycoplasmal infection may induce immunodepression in the host, favoring proliferation of pre-existent chlamydial infection and that elimination of mycoplasma would lead to improvement of the immune system resistance and the control of chlamydial proliferation. Mycoplasma has a particular parasitic relationship with host cells, involving strong adherence of their membranes, making it extremely difficult to eradicate mycoplasmal infection from the host. A new therapeutic approach is suggested using one or more agents that prevent or inhibit the adherence of mycoplasma to host cell membranes by removing sialic acid residues and preventing oxidation of the cells. The use of a neuraminidase enzyme, particularly the T. cruzi trans-sialidase enzyme, associated with treatment using anti-oxidating agents is proposed. Preliminary experimental animal and laboratory tests showed good results. The proposal that trans-sialidase from T. cruzi is efficient in combating co-infection of mycoplasma and chlamydia is based, at least in part, on the observation that chagasic patients suffering from T. cruzi infection present less mycoplasma and chlamydia infection in their tissues. Also, a lower incidence of the diseases above described to be related to mycoplasma infection is observed in chagasic patients. It is also hypothesized that co-infection with mycoplasma and chlamydia may induce oxidation of the host cells. Anti-oxidants such as those present in plant extracts may also be used in the treatment. Other diseases such as chronic hepatitis, glomerulonephritis, Multiple Sclerosis, Alzheimer's Syndrome and idiopathic encephalitis are other examples of chronic diseases where mycoplasma and chlamydia might be present, as they have the characteristics of unknown etiology, persistent chronic inflammation and fibrosis.
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PMID:Trypanosoma cruzi trans-sialidase as a new therapeutic tool in the treatment of chronic inflammatory diseases: possible action against mycoplasma and chlamydia. 1532 5

As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.
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PMID:Targeting leukocyte integrins in human diseases. 1554 73

The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S-allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning."
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PMID:Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. 1565 27

It is widely accepted that vascular mechanisms are involved in the genesis of many neurological disorders. In particular, blood-brain barrier (BBB) dysfunction has been related to the severity of Alzheimer's disease, encephalopathy due to meningitis, multiple sclerosis, HIV-associated encephalopathy, epilepsy, gliomas and metastatic brain tumors. The BBB may constitute an important therapeutic target to protect neurons after CNS diseases. Both in vivo and in vitro, the functional phenotype of vascular endothelium is dynamically responsive to circulating cytokines, growth factors and puslatile blood flow (shear stress). Shear stress can play a critical role in vascular homeostasis and pathophysiology; it is a major regulator of remodeling in developed blood vessels and in blood vessels affected by atherosclerotic lesions. The physiological fluid mechanic stimulus, shear stress, could be considered to be an important 'differentiative' stimulus capable of modulating endothelial phenotype in vivo. Endothelial cells undergo cell cycle arrest after exposure to physiological levels of shear stress. As for mature endothelial cells, in which flow mediated shear stress may play a role in the induction, progression and/or prevention of atherosclerosis by changing their function, stress may play a role in endothelial cell differentiation from hemopoietic stem cells and/or from embryonic stem cells. Stem cells may be used to repair vascular damage, including loss of EC, due to a variety of diseases (e.g. myocardial neovascularization by adult bone marrow derived angioblasts). In the brain, it was proposed that neuron-producing stem cells may be used to treat Alzheimer's disease, paralysis, etc. Surprisingly, very few investigators are exploring the use of endothelial precursors to revert or prevent cerebrovascular disease. This review summarizes the most recent data related to cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in blood-brain barrier homeostasis and pathophysiology.
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PMID:The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology. 1572 68


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