Probiotics for the Management of Oral Mucositis: An Interpretive Review of Current Evidence.

Mucositis is one of the major side effects of anti-cancer therapies. Mucositis may lead to other abnormalities such as depression, infection, and pain, especially in young patients. Although there is no specific treatment for mucositis, several pharmacological and non-pharmacological options are available to prevent its complications. Probiotics have been recently considered as a preferable protocol to lessen the complications of chemotherapy, including mucositis. Probiotics could affect mucositis by anti-inflammatory and anti-bacterial mechanisms as well as augmenting the overall immune system function. These effects may be mediated through anti microbiota activities, regulating cytokine productions, phagocytosis, stimulating IgA releasement, protection of the epithelial shield, and regulation of immune responses. We have reviewed available literature pertaining to the effects of probiotics on oral mucositis in animal and human studies. While animal studies have reported protective effects of probiotics on oral mucositis, the evidence from human studies is not convincing.

Nutraceuticals and Nutrition Supplements: Challenges and Opportunities.

The term "nutraceuticals" is derived from "nutrition" and "pharmaceuticals" and is used fornutrition products that are also used as medicine [1] [...].

RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling.

Bones as an alive organ consist of about 70% mineral and 30% organic component. About 200 million people are suffering from osteopenia and osteoporosis around the world. There are multiple ways of protecting bone from endogenous and exogenous risk factors. Planned physical activity is another useful way for protecting bone health. It has been investigated that arranged exercise would effectively regulate bone metabolism. Until now, a number of systems have discovered how exercise could help bone health. Previous studies reported different mechanisms of the effect of exercise on bone health by modulation of bone remodeling. However, the regulation of RANKL/RANK/OPG pathway in exercise and physical performance as one of the most important remodeling systems is not considered comprehensive in previous evidence. Therefore, the aim of this review is to clarify exercise influence on bone modeling and remodeling, with a concentration on its role in regulating RANKL/RANK/OPG pathway.

Anti-Atherosclerotic Properties of Wild Rice in Low-Density Lipoprotein Receptor Knockout Mice: The Gut Microbiome, Cytokines, and Metabolomics Study.

BACKGROUND AND AIM: We previously reported the anti-atherogenic properties of wild rice in low-density lipoprotein receptor knockout (LDL-r-KO) mice. The present study aimed to discover the mechanism of action for such effects. MATERIALS: Fecal and plasma samples from the wild rice treated and control mice were used. Fecal bacterial population was estimated while using 16S rDNA technology. The plasma samples were used to estimate the levels of 35 inflammatory markers and metabolomics, while using Meso Scale multiplex assay and liquid chromatography-mass spectrometry (LC-MS/MS) techniques. RESULTS: Many bacteria, particularly Anaeroplasma sp., Acetatifactor sp., and Prophyromonadaceae sp., were found in higher quantities in the feces of wild rice fed mice as compared to the controls. Cytokine profiles were significantly different between the plasma of treated and control mice. Among them, an increase in the level of IL-10 and erythropoietin (EPO) could explain the anti-atherogenic properties of wild rice. Among many metabolites tested in plasma of these animals, surprisingly, we found an approximately 60% increase in the levels of glucose in the wild rice fed mice as compared to that in the control mice. CONCLUSION: Additional studies warrant further investigation of the interplay among gut microbiome, inflammatory status, and macronutrient metabolism.

A carnosine analog with therapeutic potentials in the treatment of disorders related to oxidative stress.

Interactive relationships among metabolism, mitochondrial dysfunction and inflammation at skeletal muscle level play a key role in the pathogenesis of disorders related to oxidative stress. Mitochondrial dysfunction and oxidative stress result in cellular energy deficiency, inflammation and cell death inducing a vicious cycle that promotes muscle wasting. The histidine-containing dipeptides, carnosine and anserine, are carbonyl scavengers whose cytoprotective contributions extend beyond the antioxidant defence, but the physiological meaning of these capacities is actually limited. In the present study, we compared and investigated the potential protective effects of three different histidine-containing dipeptides: carnosine, anserine and carnosinol, a carnosine-mimetic new compound, against oxidative stress induction in rat L6 skeletal muscle cells. The hydrogen peroxide induced-oxidative stress significantly altered cell morphology, induced apoptosis, oxidative stress and inflammation, decreased mitochondrial peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)/sirtuin3 pathway and the antioxidant system. Notably, all three investigated dipeptides in the present study, with a different extent and in a concentration-dependent manner, reduced myotube oxidative stress, apoptosis and inflammation. The present study underlined that carnosinol, maintaining the safety condition of carnosine and anserine, was the more efficient studied dipeptide in the preservation of mitochondrial environment mediated by PGC-1α and sirtuin3 expression and thereby in the reduction of oxidative stress-related alterations in this in vitro skeletal muscle model. Furthermore, we observed that carnosinol's antioxidant effects are not blocked inhibiting sirtuin3, but are maintained with almost the same extend, indicating its multiple capacities of reactive carbonyl species-scavenging and of mitochondrial modulation through PGC-1α. In conclusion, carnosinol retained and surpassed the efficacy of the well-known investigated histidine-containing dipeptides improving oxidative stress, inflammation and also cell metabolism and so becoming a greatly promising therapeutic carnosine derivate.

