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Polyphenols of apples and their potential health benefits
Abstract
Based on the per capita consumption, apples are found to be one of the best sourcesof dietary polyphenols in the North American and European diet. The polyphenols foundin apples are relatively effective antioxidants and demonstrated to have numerous ofbiological effects in prevention of various chronic diseases including cardiovasculardisease, cancers and neurodegenerative diseases. Apples contain over 60 differentphenolic compounds which mainly belong to flavonoids, cinnamic and benzoic acidderivatives. The apple flavonoids are mainly 3-hydroxy flavonoids which consist ofanthocyanins, flavan-3-ols, procyanidins, and flavonols. Dihydrochalcones such asphloridzin are unique and predominant flavonoid precursors found in apples. Thedistribution and concentration of polyphenols vary greatly within the apple fruit as wellas among apple cultivars. Apple peels have higher levels of polyphenols than flesh orcore and also abundant in flavonoids such as quercetin glycosides and cyanidingalactoside. The flesh and core have relatively high concentrations of chlorogenic acid.There are many environmental factors that influence the accumulation of polyphenols inapples such as exposure to ultra-violet light, climate conditions and soil conditions suchas nitrogen supply. While extensive research exists on the health benefits of applepolyphenols, this chapter focuses on the most recent literature regarding the applepolyphenols and their health benefits associated with cardiovascular disease, type IIdiabetes, and various cancers.
... There are five major phenolic groups in apples. These include flavonols, flavanols, anthocyanins, hydroxycinnamic acids, and dihydrochalcones, but hydroxycinnamic acids and flavonoids are among the most abundant [19]. A serving of one medium apple (200 g) provides around 400 mg of total polyphenols expressed as gallic acid equivalents (GAE) [20]. ...
... Therefore, phytochemicals such as polyphenolic compounds present in apple juice can mainly contribute to its antioxidant activity. Procyanidins can contribute to more than 80% of the antioxidant capacity in apples and apple products like juices due to their abundance [19]. A procyanidin-rich apple juice extract recorded the highest antioxidant capacity followed by a hydroxycinnamic acid–rich apple juice extract as measured by trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) assays [29]. ...
... A procyanidin-rich apple juice extract recorded the highest antioxidant capacity followed by a hydroxycinnamic acid–rich apple juice extract as measured by trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC) assays [29]. Hydroxycinnamic acid was abundant in flesh compared to peel and can contribute to the antioxidant capacity of apple juices [19]. Not only fresh juice but also six commercial apple juices tested at a level of 5 µmol GAE/L inhibited oxidation of human low-density lipoprotein (LDL) at a range of 9%–34% [30]. ...
... In terms of apple production, China is currently the largest apple producer in the world, with apple planting area and output accounting for more than 50% of the world (Li et al., 2021). In addition to their economic value, apples play an important role in preventing diseases, such as Parkinson's disease and all kinds of cancer, as well as reducing the risk of diabetes and lowering cholesterol (Rupasinghe, Thilakarathna & Nair, 2013). Therefore, the improvement of apple varieties and cultivation of new varieties is particularly important. ...
Background
Apple is one of the most important temperate deciduous fruit trees worldwide, with a wide range of cultivation. In this study, we assessed the variations and phylogenetic relationships between the complete chloroplast genomes of wild and cultivated apples ( Malus spp.).
Method
We obtained the complete chloroplast genomes of 24 apple varieties using next-generation sequencing technology and compared them with genomes of (downloaded from NCBI) the wild species.
Result
The chloroplast genome of Malus is highly conserved, with a genome length of 160,067–160,290 bp, and all have a double-stranded circular tetrad structure. The gene content and sequences of genomes of wild species and cultivated apple were almost the same, but several mutation hotspot regions ( psb I- atp A, psb M- psb D, and ndh C- atp E) were detected in these genomes. These regions can provide valuable information for solving specific molecular markers in taxonomic research. Phylogenetic analysis revealed that Malus formed a new clade and four cultivated varieties clustered into a branch with M. sylvestris and M. sieversii , which indicated that M. sylvestris and M. sieversii were the ancestor species of the cultivated apple.
... One fruit that is a rich and important source of bioactive phytochemicals in Western diets is the apple [46][47][48][49]. Apples are globally consumed due to their year-round availability, their cultivar diversity, low price, and easy storage [46,50]. ...
Cancer is one of the leading causes of death globally. Epidemiological studies have strongly linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows that secondary plant metabolites known as phytochemicals, which are commonly found in fruits, have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide that is available all year round and is a rich source of phytochemicals. In this review, we summarize the association of apple consumption with cancer incidence based on findings from epidemiological and cohort studies. We further provide a comprehensive review of the main phytochemical patterns observed in apples and their bioavailability after consumption. Finally, we report on the latest findings from in vitro and in vivo studies highlighting some of the key molecular mechanisms targeted by apple phytochemicals in relation to inhibiting multiple ‘hallmarks of cancer’ that are important in the progression of cancer.
... Three stages in the life span of fruits and vegetables are maturation, ripening, and senescence. Maturation is indicative edible part of fully developed fruit which becomes physiologically capable of ripening on its own even though fruit is ready for harvest although it may not be ready for immediate consumption (Rupasinghe et al., 2012). When a fruit is capable of further development or ripening when it is harvested i.e. ready for eating or processing termed as physiological maturity while when plant and plant part possesses pre requisites for use for a particular purpose i.e. ready for harvest termed as horticultural maturity (Kader, 2005). ...
Existing post harvest handling techniques for apple fruits in Nepalese context are well documented
... M. domestica is extremely rich in polyphenols which are responsible for the main health benefits of the apple. Apple polyphenols have shown the capacity to reduce lipid oxidation [21] and possess strong antioxidant activity. [22] Potential antidiabetic effects of M. domestica have been suggested based on the α-amylase inhibitory activity of M. domestica methanolic extract in in vitro studies, while a strong hypoglycemic effect of apple cider vinegar has been documented on STZ-induced diabetic mice with profound effects on reduction of serum amylase concentrations and blood glucose concentration in glucose tolerance test [23,24]. ...
Background
The Mediterranean diet is a healthy eating pattern that protects against the development of Type 2 diabetes mellitus (T2DM), a metabolic disease characterized by elevated blood sugar levels due to pancreatic beta-cell functional impairment and insulin resistance in various tissues. Inspired by the ancient communities this diet emphasizes eating primarily plant-based foods, including vegetables, legumes, fruits, cereals, and nuts. Importantly, virgin olive oil is used as the principal source of fat. Red meat is consumed in low amounts while wine and fish are consumed moderately.
Objective
Here, we review the most beneficial components of the Mediterranean Diet and tentative mechanisms of action for prevention and/or management of T2DM, based on research conducted within the last decade.
Methods
The references over last five years have been reviewed and they have been selected properly according to inclusion/ exclusion criteria.
Results
Several bioactive diet components were evaluated to prevent inflammation and cytokine-induced oxidative damage, reduce glucose concentration, carbohydrate absorption and increase insulin sensitivity and related gene expression.
Conclusion
The adherence to a healthy lifestyle, including diet, exercise and habits remains the best approach for the prevention of diabetes as well as frequent check-ups and education. Though diabetes has a strong genetic component, in recent years many reports strongly point to the critical role of lifestyle specific epigenetic modifications in the development of T2DM. It remains to be established how different components of the Mediterranean Diet interact and influence the epigenetic landscape to prevent or treat the disease.
... Fruits harvested before they mature will be small, sour, starchy taste, poor color and tough texture, low sugars, may not ripen properly, lack flavor and susceptible to storage disorders while too late may be overripe (Kader, 1983). Maturation is indicative edible part of fully developed fruit which becomes physiologically capable of ripening on its own even though fruit is ready for harvest although it may not be ready for immediate consumption (Rupasinghe et al., 2012). When a fruit is capable of further development or ripening when it is harvested i.e. ready for eating or processing termed as physiological maturity while when plant and plant part possesses pre-requisites for use for a particular purpose i.e. ready for harvest termed as horticultural maturity (Kader, 2005). ...
Set of experiments were conducted at Horticulture Research Station (HRS), Rajikot, Jumla (2,390 m asl) from 2011-2014 to assess current production, postharvest handling, processing and marketing situation of apple; to evaluate spur type apple cultivars; to identify appropriate cushioning materials for packaging and transportation of apple from production site to collection centre and to identify appropriate packaging container and packaging method for transportation of apple from Jumla to Nepalgunj.
