Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hydroxymethylglutaryl-CoA reductase inhibitor lovastatin is used widely to treat hypercholesterolemia and has been shown to have cell cycle-specific effects. In these studies, we have examined the effects of combining lovastatin and paclitaxel (Taxol), a microtubule-stabilizing agent, in the human leukemia K562 and HL-60 cell lines. Isobologram analysis of cytotoxicity assays revealed that there is a synergistic interaction between the two agents in both cell lines. Cell cycle analyses showed that lovastatin enhances paclitaxel-induced G2-M arrest in both cell lines. In addition, Annexin V apoptotic studies revealed that lovastatin enhances paclitaxel-induced apoptosis in HL-60 cells. Lovastatin did not affect levels of [3H]paclitaxel in cells. Whereas lovastatin induced an accumulation of unmodified Ras and caused an up-regulation of both RhoB and Rap1A, paclitaxel was found to have no effect on the isoprenylated proteins. Studies of the centromere-associated protein mitosin revealed that treatment with lovastatin and paclitaxel resulted in increased mitosin levels and that lovastatin altered the association of mitosin with condensed chromosomes. These findings provide insight into the mechanisms underlying the cell cycle effects of lovastatin and support the development of a novel therapeutic strategy directed toward altering deleterious cell proliferation.
Mol Cancer Ther 2001 Dec
PMID:Synergistic interaction of lovastatin and paclitaxel in human cancer cells. 1246 31

Atherosclerosis is a disease of the arteries in which fatty plaques develop on the inner arterial wall, which eventually obstructs blood flow. Identified risk factors for atherosclerosis include genetics, diet, lifestyle, smoking, circulating lipid and cholesterol levels, and molecular and circulating signals of chronic vascular inflammation. The link between flavonoids and atherosclerosis is based partly on the evidence that some flavonoids possess antioxidant properties and have been shown to be potent inhibitors of LDL oxidation in vitro. Hypercholesterolemia, a significant cardiovascular risk factor is prevalent in the American population. Grape seed proanthocyanidin extracts are known to exhibit a broad spectrum of chemopreventive and cardioprotective properties against oxidative stress. A recent study has shown that a combination of IH636 grape seed proanthocyanidin extract (GSPE) and a niacin-bound chromium (NBC) can decrease total cholesterol, LDL and oxidized LDL levels in hypercholesterolemic human subjects. In this study, we assessed the efficacy of GSPE supplementation in hamsters, singly and in combination with NBC, since these animals have a similar lipid profile to hypercholesterolemic humans when fed a hypercholesterolemic diet of 0.2% cholesterol and 10% coconut oil (HCD). After 10 weeks of feeding HCD, these animals developed foam cells, which is a biomarker of early stages of atherosclerosis. Atherosclerosis (% of aorta covered with foam cells) was reduced by approximately 50% and 63% following supplementation of these animals with 50 mg/kg and 100 mg/kg of GSPE, respectively, in conjunction with a HCD, while approximately 32% reduction was observed following supplementation of GSPE plus NBC. A range of 7-9 animals was used in each study group. GSPE alone and in combination with NBC exerted a pronounced effect on the cholesterol, and triglyceride levels, as well as oxidative lipid damage as demonstrated by the formation of thiobarbituric acid reactive substances (TBARS). This data demonstrates that GSPE and NBC may provide significant health benefits by dramatically ameliorating the incidence of atherosclerosis as demonstrated by reducing the formation of foam cells.
Mol Cell Biochem 2002 Nov
PMID:Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a niacin-bound chromium in a hamster atherosclerosis model. 1248 76

Events leading to hyperactivity of human blood platelets are accompanied by an enhanced risk of atherosclerosis and arterial thrombosis. Lipoprotein disorders affect platelet functions, and hypersensitive platelets are observed in various stages of hyperlipidemia. Low-density lipoprotein (LDL), a circulating complex of lipids and proteins that is increased in hypercholesterolemia, enhances platelet function and increases sensitivity of platelets to several naturally occurring agonists. LDL sensitizes platelets via binding of apoB-100 to a receptor on the platelet membrane and via transfer of lipids to the platelet membrane. The receptor that mediates binding of LDL to the platelet and initiates subsequent intracellular signaling cascades has not yet been identified. Modification of native LDL generates a platelet-activating particle, and this interaction might contribute to the development of the atherosclerotic plaque. Lysophosphatidic acid is formed upon mild oxidation of LDL and is responsible for subsequent platelet activation induced by the modified LDL particle. Thus, LDL changes the functions of platelets via a broad spectrum of interactions.
Cell Mol Life Sci 2003 May
PMID:Low-density lipoprotein and its effect on human blood platelets. 1282 83

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.
Mol Immunol 2003 Jul
PMID:Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation. 1283 78

The -1131T>C polymorphism in the newly identified apolipoprotein A5 (APOA5) gene has been associated with elevated plasma triglycerides. We determined its incidence in 915 patients attending a lipid outpatient clinic. The frequency of the C allele was significantly higher in patients with triglycerides above the 90th percentile and patients with type III hyperlipidemia compared to those with hypercholesterolemia. The C allele was associated with increased plasma triglycerides and decreased plasma HDL cholesterol, conditions associated with an increased risk of coronary heart disease. The effects on plasma lipids were only observed in overweight (BMI>25) patients and were greater in patients who were also carriers of a least one epsilon4 allele in the APOE gene. Thus additional genetic and/or metabolic factors are required in order for the triglyceride raising and HDL lowering effect of the -1131T>C polymorphism in APOA5 to be expressed.
J Mol Med (Berl) 2003 Oct
PMID:The single nucleotide polymorphism -1131T>C in the apolipoprotein A5 (APOA5) gene is associated with elevated triglycerides in patients with hyperlipidemia. 1293 97

