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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Research Project #426502

Research Project: Health Promoting Roles of Food Bio-Active Phenolic Compounds on Obesity-Altered Metabolic Functions and Physiology

Location: Diet, Genomics and Immunology Laboratory

2016 Annual Report


1a. Objectives (from AD-416):
Obesity is a serious health condition, often associated with grave consequences on several chronic diseases such as diabetes, insulin resistance, cardiovascular disease, hypertension, chronic kidney disease (CKD), and other dysfunctions. U.S. government statistics show nearly two-thirds of U.S. adults are overweight and with half of them considered obese. Therefore, this plan is based on the hypothesis that diets containing phenolics and their natural derivatives help decrease risk factors of hypertension, CKD and their related events via improving obesity and its associated conditions. The objectives of this plan are: Objective 1: Determine the extent to which obesity-induced hypertension can be attenuated by polyphenolic compounds (focusing on caffeic acid, ferulic acid, chlorogenic acids and their natural derivatives) found in grains and vegetables. (NP107, C4, PS 4A) Objective 2: Determine the extent to which obesity-induced impaired kidney function can be attenuated by polyphenolic compounds (focusing on caffeic acid, ferulic acid, chlorogenic acids and their natural derivatives) found in grains and vegetables. (NP107, C4, PS 4A) Objective 3: Determine dietary components and their mechanisms that mitigate the adverse effects of exposure to environmental toxins in both parents and offspring on metabolic diseases such as obesity and diabetes. (NP107, C4, PS 4A, C5, PS 5A)


1b. Approach (from AD-416):
The extent to which obesity-induced hypertension can be reduced by polyphenolic compounds (focusing on caffeic acid, ferulic acid, chlorogenic acids, and their natural derivatives) found in grains and vegetables will be evaluated by attenuating subclinical inflammation and its related events by caffeic acid, ferulic acid, chlorogenic acids, protocatechuic acid, and their natural derivatives found in plants including grains and vegetables in an animal model. Regulation of COX enzymes, NF-kB, peroxynitrite, ox-LDL, p38, MCP-1, IL-6, TNF-alpha, and angiotensin will be investigated as mechanisms of action in-vivo. The extent to which obesity-induced impaired kidney function can be attenuated by polyphenolic compounds (focusing on caffeic acid, ferulic acid, chlorogenic acids, and their natural derivatives) found in grains and vegetables will also be determined via reactive oxygen species (ROS) investigating regulation of AGEs, p38, MCP-1, TGF-beta, EMT, and adiponectin-mediated pathways as mechanisms of action in in vitro models.


3. Progress Report:
The health benefits of numerous plant products are widely recognized worldwide and their major chemicals are relatively well documented. However, there is very little information regarding the potential beneficial effects of phenolic conjugates (e.g., safflomide-type phenolic amides (safflomide, javamide-I and-II)) on obesity, sub-clinical inflammation, hypertension, and chronic kidney disease (CKD). As a continuing research effort, this year, we investigated the potential effects of safflomide-type phenolic amides (safflomide, javamide-I and-II) on health events related to cardiovascular disease, hypertension, and CKD. In fact, Javamide-I and -II are found in coffee (0.5-3mg/g), with similar structures like safflomide. However, there is currently no information about their potential health effects on hypertension and CKD. During the study, we found that safflomide could alleviate hypertension and CKD by lowering bodyweight and increasing adiponectin in rats. Also, safflomide could inhibit NF-kB activation and COX-I and -II in vitro models, thereby alleviating subclinical inflammation attributed to obesity . Because the javamide-I and -II have very similar chemical structures to safflomide, there is on-going scientific interest about whether the javamides in coffee can do the same in vitro and in vivo. The data indicated that the amides could inhibit NF-kB activation as well as COX-I and -II in vitro models. Also, we found that javamide-I and -II could suppress the expression of IL-1beta, TNF-alpha, MCP-1 via inhibiting p38 MAPKinase, which play crucial roles in tubulointerstitial inflammation in CKD in vitro and in vivo. Also, we investigated the potential effects of javamide-I and -II on sirt1/2/3 in vitro and in cell culture models. This is the first report about potential molecular mechanisms and how safflomide, javamide-I and -II could deliver beneficial effects on cardiovascular disease, hypertension and CKD.


