Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for monocytes and memory T cells by means of their binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2 belongs to the G-protein-coupled seven-transmembrane receptor superfamily. The evidence in favor of CCR2 and MCP-1 having dominant roles in monocyte chemotaxis and chronic inflammation was provided by CCR2 and MCP-1 knockout mice. It has been recognized that CCR2 antagonists are potential therapeutic agents in preventing, treating, or ameliorating a CCR2-mediated inflammatory syndrome or disease such as psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, asthma, obesity, and chronic obstructive pulmonary disease. This review summarizes recent developments in small-molecule CCR2 antagonists disclosed by patent applications published between 2005 and 2008 and related publications.
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PMID:Recent developments in CCR2 antagonists. 1944 5

There is considerable potential for translating knowledge of aquaporin structure, function and physiology to the clinic. One area is in aquaporin-based diagnostics. The discovery of AQP4 autoantibodies as a marker of the neuromyelitis optica form of multiple sclerosis has allowed precise diagnosis of this disease. Other aquaporin-based diagnostics are possible. Another area is in aquaporin-based genetics. Genetic diseases caused by loss-of-function mutations in aquaporins include nephrogenic diabetes insipidus and cataracts, and functionally significant aquaporin polymorphisms are beginning to be explored. Perhaps of greatest translational potential is aquaporin-based therapeutics. Information largely from aquaporin knockout mice has implicated key roles of aquaporin-facilitated water transport in transepithelial fluid transport (urinary concentrating, gland fluid secretion), water movement into and out of the brain, cell migration (angiogenesis, tumor metastasis, wound healing) and neural function (sensory signaling, seizures). A subset of aquaporins that transport both water and glycerol, the 'aquaglyceroporins', regulate glycerol content in epidermal, fat and other tissues, and are involved in skin hydration, cell proliferation, carcinogenesis and fat metabolism. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of edematous states, cancer, obesity, wound healing, epilepsy and glaucoma. These exciting possibilities and their associated challenges are reviewed.
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PMID:Aquaporins: translating bench research to human disease. 1944 80

Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.
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PMID:Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. 1963 55

Psoriasis has been associated with a number of behavioral and systemic comorbidities, including psoriatic arthritis, anxiety, depression, obesity, hypertension, diabetes mellitus, hyperlipidemia, metabolic syndrome, smoking, cardiovascular disease, alcoholism, Crohn's disease, lymphoma, and multiple sclerosis. Many of these conditions have a similar immunologic pathogeneses. Canadian and international studies have not only confirmed the presence of these comorbidities but also have demonstrated that patients with psoriasis have a significantly reduced life span. Given that patients with psoriasis are often unaware of their comorbidities, they should be screened for these conditions and treated if required by their dermatologist and/or primary care physician. It is important to keep in mind that the comorbidities and drugs used to treat them have an impact on the choice of antipsoriatic treatment. In addition, comorbidities often preclude the use of traditional systemic agents. Recent studies have demonstrated that patients with preexisting comorbidities can be safely and effectively treated with biologic therapy. Furthermore, literature is evolving to suggest that better control of psoriasis might decrease cardiovascular mortality and prolong life.
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PMID:Psoriasis comorbidities. 1979 30

Vibration biomechanical stimulation as the physiological basis of vibration physical exercises (whole body vibration) causes reflecting muscle contractions like tonic vibration reflex. This type of intervention leads to high intensive stimulation of proprioceptors as called muscle spindles which result in alteration in parameters of activity and developments of human physiological functions. This type of training has broad positive influence on organism. Acceleration physical exercises improve muscle performance, flexibility, nervous function, significantly increase bone mineral density, physiological secretion of anabolic hormones, growth and anti-aging factors; normalize/decrease cortisol as anti-stress effect and are beneficial for balance and mobility as well. It is showed acceleration training caused by vibration stimulus is beneficial for people suffering from osteoporosis and obesity, for rehabilitation of nervous and motor function in patients with Parkinson's disease, multiple sclerosis and stroke.
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PMID:[Vibrational physical exercises as the rehabilitation in gerontology]. 1994

