Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun N-terminal kinases (JNK) belong to the subfamily of mitogen-activated protein kinase (MAPK). JNK is an important transducing enzyme that is involved in many facets of cellular regulation including gene expression, cell proliferation and programmed cell death. The activation of JNK pathways is critical for naturally occurring cell death during development as well as for pathological death associated with neurodegenerative diseases. Initial research concentrated on defining the components and organization of JNK signalling cascades, but more recent studies see JNK as a target to prevent cell death. Several in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with neuronal death in Parkinson's and Alzheimer's disease. So efforts are now aimed at developing chemical inhibitors of this pathway. These have proved effective in vivo, reducing brain damage and some of the symptoms of arthritis in animal models. An alternative cell penetrating peptide approach is now available, with the identification of the JNK permeable peptide inhibitor, which modifies JNK action rather than activation, preventing neuronal death with unprecedented specificity and efficacy in several experimental conditions, including two animal models of ischemia. In this review we examine in detail the role of JNK in neurodegeneration, particularly in Alzheimer's and Parkinson's disease. The possibility of intervention on the JNK pathway as a therapeutic approach is also illustrated.
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PMID:JNK signalling: a possible target to prevent neurodegeneration. 1758 14

Pain may be the most common reason patients seek treatment from physicians. When persistent and unrelieved, pain can frustrate both the person suffering with this condition and the physician trying to alleviate it. Relief from such discomfort may be particularly difficult to achieve and fraught with misconceptions. Treatment usually requires trials of physical, pharmacologic, and surgical interventions to achieve resolution. In cases that remain insoluble, patients must accept partial relief and seek adaptive strategies. Sources of persistent pain may be nociceptive or neuropathic. Both utilize the same nerve pathways for transmission, but significant physiologic differences exist in mechanisms through which these painful stimuli are biologically processed and resolved. Nociceptive pain resulting from a known or obvious source (eg, trauma, cancer metastasis, ischemia, arthritis) is often easy to identify. Neuropathic pain, however, may occur in the absence of an identifiable precipitating cause. Physicians must remain alert to differences in presentation and course of neuropathic pain syndromes, some of which may be subtle or unusual.
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PMID:Managing neuropathic pain. 1798 77

Adenosine is a primordial signaling molecule present in every cell of the human body that mediates its physiological functions by interacting with 4 subtypes of G-protein-coupled receptors, termed A1, A2A, A2B and A3. The A3 subtype is perhaps the most enigmatic among adenosine receptors since, although several studies have been performed in the years to elucidate its physiological function, it still presents in several cases a double nature in different pathophysiological conditions. The 2 personalities of A3 often come into direct conflict, e.g., in ischemia, inflammation and cancer, rendering this receptor as a single entity behaving in 2 different ways. This review focuses on the most relevant aspects of A3 adenosine subtype activation and summarizes the pharmacological evidence as the basis of the dichotomy of this receptor in different therapeutic fields. Although much is still to be learned about the function of the A3 receptor and in spite of its duality, at the present time it can be speculated that A3 receptor selective ligands might show utility in the treatment of ischemic conditions, glaucoma, asthma, arthritis, cancer and other disorders in which inflammation is a feature. The biggest and most intriguing challenge for the future is therefore to understand whether and where selective A3 agonists or antagonists are the best choice.
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PMID:The A3 adenosine receptor: an enigmatic player in cell biology. 1802 23