Germinated Brown Rice Attenuates Atherosclerosis and Vascular Inflammation in Low-Density Lipoprotein Receptor-Knockout Mice.

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p < 0.05); all diets contained 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, or glucose, or the activities of antioxidant enzymes, compared to the control diet. The adhesion of monocytes to aortas from LDLr-KO mice fed with WR diet was significantly more than that from mice receiving the control diet ( p < 0.01). GBR diet decreased monocyte adhesion to aortas compared to WR diet ( p < 0.01). GBR diet also reduced the levels of plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in plasma, and the abundances of MCP-1, PAI-1, TNF-α, intracellular cell adhesion molecule-1, toll-like receptor-4, PAI-1, LDLr-like protein, and urokinase plasminogen activator and its receptor in aortas or hearts from LDLr-KO mice in comparison to the WR diet ( p < 0.05, 0.01, respectively). The findings suggest that GBR administration attenuated atherosclerosis and vascular inflammation in LDLr-KO mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

Melatonin Modulation of Sirtuin-1 Attenuates Liver Injury in a Hypercholesterolemic Mouse Model.

Hypercholesterolemia increases and exacerbates stress signals leading also to liver damage (LD) and failure. Sirtuin1 (SIRT1) is involved in lifespan extension and it plays an essential role in hepatic lipid metabolism. However, its involvement in liver hypercholesterolemic damage is not yet completely defined. This in vivo study evaluated the role of SIRT1 in the hypercholesterolemic-related LD and, then, investigated how oral supplementation of melatonin, pleiotropic indoleamine, may be protective. Control mice and apolipoprotein E-deficient mice (ApoE-/-) of 6 and 15 weeks of age were treated or not treated with melatonin at the dose of 10 mg/kg/day for 9 weeks. In this study, we evaluated serum biochemical markers, liver SIRT1 expression, and oxidative stress markers. We observed that hypercholesterolemia increased significantly serum cholesterol and triglycerides, reduced significantly liver SIRT1, and, in turn, induced hepatic oxidative stress in untreated ApoE-/- mice with respect to control mice. Interestingly, melatonin treatment improved serum biochemical markers and hepatic morphological impairment and inhibited oxidative stress through its antioxidant properties and also by SIRT1 upregulation. In summary, melatonin oral supplementation may represent a new protective approach to block hypercholesterolemic liver alterations involving also a SIRT1-dependent mechanism.

Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation.

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7ßHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options.

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

Reduced monocyte adhesion to aortae of diabetic plasminogen activator inhibitor-1 knockout mice.

OBJECTIVE AND DESIGN: To determine the requirement of plasminogen activator inhibitor-1-knockout (PAI-1) for monocyte adhesion in animals and cells under diabetic conditions. METHODS AND SUBJECTS: Monocyte adhesion assay, enzyme-linked immunosorbent assay, and Western blotting were used in analyzing samples from PAI-1-knockout (PAI-1-KO) mice or cultured human umbilical vein endothelial cells (HUVEC). TREATMENTS: Diabetes in PAI-1-KO and wild-type mice was induced by intraperitoneal injection of streptozotocin (STZ). HUVEC was transfected with short interference RNA (siRNA) against PAI-1, tumor necrosis factor-α (TNFα), or toll-like receptor (TLR4), and then was treated with glycated low-density lipoproteins (glyLDL). RESULTS: The adhesion of monocytes to aortic intima was reduced in PAI-1-KO mice, which was associated with decreased levels of TNFα and monocyte chemotactic protein-1 (MCP-1) in plasma and cardiovascular tissue, and increased abundances of urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in cardiovascular tissue compared to wild-type mice. Significant reductions in monocyte adhesion, inflammatory, and fibrinolytic regulators were detected in cardiovascular tissue or plasma in diabetic PAI-1-KO mice compared to wild-type diabetic mice. Transfection of PAI-1, TNFα or TLR4 siRNA to HUVEC inhibited glyLDL-induced monocyte adhesion to EC. PAI-1 siRNA inhibited the abundances of TLR4 and TNFα in EC. CONCLUSION: The findings suggest that PAI-1 is required for diabetes-induced monocyte adhesion via interactions with uPA/uPAR, and it also regulates TLR4 and TNFα expression in vascular EC. Inhibition of PAI-1 potentially reduces vascular inflammation under diabetic condition.