For production system and market assessment, primary data were collected by focus group discussion (FGD) and direct field observations while secondary data were collected from the publications of various organizations. Area covered by bearing apple trees was 409 ha with total production and productivity of 3,500 mt and 8.6 mt/ha, respectively. Out of total production, 43 %, 14 % and 12 % have been used for local consumption, export and processing, respectively whereas 31 % fruits were lost due to decay. The study revealed that about 40 % of the fruit loss occurred during harvesting and postharvest handling practices. Farm gate price in Jumla and retail price at Nepalgunj market was NRs. 20 and NRs. 140, respectively. One of the reasons for greater variation in farm gate and retail price might be due to compensation of higher transportation losses. Limiting factors for quality production and marketing of apple were lack of regular bearing cultivars, poor orchard management practices, incidence of various pest and diseases, scattered production pockets, inadequate transportation and storage facilities, inappropriate handling and improper packaging.
Germplasm of twenty-five spur type apple cultivars introduced from India and Canada were evaluated at HRS, Rajikot, Jumla in a randomized complete block design (RCBD) with 3 replications for Canadian and 7 replications for Indian cultivars. Among them, Starkrimson Delicious was found superior after 3 years of planting in terms of tree growth and vigor (273 cm height, 80 mm girth diameter, 3.2 m canopy diameter), maturity (early), fruit size (78 mm), fruit weight (192 g) and TSS/TA ratio (66).
Five different cushioning materials (woolen shawl, Himalayan foundation grass, news paper, plastic and control) with three apple cultivars were evaluated in a factorial completely randomized design (CRD) with four replications. The result revealed that packaging of fruits in conical bamboo baskets lining with green Himalayan foundation grass or woolen shawl were found the most efficacious, low cost and easily available cushioning materials to reduce bruising and scratching damage for packaging and transportation from orchard to collection center. Postharvest loss in treatment without cushioning material was 24.0 % which was reduced to 11.3 % in treatment with green Himalayan foundation grass cushioning material. Fruits of Red Delicious cultivar had minimum damage during transportation (13.3 %), less physiological weight loss (11.4 %), lesser spoilage (10.1 %) and higher sensory rating (4.8) three months after storage under ambient condition (11.8±3.80 C and 65 % RH) at HRS, Rajikot, Jumla, thus could be recommended for long term storage. Besides having highest firmness (5.9 kg/cm2) for Golden Delicious, they were less preferred by the consumers because of more sensitive to damage during transportation and more shrivelling of fruits during storage. No significant variation was observed in TSS, TA, juice content, TSS/TA ratio and starch index with cushioning materials. However, TSS, TSS/TA ratio, starch index increased, while TA, firmness and juice content decreased with storage period in all treatments.
Similarly, eight different CFB boxes (5 plies CFB boxes having 140 psi, 160 psi, 180 psi bursting strength; 7 plies CFB boxes having 140 psi, 160 psi, 180 psi bursting strength; 7 plies CFB box recommended by Fruit Development Directorate and 3 plies Beer carton) were evaluated in completely randomized design (CRD) with 3 replications. The result revealed that CFB box of 10 kg capacity having 7 plies 180 psi bursting strength was identified as most appropriate container for packaging and transportation of Red Delicious apple fruits from production site to distant markets (318 km). Postharvest loss in 3 plies Beer cartons was 20.0 % which was reduced to 5.5 % in 7 plies 180 psi CFB boxes. Economic analysis revealed that additional benefit of NRs. 70,625 per truckload could be obtained in 7 plies 180 psi CFB boxes as compared to 3 plies Beer cartons.
Likewise, sixteen different packaging methods (wrapping or without wrapping of individual fruit with Styrofoam, separation or without separation of layers with deck plate, trimming or without trimming of stalk, with or without ventilation on CFB box) were evaluated in a factorial completely randomized design (CRD) with 3 replications. Wrapping of stalk trimmed individual fruits with Styrofoam in ventilated CFB box separated in layers with deck plate was found best method for packaging and transportation apples from production site to distant markets. Postharvest loss in conventional packaging method was 18.2 % which was reduced to 3.8 % in improved packaging method. Economic analysis revealed that additional benefit of NRs. 95,250 per truckload was obtained in improved packaging method (deck plate separation, trimming of stalk, wrapping of individual fruit and ventilations on CFB boxes) as compared to traditional packaging.
... The liver metabolites can be transported to targeted cells and tissues, excreted to bile and undergo enterohepatic re-circulation, or eliminated via urine and/or feces. The aglycones or flavonoid metabolites that reach the colon can undergo microbial degradation and reabsorption (LPH: lactase-phlorizin hydrolase; adapted from [43] with modifications). ...
Flavonoids are a group of phytochemicals that have shown numerous health effects and have therefore been studied extensively. Of the six common food flavonoid classes, flavonols are distributed ubiquitously among different plant foods whereas appreciable amounts of isoflavones are found in leguminous plant-based foods. Flavonoids have shown promising health promoting effects in human cell culture, experimental animal and human clinical studies. They have shown antioxidant, hypocholesterolemic, anti-inflammatory effects as well as ability to modulate cell signaling and gene expression related disease development. Low bioavailability of flavonoids has been a concern as it can limit or even hinder their health effects. Therefore, attempts to improve their bioavailability in order to improve the efficacy of flavonoids are being studied. Further investigations on bioavailability are warranted as it is a determining factor for flavonoid biological activity.
Aging is a complicated biological process in which functional and structural alterations in a living organism take place over time. Reactive oxygen species is one of the main factors responsible for aging and is associated with several chronic pathologies. The relationship between aging and diet is quite interesting and has attained worldwide attention. Healthy food, in addition to dietary antioxidants, are required to delay the process of aging and improve the quality of life. Many healthy foods such as fruits are a good source of dietary nutrients and natural bioactive compounds which have antioxidant properties and are involved in preventing aging and other age-related disorders. Health benefits linked with healthy consumption of fruit have drawn increased interest. A significant number of studies have documented the advantages of fruit intake, as it suppresses free-radical development that further reduces the oxidative stress created in the body and protects against several types of diseases such as cancer, type 2 diabetes, inflammatory disorders, and other cardiovascular diseases that ultimately prevent aging. In addition, fruits have numerous other properties like anti-inflammatory, anti-cancerous, anti-diabetic, neuroprotective, and have health-promoting effects. Mechanisms of various bioactive compounds that aids in preventing various diseases and increases longevity are also described. This manuscript provides a summary of various bioactive components present in fruits along with their health-promoting and antiaging properties.
Seven selected microbial metabolites of proanthocyanidins (MMP), 3-phenylpropionic, 4-hydroxyphenyl acetic, 3-(4-hydroxyphenyl) propionic, ρ-coumaric, benzoic acid, pyrogallol (PG), and pyrocatechol (PC) were evaluated for their ability to reduce chemical carcinogen-induced toxicity in human lung epithelial cells (BEAS-2B) and human fetal hepatic cells (WRL-68). Cells pre-treated with MMP were exposed to a known chemical carcinogen, 4-[(acetoxymethyl) nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) to assess MMP-mediated cytoprotection and reduction of DNA damage. PG in BEAS-2B and PC in WRL-68 cells mitigated the NNKOAc-induced cytotoxicity. Pre-incubation of PG depicted significant protection against NNKOAc-induced DNA damage in BEAS-2B cells. PC in WRL-68 cells showed similar activity. To understand the mechanisms of PG- and PC-mediated DNA damage reduction, the effect on DNA damage response (DDR) proteins, cellular reactive oxygen species (ROS), total antioxidant capacity (TAC), glutathione peroxidase (GPx), and caspase activity were studied. PG and PC alter the DDR and may promote ATR-Chk1 and ATM-Chk2 pathways, respectively. Cellular oxidative stress induced by NNKOAc was mitigated by PG and PC through enhanced GPx expression and TAC. PG and PC suppressed the activation of the extrinsic apoptotic pathway (caspase 3 and 8) provoked by NNKOAc. MMP are beneficial in chemoprevention by reducing cellular DNA damage.
