Studies

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Plant polyphenols in prevention of heart disease.

Polyphenols (PPH) are a group of chemical substances found in plants, characterized by the presence of more than one phenol unit . The largest and best studied polyphenols are the flavonoids, which include several thousand compounds. PPH are the most abundant antioxidants in human diets. Their sheer mass in the diet exceeds that of the consumed vitamins. The Mediterranean diet is rich in PPH because it contains abundant vegetables, fruits, unrefined cereals, legumes, nuts, garlic, olive oil and red wine. Locations where the Mediterranean diet prevails are known for a reduced premature cardiovascular disease (CVD) mortality. However, this geographic distinction is not entirely unique. Low CVD mortality is also present in countries with high consumption if plant food and fish, as Scandinavia, Switzerland and Austria. Putative mechanisms of the metabolic effect of PPH are related to multiple biologic functions that may have beneficial effect in the prevention of some inflammation-mediated disorders, including CVD. Naturally occurring dietary PPH can directly scavenge free oxygen radicals, adhesion molecules, and growth factor receptor genes. Thus, these polyphenolic compounds have potential therapeutic value as antioxidant and anti-inflammatory agents in CVD. PPH reduce the generation of oxidized low density lipoproteins (LDL), induce nitric oxide (NO) production, inhibit platelet aggregation and downregulate expression of proinflammatory mediators (Fig. 6, Tab. 1, Ref. 33).

Source: Ginter E, Simko V. Bratisl Lek Listy. 2012;113(8):476-80.

 

Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction.

BACKGROUND AND PURPOSE:

Curcumin, the natural yellow pigment extracted from the rhizomes of the plant curcuma longa, has been demonstrated to exhibit a variety of potent beneficial effects, acting as an antioxidant, anti-inflammatory and anti-fibrotic. In this study we tested the hypothesis that curcumin attenuates maladaptive cardiac repair and improves cardiac function after ischaemia and reperfusion by reducing degradation of extracellular matrix (ECM) and inhibiting synthesis of collagens via TGFβ/Smad-mediated signalling pathway.

EXPERIMENTAL APPROACH:

Sprague-Dawley rats were subjected to 45 min of ischaemia followed by 7, 21 and 42 days of reperfusion respectively. Curcumin was fed orally at a dose of 150 mg·kg(-1) ·day(-1) only during reperfusion.

KEY RESULTS:

Curcumin reduced the level of malondialdehyde, inhibited activity of MMPs, preserved ECM from degradation and attenuated collagen deposition, as it reduced the extent of collagen-rich scar and increased mass of viable myocardium. In addition to reducing collagen synthesis and fibrosis in the ischaemic/reperfused myocardium, curcumin significantly down-regulated the expression of TGFβ1 and phospho-Smad2/3, and up-regulated Smad7 and also increased the population of α-smooth muscle actin expressing myofibroblasts within the infarcted myocardium relative to the control. Echocardiography showed it significantly improved left ventricular end-diastolic volume, stroke volume and ejection fraction. The wall thickness of the infarcted middle anterior septum in the curcumin group was also greater than that in the control group.

CONCLUSION AND IMPLICATIONS:

Dietary curcumin is effective at inhibiting maladaptive cardiac repair and preserving cardiac function after ischaemia and reperfusion. Curcumin has potential as a treatment for patients who have had a heart attack.

Source: Wang NP, Wang ZF, Tootle S, Philip T, Zhao ZQ. Br J Pharmacol. 2012 Dec;167(7):1550-62. doi: 10.1111/j.1476-5381.2012.02109.x.

Effects of curcuminoids on frequency of acute myocardial infarction after coronary artery bypass grafting.

It is well established that myocardial infarction (MI) associated with coronary artery bypass grafting (CABG) predicts a poor outcome. Nevertheless, cardioprotective therapies to limit myocardial injury after CABG are lacking. Previous studies have shown that curcuminoids decrease proinflammatory cytokines during cardiopulmonary bypass surgery and decrease the occurrence of cardiomyocytic apoptosis after cardiac ischemia/reperfusion injury in animal models. We aimed to evaluate whether curcuminoids prevent MI after CABG compared to placebo. The 121 consecutive patients undergoing CABG were randomly allocated to receive placebo or curcuminoids 4 g/day beginning 3 days before the scheduled surgery and continued until 5 days after surgery. The primary end point was incidence of in-hospital MI. The secondary end point was the effect of curcuminoids on C-reactive protein, plasma malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels. Baseline characteristics were comparable between the curcuminoid and placebo groups. Mean age was 61 ± 9 years. On-pump CABG procedures were performed in 51.2% of patients. Incidence of in-hospital MI was decreased from 30.0% in the placebo group to 13.1% in the curcuminoid group (adjusted hazard ratio 0.35, 0.13 to 0.95, p = 0.038). Postoperative C-reactive protein, malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels were also lower in the curcuminoid than in the placebo group. In conclusion, we demonstrated that curcuminoids significantly decreased MI associated with CABG. The antioxidant and anti-inflammatory effects of curcuminoids may account for their cardioprotective effects shown in this study.