4. Accomplishments
1. Safflomide, Javamide-I and -II on COX-I/-II and NF-kB. Cyclooxygenases (COX-I and -II) and NF-kB transcription factor are profoundly involved in inflammatory and immune processes in humans. Especially the levels of subclinical inflammation is reported to be higher in the obese than the normal individuals. However, there is currently no information about the potential effects of bioactive components such as safflomide and javamides found in plants (e.g., coffee, cocoa) on COX-I and -II, and NF-kB transcription factor. This year, ARS scientists at the Beltsville Human Nutrition Center in Beltsville, Maryland demonstrated that safflomide and javamide-I and -II found in coffee could inhibit COX-I and –II, NF-kB, and P-selectin (a platelet activation marker), thereby, alleviating the subclinical inflammation in obesity-related cardiovascular disease and hypertension. The outcome of this study provided the information suggesting that the consumption of bioactive components such as safflomide and javamides may suppress the subclinical inflammation often observed in cardiovascular disease and hypertension.

2. Javamide-I and -II on p38 MAP Kinase. The p38 MAP kinase is an important MAPKinase which plays a vital role in regulating the production of several proinflammatory cytokines such as IL-1beta, MCP-1, TNF-beta. The inhibition of theses kinases may be considered beneficial in preventing/treating many inflammatory diseases such as cardiovascular disease and chronic kidney disease. This year, ARS scientists at the Beltsville Human Nutrition Center, Beltsville, Maryland, first demonstrated that javamide-I and -II found in coffee could inhibit p38 MAP Kinase. The outcomes of this research suggests that coffee containing the amides may help alleviate inflammation associated with the over-activation of p38 MAP Kinase which potentially lead to the expression of IL-1beta, MCP-1, TNF-beta.

3. Inflammation-associated interstitial injury is a common pathophysiological feature of cardiovascular disease (CVD), hypertension, and chronic kidney disease (CKD). The increased expression of MCP-1 with IL-1beta and TNF-beta may play a crucial role in interstitial inflammation by recruiting and activating macrophages in CVD and CKD. ARS scientists at the Beltsville Human Nutrition Center, Beltsville, Maryland, investigated the effects of javamide -II found in coffee on the expression of MCP-1, IL-1beta and TNF-beta, and found that the amide inhibited the production of MCP-1, IL-1beta and TNF-beta proteins. The outcomes of this research suggests that javamide-II found in coffee is a potent bioactive compound to suppress these inflammatory cytokines that are critically involved in vascularinterstitial/tubulointerstitial inflammation.

4. Javamide-I and sirtuin1/2/3. Last year, we reported that javamide-II found in coffee, could inhibit Sirt1/2, thereby being potentially beneficial in some human diseases including neuronal degenerative diseases and cancer. Although coffee contains both javamide-I and javamide-II, the potential effects of javamide-I on Sirt inhibition have not been investigated. Therefore, ARS scientists at the Beltsville Human Nutrition Center, Beltsville, Maryland, investigated the effects of javamide-I on Sirt1 (nuclear), Sirt2 (cytoplasm) and Sirt3 (mitochondria), and found that Javamide-I showed a strong inhibition, especially Sirt1 (IC50 of 17 µM) better than Sirt2 (IC50 of 104 µM) and Sirt3 (IC50 of 160 µM). Additionally, the scientists found that javamide-I was able to increase the acetylation of both histone H3 and p53 in in LNCap prostate cancer cells. The outcome of this study provided the information suggesting that javamide-I is likely to be a potent Sirt1 inhibitor to increase the acetylation of histone H3 and p53 in the prostate cancer cells.


5. Significant Activities that Support Special Target Populations:
None.


Review Publications
Park, J.B. 2016. Potential biological activities and bioavailability of alfrutamide and caffedymine. Journal of Nutrition. 146(2):437S-4435.

Park, J.B. 2016. Activity-guided isolation of a sirtuin2 inhibiting compound from coffee: structural and activity confirmation of Javamide-II (N-caffeoyltryptophan)and its cellular effects on histone H3 and alpha-tubulin. PLoS One. 11(3):e0150392.