The process of winemaking is the result of biochemical transformations brought about by the action of several enzymes from various microorganisms, including yeasts, especially Saccharomyces cerevisiae, resulting in alcoholic fermentation producing ethanol as the main ingredient of alcoholic beverages like wines. Lactic acid bacteria also play a very significant role in carrying out a secondary process, known as malolactic fermentation, though most bacteria are involved in the spoilage of wines, as is the case with acetic acid bacteria. Furthermore, the fruit must is also exposed to numerous enzymes originating from sources other than yeasts and bacteria that contribute to the reactions involved in winemaking. Most wines are produced from grapes, but fruits other than grapes are also used to produce wines. In recent years, however, nongrape fruit wines have been gaining consumer interest mainly due to the scientific evidence of various health benefits of habitual consumption of a wide variety of fruits and their products. The emerging fruit wines include those of blueberries, blackberries, strawberries, and cherries. The focus of this chapter is to provide a review of the chemistry behind fruit wine manufacturing; discuss the nutritional composition, antioxidant capacity, and biological activity of these wines; and compare their composition with that of traditional grape wines. In general, fruit wines are a good dietary source of minerals, such as potassium, calcium, and phosphorus; antioxidants and phytonutrients, such as carotenoids (carotene and lutein); and phenolic compounds (anthocyanins, flavonols, flavan-3-ols, proanthocyanidins, ellagitannins, and phenolic acids). In contrast to traditional red wines, limited studies have been conducted on human health benefits of fruit wines, and thereby in-depth investigations using human clinical trials are needed to better understand the potential health benefits of specific fruit wines. In discussing the chemistry, the significance of chemical reactions in winemaking is included, with illustrative pathways.
Les pommes sont considérées comme bénéfiques pour la santé, de part leur teneur en polyphénols qui leur confèrent l’étiquette "d’aliment santé". Les procédés de transformation agroalimentaire des fruits et légumes génèrent des coproduits qui sont considérés comme sans valeur par les industriels. Or, au regard des volumes générés, ce sont des sources abondantes de nutriments.Une voie possible de valorisation de ces coproduits est la réintroduction dans des produits alimentaires en tant qu’ingrédient, de façon à proposer des aliments enrichis en molécules fonctionnelles. Pour ce faire, deux voies ont été explorées: l’utilisation de poudres d’épidermes de pommes pour stabiliser une émulsion et l’extraction des polyphénols au moyen de la technologie à base de CO2 supercritique. Ce travail examine également des solutions pour remédier au problème de brunissement enzymatique, comme le traitement thermique et l’addition de poudres de fruits naturellement riches en agents antibrunissement.Les phases de préparation des pommes sont de réelles étapes de transformation qu’il faut optimiser et maîtriser afin de préserver toutes les propriétés antioxydantes des coproduits végétaux. Nos travaux ont également permis de mettre en évidence des propriétés plus fonctionnelles des pelures de pommes, comme agent stabilisant d’émulsions. L’impact des paramètres d’extraction a été mis en évidence par l’exploration de plusieurs conditions telles que la masse chargée, le broyage, le protocole ainsi que la température et la composition du fluide extractant.
Apples are a major source of dietary phytochemicals such as flavonoids in the Western diet. Here we report anticancer properties and possible mechanism of action of apple flavonoid-enriched fraction (AF4) isolated from the peels of Northern Spy apples in human hepatocellular carcinoma cells, HepG2. Treatment with AF4 induced cell growth inhibition in HepG2 cells in time- and dose-dependent manner. Concentration of 50 μg/ml (50 μg total monomeric polyphenols/ml) AF4 was sufficient to induce a significant reduction in cell viability within 6 h of treatment (92%, P < 0.05) but had very low toxicity (minimum 4% to maximum 16%) on primary liver and lung cells, which was significantly lower than currently prescribed chemotherapy drug Sorafenib (minimum 29% to maximum 49%, P < 0.05). AF4 induced apoptosis in HepG2 cells within 6 h of treatment via activation of caspase-3. Cell cycle analysis via flow-cytometer showed that AF4 induced G2/M phase arrest. Further, results showed that AF4 acts as a strong DNA topoisomerase II catalytic inhibitor, which may be a plausible reason to drive the cells to apoptosis. Overall, our data suggests that AF4 possesses a significantly stronger antiproliferative and specific action than Sorafenib in vitro and is a potential natural chemotherapy agent for treatment of liver cancer.
In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4
-/-) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4
-/- mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.
We have recently cloned the murine glucagon receptor (GR) gene and shown that it is expressed mainly in liver. In this organ,
the glucagon-GR system is involved in the control of glucose metabolism as it initiates a cascade of events leading to release
of glucose into the blood stream, which is a main feature in several physiological and pathological conditions. To better
define the metabolic regulators of GR expression in liver we analyzed GR mRNA concentration in physiological conditions associating
various glucose metabolic pathways in vivo and in vitro in the rat and in the mouse. First, we report that the concentration of the GR mRNA progressively increased from the first
day of life to the adult stage. This effect was abolished when newborn rodents were fasted. Second, under conditions where
intrahepatic glucose metabolism was active such as during fasting, diabetes, and hyperglycemic clamp, the concentration of
GR mRNA increased independent of the origin of the pathway that generated the glucose flux. These effects were blunted when
hyperglycemia was corrected by phlorizin treatment of diabetic rats or not sustained during euglycemic clamp.
In accordance with these observations, we demonstrated that the glycolytic substrates glucose, mannose, and fructose, as well
as the gluconeognic substrates glycerol and dihydroxyacetone, increased the concentration of GR mRNA in primary cultures of
hepatocytes from fed rats. Glucagon blunted the effect of glucose without being dominant. The stimulatory effect of those
substrates was not mimicked by the nonmetabolizable carbohydrate l-glucose or the glucokinase inhibitor glucosamine or when hepatocytes were isolated from starved rats. In addition, inhibitors
of gluconeogenesis and lipolysis could decrease the concentration of GR mRNA from hepatocytes of starved rats. Combined, these
data strongly suggest that glucose flux in the glycolytic and gluconeogenic pathways at the level of triose intermediates
could control expression of GR mRNA and participate in controlling its own metabolism.
The antioxidant properties of two apple dihydrochalcones, namely phloretin and phloridzin, were evaluated and compared with those of alpha-tocopherol and butylated hydroxytoluene (BHT). The effects were studied in an oil-in-water emulsion system containing methyl linolenate (ML), methyl eicosapentaenoate (MEPA), and methyl docosahexaenoate (MDHA) in which oxidation was initiated by the peroxyl radical generator 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) and in fish oil where oxidation was initiated thermally. In the emulsion system, phloretin (1 and 5 mM) completely inhibited the oxidation of ML tested as evidenced by the thiobarbituric acid reactive substances (TBARS) assay. Under the same conditions, phloridzin was less effective than phloretin, but still more effective than alpha-tocopherol. Both phloretin and phloridzin molecules had a marginal inhibitory effect against oxidation of fish oil induced by heating at 70 degrees C for 3 hours, when compared to BHT. These results indicate that phloretin and phloridzin have the potential to suppress lipid oxidation in polyunsaturated fatty acid (PUFA) containing foods.
Atherosclerosis which results from gradual deposition of lipids in medium and large arteries is a leading cause of mortality worldwide. The objective of this study was to determine the effect of apple juice on some risk factors of atherosclerosis and on the development of atherosclerosis in rabbits fed a high-cholesterol diet.
Thirty two male rabbits were randomly divided into four groups: normal diet, high cholesterol diet (%1 cholesterol), 1% cholesterol supplemented with 5 ml apple juice (low dose) and 1% cholesterol supplemented with 10 ml apple juice (high dose) for 2 month. The C-reactive protein (CRP), nitrite, nitrate, fibrinogen, total cholesterol(TC) and factor VII were measured before the experiment and by the end of period. At the end of study, fatty streak formation in right and left coronary arteries were determined using Chekanov method in all groups.
Both doses of apple juice significantly were decreased TC, TG, CRP, fibrinogen, factor VII levels, atherosclerotic lesion in right and left coronary arteries and increased nitrite and nitrate compared to cholesterolemic diet. Also using 10 ml apple juice caused significant reduce in LDL-C and increase HDL-C, but 5 ml apple juice did not change these factors. Significant differences were observed between 5 and 10 ml apple juice groups by LDL-C. No significant difference was found between 5 and 10 ml apple juice groups with regard to CRP, nitrite, nitrate, fibrinogen, factor VII, TG, HDL-C and TC concentrations.
Apple juice can effectively prevent the progress of atherosclerosis. This is likely due to antioxidant and anti-inflammatory effect of apple juice.
