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United States Department of Agriculture

Agricultural Research Service

Research Project: Antioxidant Polyphenols in Impaired Brain and Heart Functions Associated with Obesity and Metabolic Diseases
2010 Annual Report


1a.Objectives (from AD-416)
This project is based on the premise that many chronic diseases, including type 2 diabetes, cardiovascular diseases (CVD), and Alzheimer’s disease (AD), are strongly influenced by insulin resistance. The hypothesis is that diets that lead to improved insulin sensitivity will decrease risk factors to prevent and alleviate these diseases. We propose to evaluate the following objectives: Objective 1: To determine the role of insulin-potentiating, antioxidant polyphenols on improved brain insulin signaling, cognitive function, and antioxidant status in rats fed a high fat, high fructose diet to induce insulin resistance and obesity.

Objective 2: To examine the mechanisms by which antioxidant polyphenols (from cinnamon, tea, coffee, and chocolate) protect neural cells from varying levels of glucose and beta-amyloid toxicity.

Objective 3: To determine the roles of these polyphenols on the renin-angiotensin system in the heart and related organs via determining their potential effects on potential mediators such as inflammatory cytokines, nitric oxide synthase, NF-kB, ACE, PPARs, serotonin receptors, and adrenoceptors.


1b.Approach (from AD-416)
The epidemic of insulin resistance associated with obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases (CVD) is sweeping both developed and emerging countries. Insulin resistance has been implicated in the pathogenesis of Alzheimer’s disease (AD) and the term “type 3 diabetes” has been used to describe AD. Moreover, obesity has been recognized as an important risk factor for AD. Diets high in fat and (or) fructose contribute prominently to insulin resistance. We have recently shown in animal and human studies that cinnamon polyphenols, and related compounds, not only improve insulin function but also act as antioxidant and anti-inflammatory compounds to counteract the negative effects of insulin resistance and obesity. This proposal is designed to test the hypothesis that insulin-potentiating polyphenols from cinnamon, coffee, tea, and chocolate will alleviate insulin resistance and related diseases including CVD and AD. Insulin resistance and related pathologies will be induced by feeding rats diets high in fat and fructose. The effects of insulin potentiating polyphenols on insulin resistance, brain insulin signaling, AD-like neuropathology, cognitive function, antioxidant status, hypertension, and the renin-angiotensin system will be evaluated. Cell culture studies will also be used to elucidate the mechanisms of actions of polyphenols and related compounds derived from natural products. Verification of our hypothesis will support the use of natural products containing insulin-potentiating polyphenols, and related compounds, as important nutritional components for the prevention or decreasing risk of chronic diseases including diabetes, CVD, and AD.


3.Progress Report
Disturbances in insulin metabolism are involved in most pathogenic processes that promote the development of chronic diseases including obesity, hypertension, diabetes, cardiovascular diseases, cancer, and Alzheimer’s disease. This year, we demonstrated that components of cinnamon may be important in the prevention and/or alleviation of Alzheimer’s disease by preventing and reversing the formation of brain isolated tau filaments which are thought to be important in the development of Alzheimer’s disease. In cell and animal models, cinnamon components were shown to prevent the formation of new blood vessels needed for the growth of new cells related to cancer and obesity. In a rodent model, water extracts of cinnamon and green tea were also shown to be beneficial in the regulation of the formation of lipoproteins involved in cardiovascular disease and inflammation. Health benefits of fruits, vegetables, and plants are well documented in epidemiological studies; however, there is still little information regarding the potential beneficial effects of phenolic conjugates typically found in these foods (e.g., caffedymine-type phenylpropenoic acid amides and safflomide-type phenylpropenoic acid amides) on inflammation and hypertension. Unfortunately, these phenolic conjugates are not commercially available, and studies of their activity and mechanism of action have been hindered severely. This year, several phenolic conjugates (including caffedymine-type and safflomide-type phenylpropenoid acid amides, rosmarinic acid, and chlorogenic acid) found in coffee, cocoa, garlic, green onion, spices, and herbs were isolated or synthesized to investigate their action on cyclooxygenase (COX), lipoxygenase (LOX), and related enzymes in animal models to determine their effects on these important enzyme systems which are involved with initiation or progression of inflammation. In vitro culture systems were also utilized to determine potential effects of these phenolic conjugates on radical quenching, catalase, peroxidase, COX, LOX, and others enzymes that are, critically associated with the initiation and/or progression of inflammation and hypertension. Specific phenolic conjugates (N-caffeoyltyramine, N-feruloyltyramine, and other phenylpropenoic acid amides) found in coffee, cocoa, tea, garlic, green onion, spices, and herbs can affect human chronic diseases such as inflammation and hypertension. We identified and/or isolated many of the previously defined compounds and determined their potential effects, using a rodent model, on inflammation and hypertension processes, including COX and related enzymes. The results of these studies indicated that the amides found in plants are able to inhibit COX, LOX, and related enzymes that are critically associated in the inflammatory processes related to hypertension.