Dietary corn fractions reduce atherogenesis in low-density lipoprotein receptor knockout mice.

Accumulating evidence has suggested that intake of whole grains is a protective factor against pathogenesis of coronary artery disease. The exact mechanisms, however, are still not clearly understood. In this study, we hypothesized that adequate intake of corn fractions (aleurone, endosperm and germ) can modify lipid profiles in relation to atherosclerotic lesion development in low-density lipoprotein receptor knockout (LDLr-KO) mice. The purpose of the present study was to investigate the potential cardiovascular benefits of corn fractions in LDLr-KO mice through a number of biomarkers including lipid profile, and morphologic and morphometrical analysis of atherosclerotic lesions in aortic root. Four groups of male LDLr-KO mice were fed with the experimental diets supplemented with (3 treated) or without (control) 5% (wt/wt) of each of corn fractions for 10 weeks. All diets were supplemented with 0.06% (wt/wt) cholesterol. Compared with mice in the control group, atherosclerotic lesions in the aortic roots were significantly reduced (P=.003) in the mice that were fed diet supplemented with aleurone and germ fractions. This effect was associated with significant reductions in plasma total (P=.02) and LDL (P=.03) cholesterol levels, and an increase in fecal cholesterol excretion (P=.04). Furthermore, abdominal fat mass was significantly reduced by consumption of aleurone (P=.03). In summary, the consumption of aleurone and germ may help attenuate atherosclerosis by reducing plasma total and LDL cholesterol levels.

Melatonin: Protection against age-related cardiac pathology.

Aging is a complex and progressive process that involves physiological and metabolic deterioration in every organ and system. Cardiovascular diseases are one of the most common causes of mortality and morbidity among elderly subjects worldwide. Most age-related cardiovascular disorders can be influenced by modifiable behaviours such as a healthy diet rich in fruit and vegetables, avoidance of smoking, increased physical activity and reduced stress. The role of diet in prevention of various disorders is a well-established factor, which has an even more important role in the geriatric population. Melatonin, an indoleamine with multiple actions including antioxidant properties, has been identified in a very large number of plant species, including edible plant products and medical herbs. Among products where melatonin has been identified include wine, olive oil, tomato, beer, and others. Interestingly, consumed melatonin in plant foods or melatonin supplementation may promote health benefits by virtue of its multiple properties and it may counteract pathological conditions also related to cardiovascular disorders, carcinogenesis, neurological diseases and aging. In the present review, we summarized melatonin effects against age-related cardiac alterations and abnormalities with a special focus on heart ischemia/reperfusion (IR) injury and myocardial infarction.

Combination effects of wild rice and phytosterols on prevention of atherosclerosis in LDL receptor knockout mice.

Dietary modifications including healthy eating constitute one of the first line strategies for prevention and treatment of atherosclerotic cardiovascular diseases (CVD), including atherosclerosis. In this study, we assessed anti-atherogenic effects of a combination of wild rice and phytosterols in low-density lipoprotein receptor knockout (LDL-r-KO) mice. Male LDL-r-KO mice were divided into four groups and fed with: (1) control diet; (2) the control diet containing 60% (w/w) wild rice; (3) the control diet containing 2% (w/w) phytosterols; or (4) the control diet containing both wild rice and phytosterols for 20weeks. All diets were supplemented with 0.06% (w/w) dietary cholesterol. Blood samples, hearts, and feces were collected and used for biochemical and histological examination. Consumption of 60% (w/w) wild rice in combination with 2% (w/w) phytosterols significantly reduced the size and severity of atherosclerotic lesions in the aortic roots as compared to those in the control group. This effect was associated with significant reductions in plasma total, LDL and VLDL cholesterol concentrations as well as an increase in fecal cholesterol excretion. In conclusion, the dietary combination of wild rice and phytosterols prevents atherogenesis in this animal model. Further investigations are needed to understand mechanisms of action and potential clinical outcome of such dietary intervention.

Cardiovascular benefits of probiotics: a review of experimental and clinical studies.