AIM: Procyanidins (Pcy) are oligomers of catechins and epicatechins. In order to get more insight into the apoptotic effects of Pcy, we aimed to compare the death signaling pathways triggered by Pcy in TRAIL-sensitive human colon cancer cells (SW480) and in their derived TRAIL-resistant metastatic cells (SW620).METHODS: Cell death, DR4/DR5, Bcl-2/Bax proteins, mitochondrial membrane potential, and reactive oxygen species (ROS) production were analyzed by flow cytometry. Bid and cytochrome c were studied by immunoblotting and ELISA.RESULTS: Pcy (80 μg/ml) combined with exogenous TRAIL (30 ng/ml) enhanced the apoptotic effects of TRAIL in SW480 but also in SW620 cells, indicating that Pcy sensitized SW620 cells to TRAIL treatment. Pcy up-regulated the expression of death receptors DR4/DR5 of TRAIL. Activation of caspase-8 and -3 was observed in both cell lines but caspase-9 was activated only in SW620 cells. Pcy-treated SW620 cells exhibited a decrease in Bid protein level, in Bcl-2/Bax ratio, and enhanced intracellular ROS production. These events were associated with the decrease of mitochondrial membrane potential and the release of cytochrome c into the cytosol.CONCLUSION: Our data suggest that Pcy triggers apoptosis via caspase-8 and may enhance TRAIL-induced apoptosis by activation of the extrinsic pathway in both cell lines. In the TRAIL-resistant SW620 cells, the apoptotic effects of Pcy were complex and may involve a cross-talk between the extrinsic and the mitochondrial apoptotic pathways and a Pcy-triggered intracellular ROS production favoring mitochondrial disruption. These data highlight the chemopreventive potentials of apple Pcy in colorectal cancer treatments.
Apples ( MALUS sp., Rosaceae) are a rich source of nutrient as well as non-nutrient components and contain high levels of polyphenols and other phytochemicals. Main structural classes of apple constituents include hydroxycinnamic acids, dihydrochalcones, flavonols (quercetin glycosides), catechins and oligomeric procyanidins, as well as triterpenoids in apple peel and anthocyanins in red apples. Several lines of evidence suggest that apples and apple products possess a wide range of biological activities which may contribute to health beneficial effects against cardiovascular disease, asthma and pulmonary dysfunction, diabetes, obesity, and cancer (reviewed by Boyer and Liu, Nutr J 2004). The present review will summarize the current knowledge on potential cancer preventive effects of apples, apple juice and apple extracts (jointly designated as apple products). In brief, apple extracts and components, especially oligomeric procyanidins, have been shown to influence multiple mechanisms relevant for cancer prevention in IN VITRO studies. These include antimutagenic activity, modulation of carcinogen metabolism, antioxidant activity, anti-inflammatory mechanisms, modulation of signal transduction pathways, antiproliferative and apoptosis-inducing activity, as well as novel mechanisms on epigenetic events and innate immunity. Apple products have been shown to prevent skin, mammary and colon carcinogenesis in animal models. Epidemiological observations indicate that regular consumption of one or more apples a day may reduce the risk for lung and colon cancer.
We have examined the effect of chronic (4 wk) hyperglycemia on insulin secretion in vivo in an awake, unstressed rat model. Three groups of animals were examined: control, partial (90%) pancreatectomy, and partial pancreatectomy plus phlorizin, in order to normalize plasma glucose levels. Insulin secretion in response to arginine (2 mM), hyperglycemia (+100 mg/dl), and arginine plus hyperglycemia was evaluated. In diabetic compared with control animals three specific alterations were observed: (a) a deficient insulin response, in both first and second phases, to hyperglycemia; (b) an augmented insulin response to the potentiating effect of arginine under basal glycemic conditions; and (c) an inability of hyperglycemia to augment the potentiating effect of arginine above that observed under basal glycemic conditions. Normalization of the plasma glucose profile by phlorizin treatment in diabetic rats completely corrected all three beta cell abnormalities. These results indicate that chronic hyperglycemia can lead to a defect in in vivo insulin secretion which is reversible when normoglycemia is restored.
Flavonoids are effective antioxidants and, in theory, may provide protection against cancer, although direct human evidence of this is scarce. The relation between the intake of antioxidant flavonoids and subsequent risk of cancer was studied among 9,959 Finnish men and women aged 15-99 years and initially cancer free. Food consumption was estimated by the dietary history method, covering the total habitual diet during the previous year. During a follow-up in 1967-1991, 997 cancer cases and 151 lung cancer cases were diagnosed. An inverse association was observed between the intake of flavonoids and incidence of all sites of cancer combined. The sex- and age-adjusted relative risk of all sites of cancer combined between the highest and lowest quartiles of flavonoid intake was 0.80 (95% confidence interval 0.67-0.96). This association was mainly a result of lung cancer, which presented a corresponding relative risk of 0.54 (95% confidence interval 0.34-0.87). The association between flavonoid intake and lung cancer incidence was not due to the intake of antioxidant vitamins or other potential confounding factors, as adjustment for factors such as smoking and intakes of energy, vitamin E, vitamin C, and beta-carotene did not materially alter the results. The association was strongest in persons under 50 years of age and in nonsmokers with relative risks of 0.33 (95% confidence interval 0.15-0.77) and 0.13 (95% confidence interval 0.03-0.58), respectively. Of the major dietary flavonoid sources, the consumption of apples showed an inverse association with lung cancer incidence, with a relative risk of 0.42 (95% confidence interval 0.23-0.76) after adjustment for the intake of other fruits and vegetables. The results are in line with the hypothesis that flavonoid intake in some circumstances may be involved in the cancer process, resulting in lowered risks.
Initiation of atherosclerosis is characterized by accumulation of aggregates of small lipid droplets and vesicles in the extracellular matrix of the arterial intima. The droplets and vesicles have features that suggest that they are formed from modified plasma-derived low density lipoprotein (LDL) particles. A variety of hydrolytic enzymes and prooxidative agents that could lead to extracellular assembly of LDL-derived droplets and vesicles are present in the arterial intima. In fact, in vitro studies have demonstrated that extensive oxidation of LDL and treatment of LDL with either proteolytic or lipolytic enzymes will induce LDL aggregation and fusion and treatment of LDL with cholesterol esterase will cause formation of vesicles. Fusion of LDL particles proceeds faster in vitro when they are bound to components of the extracellular matrix derived from the arterial intima, such as proteoglycans, and, depending on the type of modification, the strength of binding of modified LDL to the matrix components may either increase or decrease. In the present article, we discuss molecular mechanisms that provide clues as to how aggregated lipid droplets and vesicles may be derived from modified LDL particles. We also describe how these modified forms of LDL, by means of their trapping to the extracellular matrix, may lead to extracellular lipid accumulation in the arterial intima.
—Öörni, K., M. O. Pentikäinen, M. Ala-Korpela, and P. T. Kovanen. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J. Lipid Res. 2000. 41: 1703–1714.
Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARgamma and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARgamma by PPARgamma agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARgamma activity by heterozygous PPARgamma deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARgamma deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARgamma deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor alpha, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.
Phloretin is a flavonoid found exclusively in apples and in apple-derived products where it is present as the glucosidic form, namely, phloridzin (phloretin 2'-O-glucose). In the present study, we compared the changes in plasma and urine concentrations of these two compounds in rats fed a single meal containing 0.25% phloridzin or 0.157% phloretin (corresponding to the ingestion of 22 mg of phloretin equivalents). In plasma, phloretin was recovered mainly as the conjugated forms (glucuronided and/or sulfated) but some unconjugated phloretin was also detected. By contrast, no trace of intact phloridzin was detected in plasma of rats fed a phloridzin meal. These compounds presented different kinetics of absorption; phloretin appeared more rapidly in plasma when rats were fed the aglycone than when fed the glucoside. However, whatever compound was administered, no significant difference in the plasma concentrations of total phloretin were observed 10 h after food intake. At 24 h after the beginning of the meal, the plasma concentrations of phloretin were almost back to the baseline, indicating that this compound was excreted rapidly in urine. The total urinary excretion rate of phloretin was not affected by the forms administered, and was estimated to be 8.5 micromol/24 h in rats fed phloretin or phloridzin. Thus, 10.4% of the ingested dose was recovered in urine after 24 h.
