Location: Diet, Genomics and Immunology Laboratory2015 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. 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.
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:
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 hydroxybenzoic acids, hydroxycinnamic acids, chlorogenic acids, and veskamide-type, caffedymine-type, and safflomide-type phenolic amides (e.g., safflomide, javamide-I and-II) on obesity, sub-clinical inflammation, hypertension and chronic kidney disease (CKD). This year, we investigated potential effects of safflomide and safflomide-type phenolic amides (javamide-I and-II) on health events related to hypertension and CKD. Javamide-I and -II are found in coffee, with similar structures like safflomide. Although the javamides are found in coffee (0.5-3mg/g), there is currently no information related to hypertension and CKD. We found that safflomide alleviated hypertension by lowering bodyweight in a rodent model. Since the javamides are similar in chemical structures to safflomide, animal study is under way to determine whether the javamides in coffee can act the same as safflomide in vivo. Also, we found that javamide-I and -II suppress the expression of MCP-1 in CKD in vitro and in vivo. MCP-1 is a chemokine that plays a crucial role in tubulointerstitial inflammation. Therefore, javamides protect against CKD through inhibition of inflammation pathway. To further elucidate javamides anti-inflammatory actions, we are currently performing several assays of immune-related biomarkers such as COX, NF-kB, p38, IL-6, TNF-alpha. Additionally, we also found that javamide-II may be a potent sirtuin1/2 inhibitor. The Sirtuins consist of a family of seven proteins with highly conserved NAD+-binding domain (SIRT1–7). All sirtuin proteins except SIRT4 have deacetylase activity, and they can deacetylate internal acetylated lysine residues at their e-amino groups. This reversible post-translational modification swiftly manipulates a protein’s activity, thereby regulating critical processes such as metabolism, transcription, proliferation, and cell death. In our study, potential sirtuin2 inhibitors were screened using coffee samples. The screening led to the isolation of an active compound, and the chemical structure of the compound was determined as N-caffeoyltryptophan (Javamide-II) using HPLC and NMR spectroscopic techniques for the first time. At relatively low concentrations, Javamide-II inhibited sirtuin2 activity significantly. To confirm that Javamide-II is the compound able to inhibit sirtuin2, the amide was chemically synthesized for the first time and its capability of inhibiting sirtuin2 was evaluated. We found that both isolated and synthesized N-caffeoyltryptophan exhibited very similar pattern of sirtuin2 noncompetitive inhibition. Hence, javamide may affect post-translational events.
1. Isolation and synthesis of Javamide-I and -II found in coffee. The javamides are phenolic amides found in coffee. However, there is currently no information related to their effect on human health and purified compounds are not available. A novel purification method and a chemical synthesis method were successfully developed by ARS researchers in the Beltsville Human Nutrition Research Center, Beltsville, Maryland, that allow for obtaining large quantities of Javamide-I and –II. Availability of the compounds and methods for their purification and synthesis provide valuable tools that will facilitate investigation of the biological effects on human health.
2. Javamide-I and -II and Monocyte Chemotardiv Protein 1 (MCP-1). Inflammation-associated tubulointerstitial injury is a common pathogenetic feature of chronic kidney disease (CKD). Increased expression of MCP-1 may play a crucial role in tubulointerstitial inflammation by recruiting and activating macrophages. ARS researchers in the Beltsville Human Nutrition Research Center, Beltsville, Maryland, observed, at relatively low concentrations, the amides inhibited MCP-1 mRNA expression and suppress the production of MCP-1 protein. This was the first report that coffee chemicals, javamide-I and -II, are potent suppressors of MCP-1, a major player in tubulointerstitial inflammation. Importantly, these results provide molecular evidence that coffee consumption may help alleviate tubulointerstitial inflammation in CKD.
3. Javamide-II and sirtuin2. ARS researchers in the Beltsville Human Nutrition Research Center, Beltsville, Maryland, identified Javamide II as a novel sirtuin2 inhibitor. This observation provided critical information on novel mechanisms by which coffee or coffee-derived compounds may exert their health promoting effects on human diseases.
Park, J.B. 2015. Becatamide found in Houttuynia cordata suppresses P-selectin expression via inhibiting COX enzyme, not increasing cAMP in platelets. Phytotherapy Research. DOI: 10.1002/ptr.5391
Park, J.B. 2014. Potential effects of chlorogenic acids on platelet activiation. In: Preedy, V.R., editor. Coffee in Health and Disease. Academic Press. Amersterdam, Boston, New York. Book Chapter. p709-715.