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1.
Nutr Cancer ; 67(2): 250-7, 2015.
Article in English | MEDLINE | ID: mdl-25611564

ABSTRACT

The antiproliferative potential of a crude extract from the chayote hybrid H-837-07-GISeM® and its potential for apoptosis induction were assessed in leukaemic cell lines and normal mouse bone marrow mononuclear cells (BM-MNCs). The extract strongly inhibited the proliferation of the P388, J774, and WEHI-3 cell lines (with an IC50 below 1.3 µg·mL(-1)), reduced cell viability, and induced apoptotic body production, phosphatidylserine translocation, and DNA fragmentation. However, the extract had no effect on BM-MNCs. We postulate that these properties make the extract a good candidate for an anti-tumour agent for clinical use.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cucurbitaceae , Fruit , Leukemia/drug therapy , Plant Extracts/pharmacology , Animals , Bone Marrow Cells/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chimera , Cucurbitaceae/chemistry , DNA Fragmentation , Female , Leukemia/pathology , Leukemia P388/drug therapy , Leukemia P388/pathology , Mice , Monocytes/drug effects , Phospholipid Transfer Proteins/drug effects
2.
Pflugers Arch ; 467(11): 2243-56, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25630304

ABSTRACT

Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca(2+)-activated Cl(-) channels that generate outward-rectifying ionic currents in response to intracellular Ca(2+) increase. ANO6 is also essential for Ca(2+)-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)--fluoxetine, sertraline, and paroxetine-that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1-7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl(-) current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca(2+)-dependent activation of IANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of IANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca(2+)-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca(2+)-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.


Subject(s)
Phosphatidylserines/metabolism , Phospholipid Transfer Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Anoctamins , Blood Coagulation/drug effects , Calcium Signaling/drug effects , Cell Line , Chloride Channels/metabolism , HEK293 Cells , Humans , Patch-Clamp Techniques , Phospholipid Transfer Proteins/drug effects , Plasmids/genetics , Platelet Aggregation/drug effects , RNA, Small Interfering/pharmacology , Thrombin/pharmacology , Transfection
3.
Transgenic Res ; 16(4): 503-13, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17437182

ABSTRACT

One main determinant in high-density lipoprotein (HDL) metabolism is phospholipid transfer protein (PLTP), a plasma protein that is associated with HDL. In transgenic mice overexpressing human PLTP we found that elevated plasma PLTP levels dose-dependently increased the susceptibility to diet-induced atherosclerosis. This could be mainly due to the fact that most functions of PLTP are potentially atherogenic, such as decreasing plasma HDL levels. To further elucidate the role of PLTP in lipoprotein metabolism and atherosclerosis we generated a novel transgenic mouse model that allows conditional expression of human PLTP. In this mouse model a human PLTP encoding sequence is controlled by a Tet-On system. Upon induction of PLTP expression, our mouse model showed a strongly increased PLTP activity (from 3.0 +/- 0.6 to 11.4 +/- 2.8 AU, p < 0.001). The increase in PLTP activity resulted in an acute decrease in plasma cholesterol of 33% and a comparable decrease in phospholipids. The decrease in total plasma cholesterol and phospholipids was caused by a 35% decrease in HDL-cholesterol level and a 41% decrease in HDL-phospholipid level. These results demonstrate the feasibility of our mouse model to induce an acute elevation of PLTP activity, which is easily reversible. As a direct consequence of an increase in PLTP activity, HDL-cholesterol and HDL-phospholipid levels strongly decrease. Using this mouse model, it will be possible to study the effects of acute elevation of PLTP activity on lipoprotein metabolism and pre-existing atherosclerosis.


Subject(s)
Mice, Transgenic/physiology , Phospholipid Transfer Proteins/metabolism , Phospholipid Transfer Proteins/physiology , Animals , Female , Humans , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Phospholipid Transfer Proteins/drug effects , Phospholipid Transfer Proteins/genetics , Protein Synthesis Inhibitors/pharmacology , RNA, Messenger/analysis , Tetracycline/pharmacology
4.
Diabetes ; 55(5): 1491-6, 2006 May.
Article in English | MEDLINE | ID: mdl-16644710

ABSTRACT

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA(1c), glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: -8.3%, P < 0.05; 80 mg atorvastatin: -12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in a multivariate model. The activity of PLTP in type 2 diabetes is decreased by atorvastatin. The association between the decrease in PLTP activity and apoE during statin treatment supports the hypothesis that apoE may prevent PLTP inactivation.