Apples may have selective effects on abnormalities associated with the plurimetabolic syndrome. Therefore, the effects of 20% lyophilized apple supplementation on plasma and tissue lipids and on protection against susceptibility to oxidative stress and renal dysfunction were investigated in Zucker lean (Fa/-) or obese (fa/fa) rats. The experimental diets were equilibrated for sugar supply, contained 0.25 g/100 g cholesterol and provided only one third of the vitamin E requirement. Obese Zucker rats were hypercholesterolemic with cholesterol accumulation in LDL and HDL fractions. The apple diet lowered plasma and LDL cholesterol (-22 and -70%, respectively, P < 0.01) in obese Zucker rats and, in parallel, reduced triglyceride accumulation in heart and liver. Zucker rats fed the apple diet also had a larger intestinal pool and greater fecal excretion of bile acids. The heart concentration and urinary excretion of malondialdehyde were reduced by apple consumption in obese Zucker rats, suggesting better protection against peroxidation. Glucosuria and proteinuria in obese Zucker rats were also suppressed by the apple diet. In conclusion, despite their moderate fiber content, apples improve substantially the lipid status and peroxidative parameters in obese Zucker rats, suggesting that other plant constituents such as polyphenols are involved in these effects.
Flavonoids are effective antioxidants and may protect against several chronic diseases.
The association between flavonoid intake and risk of several chronic diseases was studied.
The total dietary intakes of 10 054 men and women during the year preceding the baseline examination were determined with a dietary history method. Flavonoid intakes were estimated, mainly on the basis of the flavonoid concentrations in Finnish foods. The incident cases of the diseases considered were identified from different national public health registers.
Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003), naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80; 0.64, 0.99; P = 0.008) intakes. Men with higher quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at higher quercetin (0.76; 0.56, 1.01; P = 0.005), naringenin (0.69; 0.50, 0.94; P = 0.06), and hesperetin (0.64; 0.46, 0.88; P = 0.03) intakes. A trend toward a reduction in risk of type 2 diabetes was associated with higher quercetin (0.81; 0.64, 1.02; P = 0.07) and myricetin (0.79; 0.62, 1.00; P = 0.07) intakes.
The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.
The minor polyphenolic and nonpolyphenolic constituents of olive oil were examined, in various doses, against copper ion-induced low-density lipoprotein (LDL) oxidation and were found, in optimal doses (final concentration, 10 microM or 20 microM), to have remarkable biological activity, contributing to that previously reported for the major phenolic compounds. The main phytosterols, beta-sitosterol, campesterol, and stigmasterol, were found to have 43.8%, 37.3%, and 33.4% LDL mean protection (MP) activity, respectively, while free cholesterol exhibited 43.2% MP. The triterpenoid derivative compounds, ursolic acid, uvaol, and oleanolic acid, had similar MP activities of 50.5%, 46.8%, and 46.0%, respectively. Tocopherol (Toc) isomers exhibited an increasing effect in the following order: alpha-Toc (33.6%) < beta-Toc (36.1%) < gamma-Toc (42.9%) < delta-Toc (46.0%). The flavonoid polyphenols, quercetin, luteolin, and rutin, exhibited the highest activities--46.8%, 49.5%, and 53.7% MP, respectively, comparable to the 49.0% MP activity found for oleuropein. These findings indicate the relative independence of LDL protection activity in regard to structural differences among the involved compounds. A relation to the Mediterranean diet is also demonstrated.
Consumption of fruits and vegetables has been associated with a low incidence of cancers and other chronic diseases. Previous
studies suggested that fresh apples inhibit tumor cell proliferation. Here we report that oral administration of apple peel
extracts decreased the number of nonmalignant and malignant skin tumors per mouse induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7,12-dimethylbenz(a)anthracene-initiated mouse skin. ESR analysis indicated that apple extract strongly scavenged hydroxyl (OH) and superoxide
() radicals. Mechanistic studies showed that pretreatment with apple peel extract inhibited AP-1 transactivation induced by
ultraviolet B irradiation or TPA in JB6 cells and AP-1-luciferase reporter transgenic mice. This inhibitory effect appears
to be mediated by the inhibition of ERKs and JNK activity. The results provide the first evidence that an extract from fresh
apple peel extract may inhibit tumor promoter-induced carcinogenesis and associated cell signaling, and suggest that the chemopreventive
effects of fresh apple may be through its antioxidant properties by blocking reactive oxygen species-mediated AP-1-MAPK activation.
The chronic hyperglycemia that occurs in type 2 diabetes may cause deterioration of beta-cell function and insulin resistance in peripheral tissues. Mice that express a dominant-negative IGF-1 receptor, specifically in skeletal muscle (MKR mice), exhibit severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyper-glycemia. To determine the role of hyperglycemia in the worsening of the diabetes state in these animals, MKR mice were treated with phloridzin (PHZ), which inhibits intestinal glucose uptake and renal glucose reabsorption. Blood glucose levels were decreased and urine glucose levels were increased in response to PHZ treatment in MKR mice. PHZ treatment also increased food intake in MKR mice; however, the fat mass was decreased and lean body mass did not change. Serum insulin, fatty acid, and triglyceride levels were not affected by PHZ treatment in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated that glucose uptake in white adipose tissue was significantly increased in response to PHZ treatment. Despite the reduction in blood glucose following PHZ treatment, there was no improvement in insulin-stimulated whole-body glucose uptake in MKR mice and neither was there suppression of endogenous glucose production by insulin. These results suggest that glucotoxicity plays little or no role in the worsening of insulin resistance that occurs in the MKR mouse model of type 2 diabetes.
Clear (CleA) and cloudy (CloA) apple juices containing different amounts of analyzed procyanidins and pectin were investigated for preventive effects of colon cancer and underlying molecular mechanisms in F344 rats given intraperitoneal injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt) once a week for 4 weeks. Rats received either water (Cont), CleA or CloA (ad libitum) for 7 weeks starting 1 week before the first DMH injection. CloA inhibited DMH induced genotoxic damage in mucosa cells of the distal colon compared with Cont as investigated by single-cell microgel electrophoresis assay. The mean tail intensity in mucosa cells of DMH-treated controls (Cont/DMH: 6.1+/-0.9%) was significantly reduced by CloA (2.4+/-0.8%; P<0.01) but not by CleA intervention (4.1+/-1.2%; P>0.05). The crypt cell proliferation index induced by DMH (Cont/NaCl: 10.0+/-0.7%; Cont/DMH: 19.9+/-1.0%; P<0.001) was significantly decreased by CleA (15.7+/-0.7%; P<0.001) and CloA intervention (11.9+/-0.4%; P<0.001). CloA but not CleA significantly reduced the number of large aberrant crypt foci (ACF) consisting of more than four aberrant crypts (AC) (Cont/DMH: 37.4+/-5.4; CleA/DMH: 32.8+/-4.4, P>0.05; CloA/DMH: 18.8+/-2.5 ACF; P<0.05) and the overall mean ACF size in the distal colon (Cont/DMH: 2.31+/-0.09; CleA/DMH: 2.27+/-0.05; CloA/DMH: 2.04+/-0.03 AC/ACF; P<0.05). After treatment with DMH and/or apple juices there were no changes in transcript levels of colonic cyclooxygenase isoforms (COX-1, COX-2) or glutathione-associated enzymes (GST-M2, gamma-GCS, GST-P), the splenocyte natural killer cell activity and plasma antioxidant status. However, CloA but not CleA prevented the DMH-induced reduction of splenocyte CD4/CD8 (T-helper cells to cytotoxic lymphocytes) ratio. Since both formulations contained comparable concentrations and types of monomeric polyphenols, complex polyphenols or non-polyphenolic compounds, such as pectin might be responsible for the stronger cancer-preventive effect by CloA.
Golden delicious apples were separated for peels and pulp, dietary fibre content and some bioactive compounds were determined. Rats were fed a semipurified or LSM diet with or without the addition of cholesterol and 5% of apple peels or pulp, feed, and digestibility and lipid profiles in plasma were estimated. Apple peels were a better source of dietary fibre and bioactive compounds that had an influence on its TRAP value than apple pulp. Freeze-dried apple peels and pulp decreased protein digestibility but significantly affected the plasma lipid profile, expressed by a lowering of total cholesterol and LDL-C fraction contents only in rats fed a diet with cholesterol were noted. The high content of biologically active compounds in apples makes it preferable for dietary prevention of atherosclerosis and other diseases.
