Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for approximately 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.
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PMID:Orphan nuclear receptors: therapeutic opportunities in skeletal muscle. 1682

Evidence will be presented to support the usefulness of the altered homeostatic theory in understanding basic pathogenetic mechanisms of ischemic heart disease (IHD), hypertension, and diabetes, and in improving prevention of these disorders. The theory argues that: IHD, hypertension, and diabetes share the same basic pathogenesis; risk factors favor a sympathetic homeostatic shift; preventative factors favor a parasympathetic homeostatic shift; risk and preventative factors oppose each other through a dynamic risk/prevention balance; and prevention should be based on improving the risk/prevention balance. Prevention based on improving the risk/prevention balance should be more effective, as this method is regarded as reflecting more accurately basic pathogenetic mechanisms. As example, the theory argues that the risk of supposedly nonmodifiable risk factors as age and the risk of relatively nonmodifiable atherosclerosis can be reduced significantly. The possible validity of the altered homeostatic theory was tested by a study based on multiple associations. Findings support a common pathogenesis for IHD, hypertension, and diabetes based on a sympathetic homeostatic shift, and the usefulness of prevention based on improving the risk/prevention balance by using standard pharmaceutical and lifestyle preventative measures. The same set of multiple and diverse risk factors favored IHD, hypertension, and diabetes, and the same set of multiple and diverse pharmaceutical and lifestyle preventative measures prevented these disorders. Also, the same set of preventative agents generally improved cognitive function and bone density, and reduced the incidence of Alzheimer's disease, atrial fibrillation, and cancer. Unexpectedly, evidence was developed that four major attributes of sympathetic activation represent four major risk factors; attributes of sympathetic activation are a tendency toward thrombosis and vasoconstriction, lipidemia, inflammation, and hyperglycemia, and corresponding risk factors are endothelial dysfunction (which expresses thrombosis/vasoconstriction and epitomizes this tendency), dyslipidemia, inflammation, and insulin resistance. These findings, plus other information, provide evidence that dyslipidemia acts mainly as a marker of risk of IHD, rather than being the basic mechanism of this disorder. However, prevention generally is based solely on improvement of dyslipidemia; basing prevention on dyslipidemia relatively underemphasizes the importance of other significant risk factors and, by certifying its validity, discourages alternate pathogenetic approaches. Also, development of myocardial infarction is approached differently. It seems generally accepted that dyslipidemia results rather automatically in infarction through the sequence of atherosclerosis, atherosclerotic complications, and thrombosis. In contrast, distinction is made between development of atherosclerosis and acute induction of infarction--where atherosclerosis is only one of multiple risk factors.
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PMID:The altered homeostatic theory: A hypothesis proposed to be useful in understanding and preventing ischemic heart disease, hypertension, and diabetes--including reducing the risk of age and atherosclerosis. 1870 71

Insulin resistance is a worldwide risk factor for the two most dangerous human disease groups; namely, for cardiovascular lesions and malignancies. The insulin resistance syndrome have five basic criteria: hyperglycemia, visceral obesity, elevated serum triglyceride level, low HDL-cholesterol level (dyslipidemia) and hypertension. Each of these criteria alone are risk factors for cancer, and they mean together a multiple risk. Insulin resistance of the liver, skeletal muscles, and fatty tissue leads to a reactive hyperinsulinemia by the increased secretory activity of the beta-cells. Insulin has diverse metabolic effects, and at the same time is a growth factor. It enhances the production and mitogenic activity of other, insulin-like growth factors, and leads to pathological cell proliferation. In the uncompensated phase of insulin resistance hyperglycemia appears, which promotes tumor genesis by several pathways. The elevated serum glucose level is advantageous for the increased DNA synthesis of the tumor cells. It provokes deliberation of free radicals, which will cause derangement of both the DNA and the enzymes having a role in the repair mechanisms. Hyperglycemia leads to a nonenzymatic glycation of protein structures, and the glycated products enhance the deliberation of free radicals, cytokines and growth factors. Insulin resistance means an enhanced risk for breast, pancreas, liver, colon, bladder, prostate and oral cavity cancers. The moderately increased fasting glucose level is also a risk factor for breast, stomach and colon cancers, even without manifestation of type 2 diabetes. Insulin resistance promotes tumor progression as well. In cancer patients with hyperglycemia or type 2 diabetes, the rate of tumor recurrence, metastatic spread and fatal outcome is higher as compared with the tumor patients without metabolic disease. The correlation between insulin resistance and tumor promotion reveals new possibilities in the prevention and treatment of cancer. The healthy diet, physical activity and weight loss increase insulin sensitivity, and decrease the risk for both cardiovascular diseases and malignancies.
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PMID:[Correlations of insulin resistance and neoplasms]. 1688 76

Over the past 10 years, in conjunction with the broad availability of potent antiretroviral regimens, the care of human immunodeficiency virus (HIV)-infected patients has shifted from prevention and treatment of opportunistic infections and malignancies to management of the metabolic and related complications associated with HIV infection and its treatment. Metabolic disorders, including lipodystrophy, dyslipidemia, and insulin resistance, occur at a high rate in HIV-infected individuals receiving highly active antiretroviral therapy (HAART). These disorders are associated with increased risk of cardiovascular disease and have become an important cause of morbidity and mortality in HIV-infected patients. Herein, we present the case of a patient with HIV infection who responded well to HAART but developed multiple complications potentially related to this therapy. This article reviews the clinical characteristics of the metabolic and skeletal disturbances observed in HIV infection and discusses strategies for their management.
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PMID:Metabolic and skeletal complications of HIV infection: the price of success. 1690 89