Henoch-Schonlein Purpura (HSP) is the most common systemic vasculitis in childhood. The diagnostic criteria include palpable purpura with at least one other manifestation -- abdominal pain, IgA deposition, arthritis or arthralgia, or renal involvement. Immune complex deposits result in necrosis of the wall of small- and medium-sized arteries with infiltration of tissue by neutrophils and deposition of nuclear fragments, a process called leukocytoclastic vasculitis (LCV). It is often associated with infections, medications, or tumors. It may coexist with or mimic Crohn's disease. Periumbilical and epigastric pain worsens with meals, from bowel angina. Bleeding is usually occult or, less commonly, associated with melena. Intussusception, the most common surgical complication, is usually ileo-ileo or ileo-colic. Perforations, usually ileal, may occur spontaneously or be associated with intussusception. Ultrasound, recommended as the first diagnostic test, and CT scans may show intussusception and asymmetric bowel wall thickening mainly involving the jejunum and ileum. There are a range of endoscopic findings including gastritis, duodenitis, ulceration, and purpura, with the second portion of the duodenum characteristically being involved more than the bulb. Intestinal biopsies show IgA deposition and LCV in the submucosal vessels. Superficial biopsies may show inflammation, ulceration, edema, hemorrhage, and vascular congestion, presumably due to vasculitis-induced mucosal ischemia. The efficacy of corticosteroids in preventing severe complications or relapses is controversial. The majority of patients, however, improve spontaneously.
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PMID:Gastrointestinal manifestations of Henoch-Schonlein Purpura. 1835 68

The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity.
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PMID:Therapeutic applications of pomegranate (Punica granatum L.): a review. 1859 Mar 49

The melanocortins (alpha, beta and gamma-melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone: ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common the tetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extra-hormonal effects, so to become one of the most promising source of innovative drugs for many, important and widespread pathological conditions. The discovery of their effects on some brain functions, independently made by William Ferrari and David De Wied about half a century ago, led to the formulation of the term "neuropeptide" at a time when no demonstration of the actual production of peptide molecules by neurons, in the brain, was still available, and there were no receptors characterized for these molecules. In the course of the subsequent decades it came out that melanocortins, besides inducing one of the most complex and bizarre behavioural syndromes (excessive grooming, crises of stretchings and yawnings, repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play a key role in functions of fundamental physiological importance as well as impressive therapeutic effects in different pathological conditions. If serendipity had been an important determinant in the discovery of the above-mentioned first-noticed extra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology of these peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been the result of a planned research, aimed at testing the "pro-nociceptive/anti-nociceptive homeostatic system" hypothesis. The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonist or antagonist activity, is generating completely innovative drugs for the treatment of a potentially very long list of important and widespread pathological conditions: sexual impotence, frigidity, overweight/obesity, anorexia, cachexia, haemorrhagic shock, other forms of shock, myocardial infarction, ischemia/reperfusion-induced brain damage, neuropathic pain, rheumathoid arthritis, inflammatory bowel disease, nerve injury, toxic neuropathies, diabetic neuropathy, etc. This review recalls the history of these researches and outlines the pharmacology of the extra-hormonal effects of melanocortins which are produced by an action at the brain level (or mainly at the brain level). In our opinion the picture is still incomplete, in spite of being already so incredibly vast and complex. So, for example, several of their effects and preliminary animal data suggest that melanocortins might be of concrete effectiveness in one of the areas of most increasing concern, i.e., that of neurodegenerative diseases.
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PMID:Brain effects of melanocortins. 1899 99

Tumor necrosis factor (TNF)-alpha plays a crucial role in the pathogenesis of ischemia/reperfusion-induced renal injury. We demonstrated recently that the preischemic treatment with resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, attenuates renal TNF-alpha mRNA expression and improves ischemia/reperfusion-induced renal injury in rats. In addition, we found that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel orally active TRPV1 agonist, inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in established rat collagen-induced arthritis. In the present study, we investigated effects of treatment with SA13353 on ischemia/reperfusion-induced renal injury in rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 24 h after reperfusion. Treatment with SA13353 (3, 10, and 30 mg/kg p.o.) 30 min before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which were significantly suppressed by the SA13353 treatment. In renal tissues exposed to ischemia/reperfusion, neutrophil infiltration, superoxide production, TNF-alpha mRNA expression, and cytokine-induced neutrophil chemoattractant-1 mRNA expression were augmented, but these alterations were attenuated by the treatment with SA13353. On the other hand, ischemia/reperfusion-enhanced renal interleukin-10 mRNA expression and its plasma concentration were further augmented by SA13353 treatment. These results demonstrate that the orally active TRPV1 agonist SA13353 prevents the ischemia/reperfusion-induced AKI. This renoprotective effects seem to be closely related to the inhibition of inflammatory response via TRPV1 activation.
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PMID:Preventive effect of SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 agonist, on ischemia/reperfusion-induced renal injury in rats. 2471 33