The fruit of all apple varieties tested possessed five quercetin glycosides, namely hyperin, isoquercitrin, reynoutrin, avicularin and quercitrin, as the major flavonol components. Total flavonol levels were in the range 26.4 to 73.9μg/g fresh wt (expressed as aglycone) with hyperin the dominant form in all varieties except Egremont and Jonagored, where quercitrin predominated, and the cider apples, where avicularin predominated. The proportion of flavonol in the peel ranged from 63.0 to 97.1% for the dessert and cooking apples and was not dependent on fruit size. Juice produced from the three varieties of cider apple contained 9.9 to 12.7% of the flavonols with the remainder retained in the pomace.
The literature of the regulation of color in apple skin is reviewed and compared with current knowledge of the regulation of flower color.Color in apple skin is a blend of various amounts of chlorophyll, carotenoids, and anthocyanins/flavonols. A variety of red colors are produced by cyanidin glycosides copigmented with flavonols and other compounds. The concentration and identification of flavonols, proanthocyanidins, and cyanidin glycosides in apple skin are tabulated.From a knowledge of the pigments present in apples, and the biosynthetic pathway present in flowers, a possible biosynthetic pathway to cyanidin glycosides, proanthocyanidins (e.g., catechin), and flavonols (e.g., quercetin glycoside) can be derived. Anthocyanin biosynthesis is developmentally regulated; flavonols and proanthocyanidins are high in juvenile fruit, decrease in concentration during fruit growth, and then increase during fruit ripening. In some cultivars, anthocyanins also increase during ripening.Light is a key regulatory factor in apple skin reddening. Since nored apples, such as Granny Smith and Golden Delicious, accumulate quercetin glycosides and catechin/epicatechin, the color production in red apples is likely to involve the induction of enzymes between leucocyanidin and cyanidin glycosides. Potential research areas in molecular regulation of apple color are outlined.
Nitric oxide is a free radical involved in the pathogenesis of cancer by increasing tumour vascularization and metastasis. Studies using nitric oxide inhibitors have shown decrease in tumour growth and a role in cancer therapy. To analyse the effect of fruits on nitric oxide, we carried out experiments using a nitric oxide donor on the breast cancer cell line, MCF-7. Proliferating MCF-7 cells were treated with the methanolic extract of the fruits. The inhibitory activity of fruit extracts on cell proliferation was measured using the MTT assay. Chiku and dragon fruit showed high inhibitory activity when compared to the other fruits tested. The total polyphenol and flavonoid content and nitric oxide scavenging activity were found to be high in pomegranate, chiku, litchi, durian, grape and apple. This study shows that phytochemicals present in fruits scavenge nitric oxide and inhibit MCF-7 cell proliferation. © 2010 Elsevier Ltd. All rights reserved.
Direct thiolysis of crude plant materials and HPLC analysis of the reaction media were used to quantify and to characterise procyanidins (condensed tanins) and other main polyphenols of three dessert apple varieties. Results showed evidence of the large predominance of the procyanidin class in the polyphenolic composition of dessert apple skin and flesh. The structure of procyanidins was wholly homogeneous with (-)-epicatechin representing more than 95% of the constitutive flavan-3-ol units and with average degrees of polymerisation in the 5–7 range.
The antioxidant properties of apple polyphenols were evaluated using the β-carotene/linoleic acid system, DPPH radical and superoxide scavenging activities. The polyphenols examined were epicatechin, its dimer (procyanidin B2), trimer, tetramer and oligomer, quercetin glycosides, chlorogenic acid, phloridzin and 3-hydroxy-phloridzin. All the compounds showed strong antioxidant activities, and their DPPH-scavenging activities were 2–3 times and superoxide anion radical-scavenging activities were 10–30 times better than those of the antioxidant vitamins C and E.
This paper investigates the influence of cultivar (Annurca, Golden Delicious, Red Chief, and Stayman Neepling), rural practice (integrated and organic), and growing region (different Italian regions) on polyphenol composition and antiradical activity of the pulp and skin of apples, as presented to the consumer at the market. Antiradical activity of fruit was strongly related with the total polyphenolic content, determined both by the spectrophotometric Folin-Ciocalteu method ( R (2) = 0.90; P < 0.01) and by HPLC ( R (2) = 0.85; P < 0.01). Considering the edible portion of the fruit, polyphenolics contribute toward explaining approximately 90% of the overall antiradical activity, thus highlighting their important role in human health protection. Therefore, the data indirectly indicated that ascorbic acid and other antiradical molecules differing from polyphenols play a much less important role in explaining the health-protecting properties of apples. Cultivar effect was by far the most important, and Annurca and Golden Delicious were respectively the best and the worst apples from the point of view of the health-protecting attributes.
Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3-glucoside (C3G), a typical anthocyanin reported to possess potent anti-inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines.
Colorectal cancer (CRC) is one of the most common and preventable cancers. Regular consumption of apples is conducive to reduction in CRC risk.
To evaluate effects of modified apple polysaccharide (MAP) on tumorigenesis in a mouse model of colitis-associated colon cancer.
One hundred male ICR mice were administered with 1, 2-dimethyl-hydrazine (DMH) and dextran sodium sulfate (DSS). Forty mice were given no further treatment, the rest were fed basal diet blended with three different doses of MAP; 2.5, 5, and 10% (20 mice in each group).
MAP significantly protected ICR mice against DMH/DSS-induced tumorigenesis. The incidence of tumor development was 90% (18/20) in the mice treated with DMH/DSS, but that was reduced to 25% (5/20), 15% (3/20), and 5% (1/20), respectively, in the mice treated with basal diets plus 2.5, 5, and 10% of MAP. Study of apoptosis of colonic epithelial cells revealed that MAP moderately increased apoptosis, suggesting that the anti-tumor potency of MAP was probably attributed to its ability to induce apoptosis. Western blot analysis demonstrated that carbohydrate-binding protein galectin-3 changed in both the nucleus and the cytoplasm during the process from colitis to colon cancer in the model. And MAP could inhibit the binding of galectin-3 to its ligand: this is, at least in part, the possible mechanism of MAP by enhancing apoptosis and preventing tumorigenesis.
These data suggest that MAP has a potential role in clinical prevention and treatment for colon cancer.
Colorectal cancer, a common cause of cancer related deaths in both sexes in western population is often due to persistent oxidative stress leading to DNA damage. Antioxidants scavenge free radicals and inhibit neoplastic process. Kaempferol, a flavonol widely distributed in tea, broccoli, grape fruit, brussels sprouts and apple, is claimed to have chemopreventive action in colon cancer. The aim of our study was to evaluate the effect of kaempferol on tissue lipid peroxidation and antioxidant status in 1,2-dimethyl hydrazine induced colorectal cancer in male Wistar rats and to compare its efficacy with irinotecan. Experimental colon cancer induced by 1,2-dimethyl hydrazine in rats mimic human colon cancer and therefore is an ideal model for chemoprevention studies. The rats were divided into six groups. Group 1 served as control. Group 2 received 1,2-dimethyl hydrazine (20 mg/kg body weight) subcutaneously once a week for four weeks. Group 3 received irinotecan (100 mg/kg body weight) intravenously once a week for four weeks with 1,2-dimethyl hydrazine. Groups 4 to 6 were given a daily oral dose of 50, 100, 200 mg/kg body weight of kaempferol with 1,2-dimethyl hydrazine. The total study period was 16 weeks. Kaempferol supplementation lowered 1,2-dimethyl hydrazine induced erythrocyte lysate and liver thiobarbituric acid reactive substances level and rejuvenated anti oxidant enzymes catalase, super oxide dismutase and glutathione peroxidase. The recovery of enzyme status was maximum at the dose of 200 mg/kg body weight and was comparable to irinotecan. Our study reveals that kaempferol could be safely used as a chemopreventive agent in colorectal cancer.
The risk of cancer and other degenerative diseases is inversely correlated with consumption of fruits and vegetables. This beneficial effect is mainly attributed to secondary plant constituents such as polyphenols, supposed to play a major role in protection against ROS (reactive oxygen species)-associated toxicity.
To elucidate the potential of differently manufactured apple juices (clear AJ/cloudy AJ/smoothie, in comparison with a polyphenol-free control juice) to modulate expression of ARE-dependent genes.
In male Sprague-Dawley rats (n = 8/group; 10d juice intervention, 4d wash-out; 4 treatment cycles), expression of target genes (superoxide dismutase, SOD1/SOD2; glutathione peroxidase, GPX1/GPX2; γ-glutamylcysteine ligase, GCLC/GCLM; glutathione reductase, GSR; catalase, CAT; NAD(P)H:quinone oxidoreductase-1, NQO1 and transcription factor erythroid-derived 2-like-2, Nrf2) was quantified with duplex RT-PCR, using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as control.