Source: Wongcharoen W, Jai-Aue S, Phrommintikul A, Nawarawong W, Woragidpoonpol S, Tepsuwan T, Sukonthasarn A, Apaijai N, Chattipakorn N. Am J Cardiol. 2012 Jul 1;110(1):40-4. doi: 10.1016/j.amjcard.2012.02.043. Epub 2012 Apr 3.

 

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway.

In this study, we evaluated the effect of curcumin (Cur) post-treatment on isolated perfused rat hearts that had been subjected to a protocol of ischemia and reperfusion injury. We also examined whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway plays a role in the cardioprotective effects of Cur post-treatment. Isolated perfused rat hearts were subjected to 60 min of ischemia, followed by 60 min of reperfusion. The hearts were exposed to 1-μM Cur during the first 10 min of reperfusion in the absence or presence of the JAK kinase-specific inhibitor AG490 (AG, 1 μM). The Cur treatment conferred a cardioprotective effect, and the treated hearts demonstrated an improved post-ischemic cardiac functional recovery, a decreased myocardial infarct size and decreased lactate dehydrogenase release in the coronary flow, a reduced number of apoptotic cardiomyocytes, up-regulation of the anti-apoptotic protein Bcl2 and down-regulation of the pro-apoptotic protein Caspase3. AG blocked the Cur-mediated cardioprotection by inhibiting the JAK2/STAT3 signaling pathway, as reflected by the abrogation of the Cur-induced up-regulation of Bcl2 and down-regulation of Caspase3. The results suggest that Cur post-treatment can attenuate IR injury through the activation of the JAK2/STAT3 signaling pathway, which transmits a survival signal to the myocardium.

Source: Duan W, Yang Y, Yan J, Yu S, Liu J, Zhou J, Zhang J, Jin Z, Yi D. Basic Res Cardiol. 2012;107(3):263. doi: 10.1007/s00395-012-0263-7. Epub 2012 Mar 31.

 

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway.

In this study, we evaluated the effect of curcumin (Cur) post-treatment on isolated perfused rat hearts that had been subjected to a protocol of ischemia and reperfusion injury. We also examined whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway plays a role in the cardioprotective effects of Cur post-treatment. Isolated perfused rat hearts were subjected to 60 min of ischemia, followed by 60 min of reperfusion. The hearts were exposed to 1-μM Cur during the first 10 min of reperfusion in the absence or presence of the JAK kinase-specific inhibitor AG490 (AG, 1 μM). The Cur treatment conferred a cardioprotective effect, and the treated hearts demonstrated an improved post-ischemic cardiac functional recovery, a decreased myocardial infarct size and decreased lactate dehydrogenase release in the coronary flow, a reduced number of apoptotic cardiomyocytes, up-regulation of the anti-apoptotic protein Bcl2 and down-regulation of the pro-apoptotic protein Caspase3. AG blocked the Cur-mediated cardioprotection by inhibiting the JAK2/STAT3 signaling pathway, as reflected by the abrogation of the Cur-induced up-regulation of Bcl2 and down-regulation of Caspase3. The results suggest that Cur post-treatment can attenuate IR injury through the activation of the JAK2/STAT3 signaling pathway, which transmits a survival signal to the myocardium.

Source: Duan W, Yang Y, Yan J, Yu S, Liu J, Zhou J, Zhang J, Jin Z, Yi D. Basic Res Cardiol. 2012;107(3):263. doi: 10.1007/s00395-012-0263-7. Epub 2012 Mar 31.

Curcumin protects against regional myocardial ischemia/reperfusion injury through activation of RISK/GSK-3β and inhibition of p38 MAPK and JNK.

BACKGROUND:

Curcumin, the active ingredient of turmeric (Curcuma longa), is known to have anti-inflammatory and antioxidative properties. The present study was aimed to determine the effect of curcumin in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases and apoptotic kinases.

METHODS:

Sprague-Dawley rats (n = 109) subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion followed by reperfusion were assigned to receive saline (control), curcumin (100 mg/kg), wortmannin (inhibitor of phosphatidylinositol-3-OH kinase [PI3K]-Akt), wortmannin + curcumin, U0126 (inhibitor of extracellular signal-regulated kinase [ERK1/2]), U0126 + curcumin, SB216763 (inhibitor of glycogen synthase kinase [GSK-3β]), and SB216763 + curcumin 20 minutes before LAD occlusion. Infarct size was measured after 2 hours of reperfusion by triphenyl tetrazolium chloride staining. The phosphorylation of Akt, ERK1/2, GSK-3β, p38, and c-Jun N-terminal kinases (JNK) was determined by immunoblotting after 10 minutes of reperfusion.

