Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is major risk factor for many disorders, including diabetes, hypertension and heart disease. Unfortunately, there is a dearth of therapeutic agents available to clinicians for the treatment of obesity. The principal aim of this study was to investigate whether PEGylated all-trans retinoic acid (PRA) can have favorable stability and biological activity in 3T3-L1 preadipocytes as an antiobesity drug. Here, we found that PRA inhibits the process of adipogenesis, including survival of adipocytes and differentiation to mature adipocytes. The results showed that RA nanoparticles (NPs) were prepared by PEGylation; below 200 nm, PRA-NPs were obtained. Moreover, PRA decreased glycerol-3-phosphate dehydrogenase activity in 3T3-L1 preadipocytes by acting with major adipocyte marker proteins such as PPARgamma2, C/EBPalpha and aP2 modulators. Apoptosis, in addition, increased as the level of RA increased from 10 to 20 microM, whereas PRA reduced apoptosis with increasing concentrations. Our data suggest that PRA-NP has potential as an antiobesity drug carrier due to its small particle size and PEGylated core-shell structure. In addition, our results suggest that PRA inhibits the process of adipogenesis and may be developed to treat obesity. Based on these results, PRA is suitable for adipocyte studies, and an enhanced effect of PRA with adipocyte differentiation offers a challenging approach for pharmaceutical applications.
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PMID:Regulation of adipocyte differentiation by PEGylated all-trans retinoic acid: reduced cytotoxicity and attenuated lipid accumulation. 1696 53

Retinoic acid (RA), the active derivative of vitamin A, by acting through retinoid receptors, is involved in signal transduction pathways regulating embryonic development, tissue homeostasis, and cellular differentiation and proliferation. RA is important for the development of the heart. The requirement of RA during early cardiovascular morphogenesis has been studied in targeted gene deletion of retinoic acid receptors and in the vitamin A-deficient avian embryo. The teratogenic effects of high doses of RA on cardiovascular morphogenesis have also been demonstrated in different animal models. Specific cardiovascular targets of retinoid action include effects on the specification of cardiovascular tissues during early development, anteroposterior patterning of the early heart, left/right decisions and cardiac situs, endocardial cushion formation, and in particular, the neural crest. In the postdevelopment period, RA has antigrowth activity in fully differentiated neonatal cardiomyocytes and cardiac fibroblasts. Recent studies have shown that RA has an important role in the cardiac remodeling process in rats with hypertension and following myocardial infarction. This chapter will focus on the role of RA in regulating cardiomyocyte growth and differentiation during embryonic and the postdevelopment period.
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PMID:Retinoic acid and the heart. 1736 19

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. 1739 60

Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFbeta, TNFalpha, interleukin 6, and IFN_. TGFbeta was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFN_, and demonstrated the greatest limitation of MCT-induced TNFalpha. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.
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PMID:Effects on cytokines and histology by treatment with the ACE inhibitor captopril and the antioxidant retinoic acid in the monocrotaline model of experimentally induced lung fibrosis. 1750 18

Our understanding of pediatric idiopathic intracranial hypertension has been refined since Dr. Simmons Lessell's review in 1992. The use of rigorous methodologies and standard definitions in recent studies has demonstrated distinct demographic trends. Specifically, the incidence of idiopathic intracranial hypertension seems to be increasing among adolescent children, and among older children its clinical picture is similar to that of adult idiopathic intracranial hypertension (female and obese). Within younger age groups there are more boys and nonobese children who may develop idiopathic intracranial hypertension. The pathogenesis of the disease has yet to be elucidated. Idiopathic intracranial hypertension among young children has been associated with several new etiologies, including recombinant growth hormone and all-trans-retinoic acid. More modern neuroimaging techniques such as MRI and MRI-venograms are being used to exclude intracranial processes. Although most cases of pediatric idiopathic intracranial hypertension improve with medical treatment, those who have had visual progression despite medical treatment have undergone optic nerve sheath fenestration and lumboperitoneal shunting. Because idiopathic intracranial hypertension in young children appears to be a different disorder than in adolescents and adults, separate diagnostic criteria for younger children are warranted. We propose new criteria for pediatric idiopathic intracranial hypertension in which children should have signs or symptoms consistent with elevated intracranial pressure, be prepubertal, have normal sensorium, can have reversible cranial nerve palsies, and have an opening cerebrospinal fluid pressure greater than 180 mm H(2)O if less than age 8 and papilledema is present, but greater than 250 mm H(2)0 if age 8 or above or less than 8 without papilledema.
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PMID:Pediatric idiopathic intracranial hypertension. 1802 69