The microbiota inhabiting the human gastro-intestinal tract is reported to have a significant impact on the health of an individual. Recent findings suggest that the microbial imbalance of the gut may play a role in pathogenesis of cardiovascular diseases (CVD). Therefore, several studies have delved into the aspect of altering gut microbiota with probiotics as an approach to prevent and/or treat CVD. The World Health Organization defines probiotics as live microorganisms that, when consumed in adequate amounts, have a positive influence on the individual's health. The present review focuses on strategies of human dietary intervention with probiotic strains and their impact on cardiovascular risk factors like hypercholesterolemia, hypertension, obesity and type-2 diabetes. Accumulating evidence shows probiotics to lower low density lipoproteins (LDL)-cholesterol and improve the LDL/high density lipoproteins (HDL) ratio, as well as lower blood pressure, inflammatory mediators, blood glucose levels and body mass index. Thus, probiotics have the scope to be developed as dietary supplements with potential cardiovascular health benefits. However, there is not only ambiguity regarding the exact strains and dosages of the probiotics that will bring about positive health effects, but also factors like immunity and genetics of the individual that might influence the efficacy of probiotics. Therefore, further studies are required not only to understand the mechanisms by which probiotics may beneficially affect the cardiovascular system, but also to rule out any of their probable negative effects on health. The present review aims to critically appraise the complexity of the available data with regard to the cardiovascular benefits of probiotics.

Antioxidant properties of diverse cereal grains: A review on in vitro and in vivo studies.

Cereal grains and products have gained popularity in contributing to healthy eating behavior because of their antioxidant properties associated with protection against chronic diseases. In this review, notable studies on the in vitro and in vivo antioxidant activity of commonly consumed cereal grains are summarized. Cereals contain phytochemicals or certain minor components with antioxidant properties. The antioxidant potential of cereals depends on their bioaccessibility, absorption in the gastrointestinal and their bioavailability utilization in vivo. The in vitro gastrointestinal digestion and fermentation of cereals increased their antioxidant potentials which are significantly correlated with their total phenolic contents. Most studies performed in vivo have been concerned with the antioxidant properties of colored rice, wheat bran and rye products. There are inadequate in vitro and in vivo studies on antioxidative potentials of fermented versus unfermented cereals. Therefore, further studies are necessary to maximize possible health benefits of cereal antioxidative phytochemicals.

The Role of Dietary Cholesterol in Lipoprotein Metabolism and Related Metabolic Abnormalities: A Mini-review.

Cholesterol plays a vital role in cell biology. Dietary cholesterol or "exogenous" cholesterol accounts for approximately one-third of the pooled body cholesterol, and the remaining 70% is synthesized in the body (endogenous cholesterol). Increased dietary cholesterol intake may result in increased serum cholesterol in some individuals, while other subjects may not respond to dietary cholesterol. However, diet-increased serum cholesterol levels do not increase the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, nor do they decrease the size of LDL particles or HDL cholesterol levels. Elevated levels of LDL cholesterol, reduced HDL cholesterol levels, and small, dense LDL particles are independent risk factors for coronary artery disease. Dietary cholesterol is the primary approach for treatment of conditions such as the Smith-Lemli-Opitz syndrome. Recent studies have highlighted mechanisms for absorption of dietary cholesterol. These studies have help understand how dietary and/or pharmaceutical agents inhibit cholesterol absorption and thereby reduce LDL cholesterol concentrations. In this article, various aspects of cholesterol metabolism, including dietary sources, absorption, and abnormalities in cholesterol metabolism, have been summarized and discussed.

Endoplasmic reticulum stress in diabetic mouse or glycated LDL-treated endothelial cells: protective effect of Saskatoon berry powder and cyanidin glycans.

Endoplasmic reticulum (ER) stress is associated with insulin resistance and diabetic cardiovascular complications, and mechanism or remedy for ER stress remains to be determined. The results of the present study demonstrated that the levels of ER stress or unfolded protein response (UPR) markers, the intensity of thioflavin T (ThT) fluorescence and the abundances of GRP78/94, XBP-1 and CHOP proteins were elevated in cardiovascular tissue of diabetic leptin receptor-deficient (db/db) mice. Cyanidin-3-glucoside (C3G) and cyanidin-3-galactoside (C3Ga) are major anthocyanins in Saskatoon berry (SB) powder. The administration of 5% SB powder for 4 weeks attenuated ThT fluorescence and the UPR markers in hearts and aortae of wild-type and db/db mice. Treatment with glycated low-density lipoprotein (gLDL) increased ThT intensity in human umbilical vein endothelial cells (ECs). Elevated UPR markers were detected in gLDL-treated EC compared to control cultures. The involvement of ER stress in gLDL-treated EC was supported by that the addition of 4-phenyl butyrate acid (a known ER stress antagonist) inhibited gLDL-induced increases in ER stress or UPR markers. C3G at 30 µM or C3Ga at 100 µM reached their maximal inhibition on gLDL-induced increases in ThT, GRP78/94, XBP-1 and CHOP in EC. The results demonstrated that ER stress was enhanced in cardiovascular tissue of db/db mice or gLDL-treated EC. SB powder or cyanidin glycans prevented the abnormal increases in ER stress and UPR markers in cardiovascular tissue of diabetic db/db mice or gLDL-treated EC.