The success of liver transplantation essentially depends on the prevention and treatment of long term complications, which may be due to surgery, opportunistic infections, organ rejection and relapse of the initial liver disease. The side effects of immunosuppressive drugs--arterial hypertension, glucose intolerance and diabetes, dyslipidemia and obesity, renal failure, osteoporosis, malignancy, and anaemia--should be regularly screened and treated without delay. Surgical procedures in transplanted patients are safe and rarely followed by complications. Although pregnancy in this setting is considered at risk, because of prematurity and low birth weight, overall outcomes are favourable. The yearly influenza vaccination is strongly recommended. The survival and the quality of life of liver transplant patients also depend on a good communication between the general practitioner and the transplantation centre.
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PMID:[Management of patients after liver transplantation]. 1700 50

CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.
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PMID:Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors. 1719 16

Cardiovascular disease has been well documented in patients with Human Immunodeficiency Virus infection, especially after the introduction of highly active antiretroviral therapy. At present, HIV infection is one of the leading causes of acquired cardiovascular disease including heart failure. Some of the changes observed in these patients include left ventricular systolic dysfunction, dilated cardiomyopathy, congestive heart failure, myocarditis, lipodystrophy, dyslipidemia, insulin resistance, accelerated atherosclerosis including myocardial infarction, prothrombotic state, pericardial effusion, pulmonary hypertension, autonomic dysfunction, and malignancy. This article summarizes the main findings in the principal HIV-associated cardiovascular manifestations in order to stimulate its early recognition so helping in early intervention and therapy.
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PMID:Cardiovascular disease in HIV infection. 1720 95

Androgen deprivation therapy (ADT) is the mainstay of management of advanced-stage prostate cancer and recently has been shown to improve survival when administered in earlier stages of the disease. The oncologic benefits of ADT might be partially offset, however, by a reduction in quality of life because of adverse effects. In addition to the well-recognized adverse consequences of ADT, recent evidence suggests that ADT is associated with dyslipidemia, impaired glucose metabolism, adverse body compositional changes, and osteoporosis. Therefore, there is a pressing need to develop less toxic forms of ADT. A novel approach to this problem is the use of estrogen to induce androgen suppression. Whereas oral estrogen therapy is known to be associated with thromboembolic complications, studies of parenteral estrogen in men with prostate cancer suggest that the use of parenteral estrogen achieves target androgen suppression, does not adversely affect prothrombotic protein levels, and is not associated with adverse metabolic, skeletal, and body compositional changes when compared with conventional ADT. Herein, we review the data for parenteral estrogen use in prostate cancer, the antineoplastic mechanisms of action of estrogen in prostate cancer, the potential advantages of parenteral estrogen compared with conventional ADT, and the remaining barriers in the use of parenteral estrogen in prostate cancer.
Clin Genitourin Cancer 2006 Dec
PMID:Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities? 1723 73

Because of its growing prevalence in Western countries, the metabolic syndrome, a common metabolic disorder that clusters a constellation of abnormalities, including central obesity, hypertension, dyslipidemia and insulin resistance, is emerging as one of the most important public health problems in the world, taking into account that it is a major risk factor mainly for type 2 diabetes and cardiovascular diseases, and also for many types of cancer. Although the pathogenesis of this syndrome is complex and not fully understood, obesity and insulin resistance, accompanied by an altered profile of number of hormones and cytokines produced by the adipose tissue, seem to be the main causative agents. A prime therapeutic approach to the prevention and treatment of this syndrome involves lifestyle changes. Among dietary modifications, dietary fiber intake could play an interesting role in the management of metabolic syndrome through different mechanisms related to its dietary sources, specific chemical structure and physical properties, or fermentability in the gut. According to all of these variables, the different types of dietary fibers have been reported to take part in the control of body weight, glucose and lipid homeostasis, insulin sensitivity and in the regulation of many inflammation markers involved in the pathogenesis of metabolic syndrome, and which are also considered to be among its features.
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PMID:Effects of dietary fibers on disturbances clustered in the metabolic syndrome. 1761 8

The degree to which comorbidities affect the diagnosis of prostate cancer is not clear. The purpose of this study was to determine how comorbidities affect the stage at which prostate cancer is diagnosed in elderly white and black men. We obtained data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute merged with Medicare claims data. For each patient, we estimated associations between stage of disease at diagnosis and each of the 27 comorbidities. The sample included 2,489 black and 2,587 white men with staged prostate cancer. Coronary artery disease, benign hypertension, and dyslipidemia reduced the odds of late-stage prostate cancer. A prior diagnosis of peripheral vascular disease, severe renal disease, or substance abuse increased the odds of being diagnosed with late-stage disease. The study shows some effect modification by race, particularly among white men with substance abuse, cardiac conduction disorders, and other neurologic conditions. The strongest predictors of late-stage prostate cancer diagnosis for both white and black men were age at diagnosis of at least 80 years and lack of PSA screening. Comorbidities do affect stage at diagnosis, although in different ways. Four hypotheses are discussed to explain these findings.
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PMID:Comorbidities and the risk of late-stage prostate cancer. 1761 18


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