Pathological angiogenesis is a hallmark of various ischemic diseases (insufficient vessel growth) but also of cancer and metastasis, inflammatory diseases, blindness, psoriasis or arthritis (excessive angiogenesis). In response to ischemia (reduced blood flow and oxygen supply), new blood vessels form in order to compensate for the lack of perfusion. This natural process could protect them from the consequences of atherosclerotic diseases (myocardial angina, infarction, hindlimb arteriopathy or stroke). However, neovessel formation is altered in many patients. A better understanding of the mechanisms of functional vessel formation is a pre-requisite to improving the treatment of ischemic pathologies. To this end, it is essential to create easily accessible animal models in which vessel formation can be both manipulated and studied. In this review, we will describe different angiogenic mouse models in the context of cardiovascular diseases, either in an ischemic context (hindlimb ischemia, heart ischemia, skin model) or in a non-ischemic context (plug and eye assay, wound healing, ovarian model). We will also discuss quantitative techniques for assessing angiogenesis in these assays.
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PMID:Mouse models to study angiogenesis in the context of cardiovascular diseases. 1927 76

Lysine acetylation is becoming increasingly appreciated as a key post-translational modification in the endogenous regulation of protein function. The so-called histone acetyl transferases (HATs) and histone deacetylases (HDACs), best known for their roles in controlling chromatin remodeling via histone acetylation/deacetylation, are now known to modify a large number of non-histone proteins to control diverse cell processes. In relation to inflammation, acetylation modulates the activity or function of cytokine receptors, nuclear hormone receptors, intracellular signaling molecules and transcription factors. Small molecule inhibitors of HDACs have been found to trigger both pro- and anti-inflammatory effects in a range of inflammation-relevant cell types. Although their inflammatory profiles have only just begun to be elucidated, some HDAC inhibitors are already showing therapeutic promise in animal models of inflammatory diseases such as arthritis, inflammatory bowel diseases, septic shock, ischemia-reperfusion injury, airways inflammation and asthma, diabetes, age-related macular degeneration, cardiovascular diseases, multiple sclerosis and other CNS and neurodegenerative diseases. This article describes those HDAC inhibitors which have been most examined to date for their potentially beneficial effects on inflammatory cells or in animal models of inflammatory disease.
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PMID:Histone deacetylase inhibitors in inflammatory disease. 1935 93

Hypoxia and inflammation are coincidental events in a diverse range of disease states including tumor growth, ischemia, and chronic inflammation. Hypoxia contributes to the development of inflammation, at least in part through the activation and/or potentiation of NF-kappaB, a master regulator of genes involved in innate immunity, inflammation, and apoptosis. NF-kappaB can be activated through two distinct signaling pathways termed the canonical and noncanonical pathways, respectively. The canonical pathway is activated through the IKKalpha/beta/gamma complex, while the noncanonical pathway involves NIK-mediated activation of IKKalpha homodimers. In the current study, we have investigated the relative roles of these two pathways in hypoxia-dependent NF-kappaB activation. Lymphotoxin alpha1beta2 (LTalpha1beta2) activated both the canonical and noncanonical NF-kappaB signaling pathways in HeLa cells. Sustained hypoxia enhanced basal and LTalpha1beta2-induced NF-kappaB activity in a manner that was dependent upon the canonical but not the noncanonical signaling pathway. Intermittent hypoxia activated NF-kappaB in a manner that was also primarily dependent upon the canonical pathway. Knockdown of the p65 subunit of the canonical NF-kappaB pathway was sufficient to abolish the effects of hypoxia on LTalpha1beta2-induced NF-kappaB activity. Furthermore, in synovial biopsies obtained at arthroscopy from patients with active inflammatory arthritis, the canonical pathway was preferentially activated in those patents with lower joint pO2 values. In summary, we hypothesize that hypoxia enhances NF-kappaB activity primarily through affecting the canonical pathway.
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PMID:Hypoxia activates NF-kappaB-dependent gene expression through the canonical signaling pathway. 1942 87


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