Subject(s)
Apolipoproteins E/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Heptanoic Acids/therapeutic use , Phospholipid Transfer Proteins/blood , Pyrroles/therapeutic use , Apolipoprotein A-I/blood , Apolipoprotein A-II/blood , Apolipoproteins E/drug effects , Apolipoproteins E/genetics , Atorvastatin , Cholesterol/blood , Genotype , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Middle Aged , Phospholipid Transfer Proteins/drug effects , Placebos
5.
Nephrol Dial Transplant ; 21(1): 101-6, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16141462

ABSTRACT

BACKGROUND: Lipid derangements are assumed to contribute to the elevated cardiovascular risk in proteinuric patients. The impact of proteinuria on reverse cholesterol transport (RCT) is unknown. The first step in RCT, cellular cholesterol efflux to plasma, may be altered in proteinuria, consequent to changes in pre-beta high-density lipoprotein (HDL) formation and plasma phospholipid transfer protein (PLTP) activity. METHODS: In six non-diabetic male patients with nephrotic-range proteinuria and 12 matched healthy men, plasma (apo)lipoproteins, pre-beta HDL formation, PLTP activity as well as the ability of plasma to promote cholesterol efflux out of cultured human skin fibroblasts were determined. These variables were also measured in response to antiproteinuric treatment, consisting of single and dual RAAS blockade by losartan and lisinopril. RESULTS: Plasma total cholesterol (P<0.05), triglycerides (P<0.05), apolipoprotein (apo) A-I (P<0.001), apo B (P<0.001), PLTP activity (P<0.005) and pre-beta HDL formation (P<0.001) were higher in proteinuric patients. Cellular cholesterol efflux to plasma from proteinuric patients was 41% higher than to plasma from healthy subjects (P<0.001). Reduction of proteinuria from 5.0 to 1.4 g/day by dual RAAS blockade was associated with a 23% reduction in plasma apo B levels (P<0.05). Pre-beta HDL formation and plasma PLTP activity did not change significantly. Combined antiproteinuric treatment did not reduce the elevated cellular cholesterol efflux. CONCLUSION: Cellular cholesterol efflux to plasma from patients with nephrotic-range proteinuria is enhanced, in conjunction with elevated pre-beta HDL formation and plasma PLTP activity. These changes may attenuate the cardiovascular risk associated with proteinuria-associated hyperlipidaemia. Antiproteinuric therapy lowers plasma apo B, but does not affect cell-derived cholesterol efflux, suggesting that this therapy beneficially affects cardiovascular risk in proteinuric patients.


Subject(s)
Apolipoproteins/metabolism , Cholesterol, HDL/metabolism , Hyperlipidemias/drug therapy , Kidney Failure, Chronic/diagnosis , Phospholipid Transfer Proteins/metabolism , Proteinuria/diagnosis , Adult , Analysis of Variance , Apolipoproteins/blood , Biological Transport , Case-Control Studies , Cholesterol, HDL/drug effects , Humans , Hyperlipidemias/diagnosis , Kidney Failure, Chronic/blood , Kidney Function Tests , Lisinopril/therapeutic use , Losartan/therapeutic use , Male , Middle Aged , Phospholipid Transfer Proteins/drug effects , Probability , Prognosis , Proteinuria/blood , Reference Values , Risk Factors , Sensitivity and Specificity , Severity of Illness Index
6.
Biochim Biophys Acta ; 1738(1-3): 48-53, 2005 Dec 30.
Article in English | MEDLINE | ID: mdl-16298159

ABSTRACT

In humans, fibrates are used to treat dyslipidemia, because these drugs lower plasma triglycerides and raise HDL cholesterol. Treatment with fibrates lowers plasma phospholipid transfer protein (PLTP) activity in humans, but increases PLTP activity in mice, without a consistent effect on HDL-cholesterol concentration. Earlier, we found that PLTP overexpression in transgenic mice results in decreased plasma HDL levels and increased diet-induced atherosclerosis. So it seems that the interplay between fibrates, PLTP and HDL is different in mice and man, which may be important for atherosclerosis development. In the present study, we measured the effects of fibrates on PLTP expression in cultured human hepatocytes and effects of fibrate treatment on human PLTP expression, plasma PLTP activity and HDL levels in human PLTP transgenic mice. Fibrate treatment did not influence PLTP mRNA levels in human hepatocytes. Hepatic human PLTP mRNA levels and PLTP activity were both moderately elevated by fenofibrate treatment in human PLTP transgenic mice. In wild-type mice, however, feeding fenofibrate resulted in a strong induction of PLTP mRNA in the liver and a more than 4-fold increase of plasma PLTP activity. Plasma triglycerides were reduced in all mice by 48% or more by fenofibrate treatment. HDL-cholesterol concentrations were substantially increased by fenofibrate in PLTP overexpressing mice (+72%), but unaffected in wild-type mice. We conclude that fenofibrate treatment reverses the HDL-lowering effect of PLTP overexpression in human PLTP transgenic mice.


Subject(s)
Cholesterol, HDL/blood , Fenofibrate/pharmacology , Hypolipidemic Agents/pharmacology , Phospholipid Transfer Proteins/drug effects , Animals , Cells, Cultured , Cholesterol, HDL/drug effects , Gene Expression Regulation/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phosphatidylcholine-Sterol O-Acyltransferase/drug effects , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , Phospholipid Transfer Proteins/genetics , Phospholipid Transfer Proteins/metabolism , RNA, Messenger/drug effects , Triglycerides/blood
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