DNA samples of 2303 individuals from nine different population groups were screened for variant -175g-->t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The -175g-->t variant detected at carrier frequencies of 3-10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.0001). Haplotype and mutation analysis excluded the likelihood that this finding is due to association with a specific disease-related mutation in FH patients, although reversal of the positive association with FH observed in the Black population may, at least in part, be due to admixture linkage disequilibrium. Transient transfection studies in HepG2 cells demonstrated that the -175t allele is associated with a non-significant decrease ( approximately 7%) of LDLR transcription in the absence of sterols. The data presented in this study raise the possibility that the -175g-->t polymorphism may have subtle effects that become clinically important within certain genetic and/or environmental contexts.
Mol Cell Probes 2003 Aug
PMID:Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element. 1294 20

Recruitment for the inaugural double-blind placebo-controlled trial investigating a cholesterol-lowering treatment for benefit in Alzheimer's disease (AD) (ADCLT) ended after obtaining 98 informed consents. Suspension of recruitment of the ADCLT occurred in concert with initiation of two separate multicenter trials testing similar hypotheses. Although occurring at very low rates (<2%), altered-chemistry adverse events requiring discontinuation of therapy (withdrawal AEs) are not unexpected with use of cholesterol-lowering statins. We suggest that exceptionally close monitoring for altered chemistry among individuals with AD should be undertaken in future statin treatment trials, as limited data from the ADCLT indicate that chemically based withdrawal AEs could be more prevalent among female AD patients. There was no apparent correlation between the occurrence of withdrawal-AE incidence and lower body mass among the female AD trial subjects and, therefore, probably was not a dose-related resultant. This might indicate that cognitively intact elderly women at risk for heart disease and those with clinically documented AD should not be presumed to be pharmocodynamically equivalent. Lipid profiles obtained at screening in the ADCLT are consistent with a possible difference between patients with current AD and those at risk for heart disease. Elevated cholesterol, increased cholesterol/high-density lipid (HDL) ratios, and elevated triglycerides are routinely observed among those at risk for heart disease; however, among ADCLT study participants, only cholesterol levels were increased while cholesterol/HDL ratio and triglyceride levels remained within normal limits.
J Mol Neurosci 2003
PMID:A position paper: based on observational data indicating an increased rate of altered blood chemistry requiring withdrawal from the Alzheimer's Disease Cholesterol-Lowering Treatment Trial (ADCLT). 1450 Oct 25

Megalin is an endocytic receptor that binds multiple ligands and is essential for many physiological processes such as brain development and uptake of proteins by the kidney tubule, yolk sac, and thyroid. The cytoplasmic tail of megalin contains two FXNPXY motifs. Autosomal recessive hypercholesterolemia (ARH) is an adaptor protein that binds to the FXNPXY motif of the low-density lipoprotein receptor as well as clathrin and AP-2. We found that ARH also binds to the first FXNPXY motif of megalin in two-hybrid, pull-down and coimmunoprecipitation assays. ARH colocalizes with megalin in clathrin coated pits and in recycling endosomes in the Golgi region. When cells are treated with nocodazole, the recycling endosomes containing megalin and ARH disperse. On internalization of megalin, ARH and megalin are first seen in clathrin coated pits followed by sequential localization in early endosomes and tubular recycling endosomes in the pericentriolar region followed by their reappearance at the cell surface. Expression of ARH in Madin-Darby canine kidney cells expressing megalin mini-receptors enhances megalin-mediated uptake of 125I-lactoferrin, a megalin ligand. These results show that ARH facilitates endocytosis of megalin, escorts megalin along its endocytic route and raise the possibility that transport through the endosomal system is selective and requires interaction with specific adaptor proteins.
Mol Biol Cell 2003 Dec
PMID:The adaptor protein ARH escorts megalin to and through endosomes. 1452 14

Melanoma is a deadly cancer due to its propensity to metastasize. Pharmacological inhibition of cell motility may benefit patients with cutaneous melanoma by preventing metastasis to internal organs. The Rho GTPases are signaling molecules that drive metastasis by controlling cell motility. We found RhoC to be expressed in clinical melanoma specimens and hypothesized that inhibiting its activation might prevent metastasis. Some Rho proteins, such as RhoC, depend on posttranslational geranylgeranylation for biological activity. We investigated the effect that Atorvastatin, a 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) reductase inhibitor that prevents Rho geranylgeranylation, had on subcellular localization and activity of Rho proteins as well as the metastatic ability of melanoma cells. Atorvastatin inhibited Rho activation and reverted the metastatic phenotype of human melanoma cells in vitro. Moreover, Atorvastatin, at plasma levels comparable to those used to treat of hypercholesterolemia, inhibited in vivo metastasis of melanoma cells overexpressing RhoC. These results support further examination of statins for primary prophylaxis of melanoma metastasis.
Mol Cancer Ther 2003 Oct
PMID:Atorvastatin prevents RhoC isoprenylation, invasion, and metastasis in human melanoma cells. 1457 59

The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk (genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.
Mol Interv 2002 Dec
PMID:Toward a role for statins in immunomodulation. 1499 98


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