Vitamin A (retinol) and its analogs (retinoids) are important regulators of cell proliferation, differentiation, immune function, and apoptosis. The kidneys are target organs for vitamin A action. Retinoic acid (RA), a vitamin A metabolite, is involved in embryonic kidney patterning through the control of receptor tyrosine kinase expression, which modulates ureteric bud branching morphogenesis. Vitamin A status of the mother profoundly affects kidney organogenesis of the newborn. In rodents, mild vitamin A deficiency results in a 20% reduction of nephron number. In adult humans, nephron number varies between 0.3 and 1.3 million per kidney, which is accepted as normal. However, recent studies indicate that humans at the low end of nephron number are predisposed to primary hypertension. Because RA regulates nephron mass, its optimal availability during nephrogenesis is critical. RA levels in the embryo are affected by several factors, such as maternal vitamin A nutrition and disturbances in retinol metabolism. Maternal vitamin A deficiency during pregnancy is widespread in developing countries and segments of these populations may be exposed to low vitamin A during fetal life when nephron number is determined. Infants are likely to be born with suboptimal nephrons and may develop primary hypertension later in life. Although maternal vitamin A deficiency is not common in developed countries, congenital nephron number nevertheless varies widely, indicating low fetal RA levels due to common variants of the enzymes that convert retinol to RA. These infants might require heightened surveillance for hypertension later in life.
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PMID:Role of vitamin A in determining nephron mass and possible relationship to hypertension. 1864 Nov 82

Complete transcriptome profiling of contractile smooth muscle cells (SMCs) differentiated from embryonic stem cells is crucial for the characterization of smooth muscle gene expression signatures and will contribute to defining biological and physiological processes in these cells. We have generated a transgenic embryonic stem cell line expressing both the puromycin acetyl transferase and enhanced green fluorescent protein cassettes under the control of the Acta2 promoter. Applying a specific monolayer culture protocol using retinoic acid, a puromycin-resistant and enhanced green fluorescent protein-positive Acta2(+) SMC population of 95% purity was isolated. Acta2(+) SMCs were characterized by semiquantitative and quantitative RT-PCR profiling of SMC markers and by microarray expression profiling, as well as by immunostaining for SMC-specific cytoskeletal proteins. Patch-clamp electrophysiological characterization of these cells identified SMC-specific channels such as the ATP-sensitive potassium channel and the Ca(2+)-activated potassium channel. Culturing of Acta2(+) SMCs in serum-containing medium resulted in a significant number of hypertrophic and binucleated cells failing to complete cell division. Functional characterization of the cells has been proved by stimulation of the cells with vasoactive agents, such as angiotensin II and endothelin. We concluded that our embryonic stem cell-derived SMC population possesses the contractile and hypertrophic phenotype of SMCs incapable of proliferation. This is the first study describing the complete transcriptome of ES-derived SMCs allowing identification of specific biological and physiological processes in the contractile phenotype SMCs and will contribute to the understanding of these processes in early SMCs derived from embryonic stem cells.
Hypertension 2009 Feb
PMID:Functional characterization and transcriptome analysis of embryonic stem cell-derived contractile smooth muscle cells. 1906 16