Autotaxin (ATX) is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family and is a lysophospholipase D that cleaves the choline headgroup from lysophosphatidylcholine to generate the bioactive lipid lysophosphatidic acid (LPA). Enhanced expression of ATX and specific receptors for LPA in numerous cancer cell types has created an interest in studying ATX as a potential chemotherapeutic target. Likewise, ATX has been linked to several additional human diseases including multiple sclerosis, diabetes, obesity, neuropathic pain, and Alzheimer's disease. ATX inhibitors reported to date consist of metal ion chelators, lipid-like product analogs, and non-lipid small molecules. In the current research, we examined the pharmacology of the best of our previously reported non-lipid small molecule inhibitors. Here, these six inhibitors were studied utilizing the synthetic fluorescent lysophospholipid substrate FS-3, the nucleotide substrate pNP-TMP and the endogenous substrate LPC (16:0). All six compounds inhibited FS-3 hydrolysis >or=50%, whereas only three inhibited the hydrolysis of pNP-TMP to this degree. None of the six compounds blocked LPC 16:0 hydrolysis within the desired 50% inhibition range. The most potent analog (5, H2L 7905958) displayed an IC(50) of 1.6microM (K(i)=1.9microM, competitive inhibition) with respect to ATX-mediated FS-3 hydrolysis and an IC(50) of 1.2microM (K(i)=K(i)(')=6.5microM, non-competitive inhibition) against ATX-mediated pNP-TMP hydrolysis. All six inhibitors were specific for ATX as they were without affect on two additional lipid preferring NPP isoforms.
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PMID:Characterization of non-lipid autotaxin inhibitors. 2000 24

Infectious diseases, including tuberculosis, malaria, hepatitis, pneumonia, dysentery, and helminth infestations, still constitute a profound threat in developing countries. Curiously, their decline in high-income societies is paralleled by an unprecedented emergence of allergic disorders, notably asthma and atopy, and chronic inflammatory and autoimmune diseases, such as Crohn's disease, type 1 diabetes, and multiple sclerosis. Several changes in lifestyle are associated with this transition, including diminished exposure to soil and animals, nutritional bias, obesity and increased exposure to pollutants and antibiotics, which all impact the intestinal microbiota. Understanding the mechanistic links behind the epidemiological observations, the complexity of a changing microbiome, and the immunoregulatory consequences of microbial encounter in barrier organs was the subject of the 99(th) Dahlem Conference.
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PMID:Infection, inflammation, and chronic diseases: consequences of a modern lifestyle. 2039 9

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARgamma, alpha and delta agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARdelta agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-gamma and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARdelta agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARdelta agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.
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PMID:Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis. 2040 5

Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor alpha (TNFalpha), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon alpha develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFalpha; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role.
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PMID:Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. 2041 47

Although the interaction between comorbidities and chronic diseases is strong, the effect of comorbidities receives little attention in many chronic diseases. In multiple sclerosis (MS), an increasing amount of evidence suggests that physical and mental comorbidities, and adverse health factors such as smoking and obesity, are common and can affect the disease. These comorbid diseases and lifestyle factors affect clinical phenotype, the diagnostic delay between symptom onset and diagnosis, disability progression, and health-related quality of life. Future studies of comorbidity and MS should consider comorbidities and health behaviours and should take into account the modifying effects of socioeconomic status, ethnic origin, and cultural factors. Studies of the frequency of comorbidities in patients with MS should be population based, incorporating appropriate comparator groups. These studies should expand the range of comorbidities assessed, and examine how the frequency of comorbidities is changing over time. Further research is needed to answer many other questions about comorbidities and their associations with MS, including the best way to measure and analyse comorbidities to understand these associations.
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PMID:Emerging effects of comorbidities on multiple sclerosis. 2065 Apr 3


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