4.Accomplishments
1. Water extracts of cinnamon improve and reverses factors related to Alzheimer’s disease in a cell model of this human disease. Alzheimer's destroys brain cells, causing problems with memory, thinking, and behavior. Alzheimer’s gets worse over time, and it is fatal. Today it is the sixth-leading cause of death in the United States. We determined the effects of an aqueous extract of cinnamon on the formation of factors that are hallmarks of Alzheimer’s disease, namely, brain derived- tau protein aggregation and filament formation. The cinnamon extract caused complete disassembly of tau filaments in vitro and substantial alteration of the morphology of paired-helical filaments isolated from the brain of people who died of Alzheimer’s disease. This work suggested that compounds in cinnamon may be beneficial to the prevention, or alleviation of Alzheimer’s disease. This study will be of benefit to scientists working on the causes and prevention of Alzheimer’s disease and potentially relevant to the millions of people affected by Alzheimer’s disease.

2. Water soluble extracts of cinnamon prevent the growth of tumor cells in cell culture and animal studies. For tumor cells to grow in the body, a newly developed blood supply is needed. Blockade of the growth of this new blood supply is therefore an important approach for cancer treatment and prevention. A factor circulating in the blood, vascular endothelial growth factor (VEGF), is one of the critical factors that induces angiogenesis or the formation and differentiation of new blood vessels. VEGF has emerged as an attractive target for anti-cancer treatment. However, most of current anti-VEGF agents often cause side effects when taken chronically. In this study, we found that a water extract of cinnamon containing components of cinnamon called type-A polyphenols, can effectively inhibit the formation of the new blood supply needed for tumor cells to grow in vitro and in a rodent model. This has the potential to lead to the prevention of many forms of cancer. This work is important to the scientific community involved in the prevention and treatment of cancer but also to the millions of people who may develop cancer.


Review Publications
Peterson, D.W., George, R.C., Scaramozzino, F., Lapointe, N.E., Anderson, R.A., Graves, D.J., Lew, J. 2009. Cinnamon extract inhibits tau aggregation associated with Alzheimer’s Disease in vitro. Journal of Alzheimer's Disease. 17(3):585-597.

Hininger-Favier, I., Benaraba, R., Coves, S., Anderson, R.A., Roussel, A.M. 2009. Green tea extract decreases oxidative stress and improves insulin sensitivity in an animal model of insulin resistance, the fructose-fed rat. Journal of the American College of Nutrition. 28:355-361.

Qin, B., Dawson, H.D., Anderson, R.A. 2010. Elevation of tumor necrosis factor-alpha induces the overproduction of postprandial intestinal apolipoprotein B48-containing very low-density lipoprotein ..... the inflammatory and insulin signaling pathways in enterocytes. Experimental Biology and Medicine(Maywood). 235(2):199-205.

Lu, J., Zhang, K., Nam, S., Anderson, R.A., Jove, R., Wen, W. 2010. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis. 31:481-488.

Qin, B., Polansky, M.M., Sato, Y., Adeli, K., Anderson, R.A. 2009. Cinnamon extract inhibits the postprandial overproduction of apolipoprotein B48-containing lipoproteins in fructose-fed animals. Journal of Nutritional Biochemistry. 20(11):901-908.

Cao, H., Roussel, A., Anderson, R.A. 2010. Green tea: molecular targets in glucose uptake, inflammation, and insulin signaling pathways. Comprehensive Bioactive Natural Products. Vol. 2-Efficiacy, Safety & Clinical Evaluation I, Stadium Press LLC, P. 429-448.

Schoene, N.W., Kelly, M.A., Polansky, M.M., Anderson, R.A. 2008. A polyphenol mixture from cinnamon targets p38 MAP kinase-regulated signaling pathways to produce G2/M arrest. Journal of Nutritional Biochemistry. 20(8):614-620.

Cafalu, W.T., Rood, J., Pinsonat, P., Qin, J., Sereda, O., Levitan, L., Anderson, R.A., Zhang, X.H., Martin, J.M., Martin, C.K., Wang, Z.Q., Newcomer, B. 2010. Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus. Metabolism. 59(3):755-762.

Qin, B., Panickar, K.S., Anderson, R.A. 2010. Cinnamon: potential role in the prevention of insulin resistance, metabolic syndrome, and type 2 diabetes. Journal of Diabetes Science and Technology. 4(3):685-693.

Qin, B., Polansky, M.M., Dawson, H.D., Anderson, R.A. 2010. Green tea polyphenols improve cardiac muscle mRNA, and protein levels of signal pathways related to insulin and lipid metabolism and inflammation in insulin-resistant rats. Molecular Nutrition and Food Research. 54(S1)S14-S23.

Panickar, K.S., Anderson, R.A. 2010. Role of dietary polyphenols in attenuating brain edema and cell swelling in cerebral ischemia. Recent Patents on Central Nervous System Drug Discovery. 5(2):99-108.

Cao, H., Urban Jr, J.F., Anderson, R.A. 2010. Cinnamon: Molecular evidence for the health benefits through its insulin-like and anti-inflammatory effects. In: Gupta V.K., Taneja, S.C., Gupta, B.D., editors. Comprehensive Bioactive Natural Products, Vol.6 - Extraction, Isolation & Characterization. Studium Press LLC, USA. p203-227.

Qin, B., Polansky, M.M., Anderson, R.A. 2010. Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats. Hormone and Metabolic Research. 42:187-193.

Park, J.B. 2009. Isolation and characterization of N-feruloyltyramine as the P-selectin expression suppressor from garlic (Allium sativum). Journal of Agricultural Food & Chemistry. 57(19):8868-8872.

Last Modified: 11/21/2014
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