Use of Animal Models in Plant Sterol and Stanol Research.

Cholesterol-lowering properties of plant sterols were reported approximately six decades ago. However, over the past couple of decades we have learnt more about other cardiovascular benefits of regular consumption of plant sterols and/or plant stanols. In particular a series of animal studies has consistently reported that dietary plant sterols and/or plant stanols or their fatty acid esters can reduce atherogenesis to a different extent in different animal models. Such effects may be mediated not only through reductions in LDL cholesterol levels, but also through other mechanisms including anti-inflammatory effects. In this manuscript, various animal models including mice, rabbits, hamsters, and others which have been used to establish cardiovascular benefits of plant sterols are discussed.

Carotenoids of aleurone, germ, and endosperm fractions of barley, corn and wheat differentially inhibit oxidative stress.

The antioxidant potential of carotenoids from aleurone, germ, and endosperm fractions of barley, corn, and wheat has been evaluated. HPLC analysis confirmed the presence of lutein and zeaxanthin carotenoids (nd-15139 µg/kg) in extracts of cereal grain fractions. The antioxidant properties using 2,2-diphenyl-1-picrylhydrazyl, oxygen radical absorbance capacity, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays revealed significantly higher (P<0.001) antioxidant activity in the germ than in the aleurone and endosperm fractions. Using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, 2,2'azobis (2-amidinopropane)dihydrochloride (AAPH)-induced cell loss was effectively reduced by preincubating Caco-2, HT-29, and FHs 74 Int cells with carotenoid extracts. Moreover, carotenoid extracts reduced (P<0.001) AAPH-induced intracellular oxidation in the cell lines, suggesting antioxidant activity. Of the 84 antioxidant pathway genes included in microarray array analysis (HT-29 cells), the expressions of 28 genes were enhanced (P<0.05). Our findings suggest that carotenoids of germ, aleurone, and endosperm fractions improved antioxidant capacity and thus have the potential to mitigate oxidative stress.

Practical strategies for modulating foam cell formation and behavior.

Although high density lipoprotein (HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modulating HDL cholesterol levels lower cardiovascular risk only to the extent that they concurrently decrease low density lipoprotein (LDL) cholesterol. This corresponds well with findings of a recent Mendelian randomization analysis, in which genetic polymorphisms associated with HDL cholesterol but no other known cardiovascular risk factors failed to predict risk for myocardial infarction. Although it is still seems appropriate to search for therapies that could improve the efficiency with which HDL particles induce reverse cholesterol transport, targeting HDL cholesterol levels per se with current measures appears to be futile. It may therefore be more promising to promote reverse cholesterol transport with agents that directly target foam cells. Macrophage expression of the cholesterol transport proteins adenosine triphosphate binding cassette transporter A1, adenosine triphosphate binding cassette transporter G1, and scavenger receptor class B member 1 is transcriptionally up-regulated by activated liver X receptors (LXR), whereas nuclear factor (NF)-kappaB antagonizes their expression. Taurine, which inhibits atherogenesis in rodent studies, has just been discovered to act as a weak agonist for LXRalpha. Conversely, it may be possible to oppose NF-kappaB activation in macrophages with a range of measures. Induction of heme oxygenase-1, which can be attained with phase 2 inducer phytochemicals such as lipoic acid and green tea catechins, promotes reverse cholesterol transport in macrophages and inhibits atherogenesis in rodents, likely due to, in large part, NF-kappaB antagonism. Inhibition of macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity with the spirulina-derived bilirubin-mimetic phycocyanobilin may also oppose NF-kappaB activation, and salicylic acid similarly should be useful for this purpose. The 5' adenosine monophosphate-activated protein kinase activator berberine promotes macrophage reverse cholesterol transport in cell culture; metformin probably shares this property. Many of these measures could also be expected to promote plaque stability by suppressing foam cell production of inflammatory cytokines and matrix metalloproteinases, and to reduce intimal monocyte infiltration by anti-inflammatory effects on vascular endothelium. Direct targeting of foam cells with agents such as phase 2 inducers, spirulina, salicylate, taurine, and berberine or metformin, may hence have considerable potential for preventing and reversing atheroma, and for preventing the plaque rupture that triggers vascular thrombosis.