RESULTS:

Curcumin significantly reduced the infarct size compared with the control (33.1% ± 6.2% vs 50.1% ± 3.9%; P < .05). Wortmannin or U0126 alone did not affect the infarct size but abolished the curcumin-induced cardioprotective effect. Curcumin significantly enhanced the phosphorylation of Akt, ERK1/2, and GSK-3β, while it reduced that of p38 and JNK. Wortmannin or U0126 abolished enhanced phosphorylation of GSK-3β induced by curcumin. SB216763 alone or combined with curcumin reduced the infarct size and enhanced phosphorylation of GSK-3β compared with the control.

CONCLUSIONS:

Preconditioning by curcumin effectively protects against regional myocardial I/R injury through the activation of prosurvival kinases involving PI3K-Akt, ERK1/2, and GSK-3β, and attenuation of p38 and JNK.

Source: Jeong CW, Yoo KY, Lee SH, Jeong HJ, Lee CS, Kim SJ. J Cardiovasc Pharmacol Ther. 2012 Dec;17(4):387-94. doi: 10.1177/1074248412438102.

Curcumin attenuates diet-induced hypercholesterolemia in rats.

BACKGROUND:

Curcumin (a component of turmeric) has long been used as a spice and food-coloring agent. In experimental animals, curcumin has shown anti-diabetic, anti-inflammatory, cytotoxic and anti-oxidant properties.

MATERIAL/METHODS:

The possible hypolipidemic effect of curcumin was investigated in rats fed a high-cholesterol diet (HCD). The lipid profile and activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed in serum, as well as anti-oxidant parameters in liver tissues.

RESULTS:

Feeding the animals a high cholesterol diet (HCD) for 7 consecutive days (1 ml 100 g(-1)) resulted in marked hypercholesterolemia, increased serum level of low-density lipoprotein cholesterol (LDL-C), but a decreased serum high-density lipoprotein cholesterol (HDL-C). Curcumin admixed with the diet (0.5% w/w) decreased serum total cholesterol (TC) by about 21% and LDL-C by 42.5%, but it increased serum HDL by 50%. The atherogenic indices (LDL-C/HDL-C and TC/HDL-C) were reduced by 52% and 35%, respectively. Curcumin also decreased the enzyme activities of serum AST and ALT, which were increased in HCD animals.

CONCLUSIONS:

Curcumin showed an obvious hypocholesterolemic effect that could be due to an effect on cholesterol absorption, degradation or elimination, but not due to an anti-oxidant mechanism. This could be supported by the finding in our study that neither HCD nor curcumin-admixed HCD had any effects on the liver content of glutathione (GSH) or superoxide dismutase (SOD) activity. Thus one could argue that ingestion of curcumin-containing spices in the diet, especially one rich in fats, could have a lipid-lowering effect.

Source: Arafa HM. Med Sci Monit. 2005 Jul;11(7):BR228-234. Epub 2005 Jun 29.

Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B.

Binding of plasma factor VII(a) to tissue factor (TF) initiates the coagulation cascade. In health, TF is not expressed in endothelial cells. However, endothelial cells express TF in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and other biological stimuli. TF expression by endothelial cells is implicated in thrombotic disorders in patients with a variety of clinical disorders. In the present study, we demonstrate that curcumin (diferulolylmethane), a known anticarcinogenic and anti-inflammatory agent, inhibited phorbol 12-myristate 13-acetate (PMA), LPS, TNF alpha, and thrombin-induced TF activity and TF gene transcription in human endothelial cells. The present data show that curcumin prevented the activation of c-Rel/p65, which is essential for TF gene activation in endothelial cells, by impairing the proteolytic degradation inhibitor protein, I kappa B alpha. The data also show that curcumin downregulated AP-1 binding activity. The present studies are the first to demonstrate that PMA, but not LPS, TNF alpha, and thrombin, induced Egr-1 binding to the second serum-responsive region (SRR-2) of TF promoter and that curcumin inhibited the PMA-induced Egr-1 binding to SRR-2. Overall, the data suggest that the anticarcinogenic and anti-inflammatory properties of curcumin may be related to its ability to inhibit cellular gene expression regulated by transcription factors NF-kappa B, AP-1, and Egr-1.

Source: Pendurthi UR, Williams JT, Rao LV. Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3406-13.

For complete study: http://atvb.ahajournals.org/content/17/12/3406.long

 

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro.