Angiotensin type 1 receptor blockers are widely used for the treatment of hypertension, and one angiotensin type 1 receptor blocker, telmisartan, specifically activates the peroxisome proliferator-activated receptor (PPAR)-gamma. We studied the impact of PPARgamma mutants on transcriptional control and interaction with cofactors to elucidate differences in the molecular mechanism between telmisartan and other PPARgamma agonists, thiazolidinediones (TZDs). We created several amino acid substitutions in the ligand binding domain of PPARgamma that, based on molecular modeling, may affect the binding of these agents. In transient expression experiments, wild-type PPARgamma-mediated transcription stimulated by telmisartan was more than one third of that stimulated by TZDs. The activation stimulated by TZDs was impaired, whereas activation stimulated by telmisartan was retained, in the H323Y, S342A, and H449A mutants. In the Y473A mutant, the TZD-induced activation was further impaired and lower than that of telmisartan-induced activation. Coexpression of coactivators enhanced the activation by both telmisartan and TZDs, but activation by telmisartan always exceeded that of TZDs in the Y473A mutant. Based on a mammalian two-hybrid assay, the interaction with corepressors was retained in Y473A. Telmisartan and TZDs, but not 9cis retinoic acid, dissociated corepressors from the wild-type PPARgamma. Telmisartan most effectively dissociated corepressors from Y473A. The interaction with coactivators was enhanced by TZD activation of wild-type PPARgamma and both telmisartan and TZD activation of Y473A. Thus, the Y473A mutant is selectively stimulated by telmisartan but not TZDs, suggesting that telmisartan and TZDs have differential effects on the transcriptional control. In conclusion, these PPARgamma mutants could be powerful tools for developing novel therapeutic agents that retain the metabolic efficacy of PPARgamma activation with fewer adverse effects, such as the increase in body weight associated with TZDs.
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PMID:A selective peroxisome proliferator-activated receptor-gamma modulator, telmisartan, binds to the receptor in a different fashion from thiazolidinediones. 1914 80

Hyaluronic acid (HA) is present in high concentrations in the intercellular spaces of the epidermis and the connective tissues of the dermis. It is associated with many beneficial biological activities including water retention, maintenance of various cellular functions, and skin homeostasis. Puerariae Radix (PR), a Chinese herb and a popular food in Asia, is used for various medicinal purposes including anti-hypertension, anti-angina pectoris and anti-dipsotropic. PR is rich in isoflavone glycosides like genistin and daidzin as soya. In this study, Bifidobactericum breve CCRC 14061 and CCRC 11846 were used for the fermentation of PR; moreover, acid was used to hydrolyze PR decoction. Genistein and daidzein in the hydrolysate were determined by HPLC. The HA production in normal human epidermal keratinocytes (NHEK) was measured after 48 hours incubation with PR and its hydrolysate, respectively. HA was assayed by enzyme-linked immunosorbent assay (ELISA), and retinoic acid was used as the positive control. After fermentation with Bifidobactericum breve, the contents of daidzein and genistein were increased 785% and 1,010% by CCRC 14061, and 192% and 406% by CCRC 11846, respectively, whereas after acid hydrolysis, only daidzein was increased by 990%. The production of HA in NHEK was increased after incubation with the fermentation product of CCRC 14061, acid hydrolysate, PR decoction and retinoic acid (22+/- 0.2%), whereas no increase of HA concentration was found after incubation with the fermentation product of CCRC 11846. Furthermore, the PR hydrolysate stimulated the HA production of NHEK, and the effect was dose-dependent (18.6%-83.9%). In conclusion, PR preparations would stimulate HA production in NHEK cells which might be used as a new cosmetic ingredient in moisturizers and an anti-aging agent.
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PMID:Comparison of Puerariae Radix and its hydrolysate on stimulation of hyaluronic acid production in NHEK cells. 2012 51

Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.
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PMID:Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT. 2069 72


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