In colon and liver of rats consuming polyphenol-free control juice, rather similar basic expressions were observed (relative GAPDH ratios ranging from 2 to 0.7 and 2.5-0.3, respectively). In the distal colon, apple juice intervention slightly but significantly induced most genes (e.g. GPX2, GSR, CAT, Nrf2; p < 0.001), whereas in the liver only GPX1 and NQO1 mRNA were up-regulated; other hepatic target genes were not affected or down-regulated (SOD1, SOD2, GCLC/M, GSR), concomitant with the absence of Nrf2 induction. Induction of antioxidant gene expression differed with juice type (cloudy AJ > clear AJ ~ smoothie).
Taken together, the results underline the potential of polyphenol-rich apple juice to increase the expression of ARE-dependent antioxidant genes.
To study possible insulin sensitizing, anti-inflammatory and anti-oxidative effects of the flavonol quercetin, rats were fed a high-fat diet (19%, w/w) with (HFQ) or without (HF) 0.03% quercetin or a flavonoid-poor low-fat (5%, w/w) maintenance diet (LF) over 4 weeks. Body weight was measured weekly, and plasma concentrations of adiponectin, leptin, insulin, glucose, triacylglycerols, total cholesterol, as well as of markers of inflammation and oxidative stress were measured (12h fasted) at the end of the feeding period. Adiponectin and peroxisome-proliferator-activated-receptor (PPAR)-gamma mRNA were measured in adipose tissue (WAT) by real-time RT-PCR. PPAR-gamma transactivation was investigated by means of a reporter gene assay. HF feeding resulted in elevated fasted plasma glucose concentrations, while HFQ did not differ from LF feeding. In the HFQ group plasma concentrations and WAT mRNA levels of adiponectin were elevated compared with the HF group, however, PPAR-gamma mRNA concentration in WAT was decreased (HFQ vs. HF). Compared to both other groups quercetin feeding significantly reduced oxidative stress, measured by plasma 8-iso-PGF(2alpha), while body weight gain, body composition and plasma leptin levels were not affected. Neither quercetin nor its metabolites induced PPAR-gamma-mediated transactivation in vitro. Adiponectin stimulating effects of quercetin are PPAR-gamma-independent and prevent impairment of insulin sensitivity without affecting body weight and composition.
Studies have shown an inverse relationship between the consumption of apples and the risk of several cancers. The peels of apple, which have been shown to possess exceptionally high concentrations of antioxidants, are often discarded. In this study, we evaluated the antiproliferative effects of apple peel extract (APE) in variety of cancer cell types. Our data demonstrated that APE, obtained from organic Gala apples, imparted significant reduction in the viability of a variety of cancer cell lines. Further, our data showed a significant decrease in growth and clonogenic survival of human prostate carcinoma CWR22Rnu1 and DU145 cells and breast carcinoma Mcf-7 and Mcf-7:Her18 cells. Also, the antiproliferative effects of APE were found to be accompanied by a G0-G1 phase arrest of prostate and breast cancer cells. Furthermore, APE treatment resulted in a marked concentration-dependent decrease in the protein levels of proliferative cell nuclear antigen, a marker for proliferation. In addition, APE treatment resulted in a marked increase in maspin, a tumor suppressor protein that negatively regulates cell invasion, metastasis, and angiogenesis. Our data suggested that APE possesses strong antiproliferative effects against cancer cells, and apple peels should not be discarded from the diet. Detailed mechanistic studies, especially in appropriate in vivo animal models, are needed to further examine the antiproliferative and preventive effects of APE against cancer.
Environmental factors play an important role in the etiology of colorectal cancer, the second-most common malignancy in both genders in developed countries. Evidence has shown that potential cancer-inducing oxidative damage might be prevented or restricted largely by the presence of dietary antioxidants of plant origin, such as fruits or vegetables. The protective antioxidant effect of fruits and vegetables has been attributed to flavonoids, a major class of phytochemicals naturally occurring in fruits, vegetables, and various foods of plant origin. Yet, epidemiologic cohort studies relating flavonoid intake to risk of colorectal cancer have been sparse and inconclusive. Apples are a rich source of flavonoids and have the second highest level of antioxidant power among all fruits, with peels having a stronger antioxidant activity than apple flesh. A recent reanalysis of several case-control studies in Italy demonstrated a consistent inverse association between apple consumption and the risk of various cancers, and among them ofcolorectal cancer. Here we assessed the potential protective impact of apples on risk of colorectal cancer in the course of a recently performed hospital-based case-control study in a country with dietary habits very different from those of Mediterranean region. The results showed that highest risk of colorectal cancer was among older persons and those who were residents of villages or small towns. The risk of colorectal cancer was inversely correlated with daily number of apple servings, but the most significant reductions of OR estimates were observed for an intake one or more apple servings daily (OR = 0.37, 95% CI: 0.15-0.91). No other fruit was significantly associated with altering the risk of colorectal cancer.
Insulin resistance is characteristic of the diabetic state. To define the role of hyperglycemia in generation of the insulin resistance, we examined the effect of phlorizin treatment on tissue sensitivity to insulin in partially pancreatectomized rats. Five groups were studied: group I, sham-operated controls; group II, partially pancreatectomized diabetic rats with moderate glucose intolerance; group III, diabetic rats treated with phlorizin to normalize glucose tolerance; group IV, phlorizin-treated controls; and group V, phlorizin-treated diabetic rats restudied after discontinuation of phlorizin. Insulin sensitivity was assessed with the euglyemic hyperinsulinemic clamp technique in awake, unstressed rats. Insulin-mediated glucose metabolism was reduced by approximately 30% (P less than 0.001) in diabetic rats. Phlorizin treatment of diabetic rats completely normalized insulin sensitivity but had no effect on insulin action in controls. Discontinuation of phlorizin in phlorizin-treated diabetic rats resulted in the reemergence of insulin resistance. These data demonstrate that a reduction of beta-cell mass leads to the development of insulin resistance, and correction of hyperglycemia with phlorizin, without change in insulin levels, normalizes insulin sensitivity. These results provide the first in vivo evidence that hyperglycemia per se can lead to the development of insulin resistance.
DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10(6) oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).
Utilizing the rat mammary adenocarcinoma and Fischer bladder cell carcinoma cell lines, this study demonstrated the ability of two known glucose transport inhibitors, phloridzin (P1) and its aglucone, phloretin (P2), to block glucose transport into whole viable tumor cells in vitro and tumor tissues in vivo. This work represents the first in a series of experiments designed to explore the efficacy of P1 and P2 administration in restraining tumor cell growth via the inhibition of glucose transmembrane transport.
Posttraining intraperitoneal administration of phlorizin (3.0-300.0 microg/kg), a competitive inhibitor of glucose transport from blood to brain, facilitated 48-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted-U shape. Phlorizin did not increase the retention latencies of mice that had not received a foot shock during training. The effects of phlorizin (30.0 microg/kg) on retention were time dependent, and the administration of phlorizin (30.0 microg/kg) 5 or 10 min prior to the retention test did not affect the retention performance of mice given posttraining injections of saline or phlorizin (30.0 microg/kg). These findings indicate that phlorizin influenced memory storage, but not memory retrieval. Finally, the simultaneous administration of phlorizin (3. 0-300.0 microg/kg, ip) antagonized, in a dose-related manner, the memory impairment induced by insulin (8 IU/kg, ip). Taken together, the results show that phlorizin enhance retention acting as a "glucose-like substance" although the mechanism(s) of this enhancement is unknown.
Type 2 diabetes is associated with increased circulating concentrations of markers of the acute-phase response and interleukin-6 (IL-6). An augmented acute-phase response may be a mechanism which explains many of the clinical and biochemical features of type 2 diabetes and its complications. We sought to confirm that circulating concentrations of the cytokine acute-phase mediators IL-6 and tumour necrosis factor alpha [TNFalpha] are elevated in type 2 diabetes, and investigated blood as a source of cytokines in type 2 diabetes. Blood samples from 20 type 2 diabetic and 17 age-matched healthy subjects were incubated in vitro for 24 hr with and without lipopolysaccharide (LPS) stimulation and secreted cytokines measured. Plasma IL-6 and TNFalpha were significantly increased in type 2 diabetes compared to normal subjects. However, basal production of IL-6 and TNFalpha in cultured diabetic blood was markedly depressed in comparison with non-diabetic samples. IL-6 and TNFalpha production was increased in blood in response to LPS, reaching similar levels in diabetic and non-diabetic subjects, though IL-6 was slightly but significantly higher in controls. We conclude that circulating levels of IL-6 and TNFalpha are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells in type 2 diabetes. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFalpha concentrations may be from non-circulating cells.