Source: Bierhaus A, Zhang Y, Quehenberger P, Luther T, Haase M, Müller M, Mackman N, Ziegler R, Nawroth PP. Thromb Haemost. 1997 Apr;77(4):772-82.

 

Neuroprotective and neurotrophic curcuminoids to treat stroke: a translational perspective.

IMPORTANCE OF THE FIELD:

Curcumin has been investigated in preclinical and translational stroke models because of its pleiotropic 'neuroprotective' activities. Since curcumin has poor blood-brain barrier (BBB) penetration following acute administration, creative medicinal chemistry has been used to modify the parent curcumin molecule, resulting in second generation curcuminoids, which have enhanced BBB penetration, improved pharmacokinetics and interact with multiple viable targets to treat stroke.

AREAS COVERED IN THIS REVIEW:

This review covers epidemiological, preclinical and translational data published between 2002 and 2010.

WHAT THE READER WILL GAIN:

There are two main goals: First, epidemiological data comparing the incidence of stroke in North America to that of India, a country where curcumin is a main-stay of the diet is presented. Second, the pharmacological characteristics of curcuminoids are detailed to determine if they should be further studied in translational stroke models for safety and efficacy prior to initiating clinical trials.

TAKE HOME MESSAGE:

Curcumin and curcuminoids are neuroprotective in a variety of preclinical stroke models. The novel multi-target curcuminoid, CNB-001, has a superior safety and pharmacokinetic profile and should be further developed as an acute monotherapy or to be used in conjunction with thrombolytics for acute ischemic stroke.

Source: Lapchak PA. Expert Opin Investig Drugs. 2011 Jan;20(1):13-22. doi: 10.1517/13543784.2011.542410.

 

The curcuma antioxidants: pharmacological effects and prospects for future clinical use. A review.

In agreement with the predictions of the oxygen-stress theory of aging and age-related degenerative diseases, diet supplementation with a number of phenolic or thiolic antioxidants has been able to increase the life span of laboratory animals, protect against senescent immune decline and preserve the respiratory function of aged mitochondria. In addition to the above, more recent data reviewed here suggest that the polyphenolic compound curcumin and related non-toxic antioxidants from the rhizome of the spice plant Curcuma longa have a favorable effect on experimental mouse tumorigenesis as well as on inflammatory processes such as psoriasis and ethanol-caused hepatic injury. Our own research has focused on the effects of diet supplementation with an antioxidant-rich hydroalcoholic extract of the curcuma rhizome on key risk factors of atherogenesis and related cardiovascular disease. Our reviewed data show that, in human healthy subjects, the daily intake of 200 mg of the above extract results in a decrease in total blood lipid peroxides as well as in HDL and LDL-lipid peroxidation. This anti-atherogenic effect was accompanied by a curcuma antioxidant-induced normalization of the plasma levels of fibrinogen and of the apo B/apo A ratio, that may also decrease the cardiovascular risk. The reviewed literature indicates that curcumin and related plant co-antioxidants are powerful anti-inflammatory agents. Further, since they potentiate the anti-atherogenic effect of alpha-tocopherol, more extensive clinical testing of their probable usefulness in cardiovascular risk reduction seems justified.

Source: Miquel J, Bernd A, Sempere JM, Díaz-Alperi J, Ramírez A. Arch Gerontol Geriatr. 2002 Feb;34(1):37-46.

 

An hydroalcoholic extract of curcuma longa lowers the apo B/apo A ratio. Implications for atherogenesis prevention.

It is generally accepted that free-radical induced blood lipid peroxidation and especially peroxidized LDL play a central role in the pathogenesis of atherosclerosis and related cardiovascular disease. Moreover, recent research highlights the key contribution of apolipoprotein B (apo B) to atherogenesis as the main inductor of one of its earlier steps, i.e. macrophage proliferation. This has led us to investigate the apo B response to a very effective phenolic lipid-antioxidant, namely an hydroalcoholic extract of Curcuma longa, which according to our previous work does not show any toxic effects and decreases the levels of blood lipid peroxides, oxidized lipoproteins and fibrinogen. The present study shows that a daily oral administration of the extract decreases significantly the LDL and apo B and increases the HDL and apo A of healthy subjects. This and recent data on the increased anti-atherogenic action of the physiological antioxidant tocopherol in the presence of phenolic co-antioxidants (which eliminate the tocopheroxyl radical), justifies planned clinical research to test the usefulness of the curcuma extract as a co-antioxidant complement to standard treatments to prevent or retard atherosclerosis.

Source: Ramírez-Boscá A, Soler A, Carrión MA, Díaz-Alperi J, Bernd A, Quintanilla C, Quintanilla Almagro E, Miquel J. Mech Ageing Dev. 2000 Oct 20;119(1-2):41-7.