A new method was developed for the fractionation of procyanidin oligomers according to their degree of polymerization. Monomeric flavan-3-ols and low molecular mass procyanidins were selectively extracted from the lyophilized powder of apple condensed tannins (ACTs) by methyl acetate extraction. Sequentially, the separation of each oligomer from dimer to pentamer in this extract was carried out by normal-phase high-performance liquid chromatography using a silica-beads packed column. The best separation was achieved with a mobile phase system containing hexane; (1) hexane-methanol-ethyl acetate, (2) hexane-acetone. These sequential treatments can be easily adapted to large-scale fractionation.
Evidence exists that red wine, which contains a large array of polyphenols, is protective against cardiovascular disease and possibly cancer.
We tested the hypothesis that catechin, the major monomeric polyphenol in red wine, can delay tumor onset in transgenic mice that spontaneously develop tumors.
Mice were fed a nutritionally complete amino acid-based diet supplemented with (+)-catechin (0-8 mmol/kg diet) or alcohol-free solids from red wine. Mice were examined daily; the age at which a first tumor appeared was recorded as the age at tumor onset. Plasma catechin and metabolite concentrations were quantified at the end of the study.
Dietary catechin significantly delayed tumor onset; a positive, linear relation was observed between the age at tumor onset and either the amount of dietary catechin (r(2) = 0.761, P < 0.001) or plasma catechin and metabolite concentrations (r(2) = 0.408, P = 0.003). No significant effects on tumor onset were observed when mice consumed a diet supplemented with wine solids containing <0.22 mmol catechin/kg diet, whereas a previous study showed that wine solids with a similar total polyphenol concentration but containing approximately 4 times more catechin significantly delayed tumor onset by approximately 30 d compared with a control diet. The catechin composition of the wines is directly related to processing conditions during vinification.
Physiologic intakes of specific dietary polyphenols, such as catechin, may play an important role in cancer chemoprevention. Wines have different polyphenol concentrations and compositions; therefore, the overall health benefits of individual wines differ.
Early hypercholesterolaemia-induced vascular disease is characterized by an attenuated capacity for endothelial production of the antiatherogenic molecule nitric oxide (NO), which is generated by endothelial NO synthase (eNOS). In recent studies we have determined the impact of lipoproteins on eNOS subcellular localization and action, thereby providing a causal link between cholesterol status and initial abnormalities in endothelial function. We have demonstrated that eNOS is normally targeted to cholesterol-enriched caveolae where it resides in a signalling module. Oxidized low density lipoprotein (LDL; oxLDL) causes displacement of eNOS from caveolae by binding to endothelial cell CD36 receptors and by depleting caveolae cholesterol content, resulting in the disruption of eNOS activation. The adverse effects of oxLDL are fully prevented by high density lipoprotein (HDL) via binding to scavenger receptor BI (SR-BI), which is colocalized with eNOS in endothelial caveolae. This occurs through the maintenance of caveolae cholesterol content by cholesterol ester uptake from HDL. As importantly, HDL binding to SR-BI causes robust stimulation of eNOS activity in endothelial cells, and this process is further demonstrable in isolated endothelial cell caveolae. HDL also enhances endothelium- and NO-dependent relaxation in aortae from wild-type mice, but not in aortae from homozygous null SR-BI knockout mice. Thus, lipoproteins have potent effects on eNOS function in caveolae via actions on both membrane cholesterol homeostasis and the level of activation of the enzyme. These processes may be critically involved in the earliest phases of atherogenesis, which recent studies suggest may occur during fetal life.
The polyphenolic compositions of 31 Basque cider apple cultivars were determined in pulp, peel, and juice by high-performance liquid chromatography with diode array detection analysis of crude extracts and after thiolysis. Total polyphenols are distributed in a wide concentration range depending on the cultivar. Procyanidins are the class of polyphenols that present major concentrations in apple. Their average degrees of polymerization range from 4 to 8 depending on the cultivar. Apple cultivars were technologically classified into bitter and nonbitter categories using different classification systems obtained by applying several pattern recognition techniques, such as principal component analysis, K-nearest neighbors, soft independent modeling of class analogy, partial least-squares, and multilayer feed-forward-artificial neural networks, to apple pulp, peel, or juice data (individual polyphenol concentrations, total procyanidin content, and the average degree of polymerization of procyanidins). Bitter apple cultivars present higher contents of flavan-3-ols and/or dihydrochalcones than nonbitter cultivars. Detailed knowledge of the polyphenolic profile of each apple cultivar affords information about their susceptibility to oxidation, their sensory properties (bitterness, astringency), and their possible influence on the characteristics and quality of the final product (juice, cider) when apples are processed.
We have investigated the effects of three types of procyanidin isolated from apple (Rosaceae Malus pumila) on DNA of human stomach cancer KATO III cells. Induction of apoptosis by these procyanidins was observed in human stomach cancer KATO III cells. Morphological changes showing apoptotic bodies were observed in the KATO III cells treated with procyanidins. The fragmentation of DNA by procyanidins to oligonucleosomal-sized fragments, a characteristic of apoptosis, was observed to be concentration- and time-dependent in the KATO III cells. N-acetyl-L-cysteine, an antioxidant, suppressed the DNA fragmentation induced by these procyanidins. The present study shows that the suppression of KATO III cell-growth by three types of procyanidin results from the induction of apoptosis by these compounds, and that active oxygen is involved in the induction of apoptosis by these compounds in the KATO III cells.
This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.
The polyphenol-rich extract of a consumer-relevant apple juice blend was found to potently inhibit the growth of the human colon cancer cell line HT29 in vitro. The epidermal growth factor receptor (EGFR) and its subsequent signaling cascade play an important role in the regulation of cell proliferation in HT29 cells. The protein tyrosine kinase activity of an EGFR preparation was effectively inhibited by the polyphenol-rich apple juice extract. Treatment of intact cells with this extract resulted in the suppression of the subsequent mitogen-activated protein kinase cascade. Amongst the so far identified apple juice constituents, the proanthocyanidins B1 and B2 as well as quercetin-3-glc (isoquercitrin) and quercetin-3-gal (hyperoside) were found to possess substantial EGFR-inhibitory properties. However, as to be expected from the final concentration of these potential EGFR inhibitors in the original polyphenol-rich extract, a synthetic mixture of the apple juice constituents identified and available so far, including both proanthocyanidins and the quercetin glycosides, showed only marginal inhibitory effects on the EGFR. These results permit the assumption that yet unknown constituents contribute substantially to the potent EGFR-inhibitory properties of polyphenol-rich apple juice extract. In summary, the polyphenol composition of apple juice possesses promising growth-inhibitory properties, affecting proliferation-associated signaling cascades in colon tumor cells.
Forty-one samples of apples (peel plus pulp), obtained from eight cultivars, were examined for concentration of some important phytochemicals and for antioxidant activity expressed as peroxyl radical trapping efficiency. Five major polyphenolic groups plus ascorbate were identified and quantified by HPLC in the apple varieties. Oligomeric and polymeric proanthocyanidins were found to be about two-thirds of total polyphenols. The antioxidant efficiency of the apple extracts and of representative pure compounds for each group of phytochemicals was measured in a micellar system mimicking lipid peroxidation in human plasma. Although the amount of polyphenols measured by HPLC is similar to that measured by standard methods, the antioxidant efficiency calculated on the basis of the contribution of the pure compounds was lower than the antioxidant efficiency of the apple extracts. The higher efficiency of apples appears to be strictly related to the overwhelming presence of oligomeric proanthocyanidins.
Recently, adipocytes have been shown to be endocrine cells that secrete a variety of bioactive substances-the so-called adipocytokines. Among adipocytokines, tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as already known organs, and they contribute to the development of vascular diseases. Visfatin is a very recently discovered visceral fat-specific protein that may be related to the development of obesity-related diseases such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, also a newfound adipose tissue-specific collagen-like protein, has been noted recently as an important antiatherogenic as well as antidiabetic protein. The function of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysfunction of adipocytes including oversecretion of tumor necrotizing factor alpha, plasminogen activator inhibitor 1, and heparin-binding epidermal growth factor-like growth factor, as well as hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, including adiponectin, is discussed with respect to atherosclerosis.