Progress 01/14/14 to 12/31/18
Outputs
Target Audience:Scientic community: through scientific publications, presentations, workshops and symposia at scientific meetings, Presentations to non-science based audiences, classroom instruction to students, the public through individual dissemenation and inqueries and to Industry through invited presentations. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?We have trained graduate and undergraduate students from my laboratory and the laboratories of my fellow faculty members How have the results been disseminated to communities of interest?We have presented our research at area hospitals, to physicians and community groups. We have presented at a variety of scientific meetings. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Specific aim #1 was accomplished and these data were reported in the following publications: A diagnosis for cancer can be very devastating to anyone. Treatments can be painful, with severe side effects. Individual variation to treatment is not uncommon where one individual responds to treatment and another does not. When the cancer "appears" to be eliminated, recurrence is always in the back of a cancer survivors mind. This research is designed to determine if bioactive foods can increase the effectiveness of standard therapies, reduce the variability of response from individual to individual, and delay the recurrence of the disease whereby the individual will more likely die from something else (i.e., the cancer is no longer clinically relevant). In order for us to determine all of these things and identify the mechanisms of action (i.e., what genes are turned on and off; what signaling pathways are responsible), we needed to do the following. First, we had to figure out a way to duplicate how people eat using a mouse. We then had to show that "food" is more effective than individual nutrients in the food. We then had to demonstrate that when a combination of foods are provided they are very effective at fighting cancer. Finally, no one will believe you if you can't explain how all of this works, and that was the last part of the research (mechanisms). For Specific Aim #1: Food and bioactives in food are increasingly becoming important in health promotion and disease prevention. In order to better investigate the potential physiological effects of dietary constituents and their potential mechanism of actions, preclinical experimental rodent models are used because they are cost effective, duration of the experiments are much shorter, experimental conditions can be highly controlled, and working with humans present unique challenges not experienced with these other models. A huge challenge in this process is the lack of standardization in the design of experiments when translation of results to humans is inferred or desired; meaning how much should we be feeding to a mouse and what should the background diet look like so we get the same results in humans? Another way of saying this, we shouldn't be "bathing" rodents with a nutrient (pharmacological doses used in our experiments) when humans consume a tiny fraction of that in comparison. In order to insure that our experimental results can be translated to humans, we analyzed all of the most relevant mathematical models for these extrapolations and tested the best model. We found that translating dietary components based on differences of caloric consumption resulted in translational validity between species (i.e., rodents and humans). This information allows us to better design dietary experiments so that if the results are positive in rodents, they should also be positive in humans in the same way. For Specific Aim #2: Based on the results from Specific Aim #1, we then designed dietary experiments to figure out why consuming whole food is better that individual nutrients. A large body of evidence suggests that plant and botanical source of foods (vegetables, fruits, herbs, etc) can reduce the risk of a variety of cancers, but it has been difficult determining whether this is the result of the food or the nutrient in the food; meaning is the "whole" better than the "individual" parts. For example, turmeric has been identified as an anticancer food (herb) and much of its activity has been attributed to one component in that herb, curcumin. Is it really the curcumin or is curcumin working in synergy with all of the other bioactives in turmeric to account for the anticancer activity? Our results show that it is the combination of bioactives that give food its cancer fighting properties. To illustrate this, foods that contain vitamin E reduce the risk of skin cancer, while vitamin E supplements increase the risk. Foods that contain beta-carotene (the antioxidant on carrots) reduce the risk of lung cancer, while beta-carotene supplements increase the risk. It is the whole food, not the components that is most important. For Specific Aim #3: We have been working with a combination of 10 herbs as a cancer-fighting cocktail when used with standard therapies. This product, known as Zyflamend, has been shown to work with the following cancers: prostate, head&neck, breast, bone, skin, pancreas and the colon. Our research has shown that this combination works in humans and at human equivalent doses (see Specific Aims 1 & 2). We have found that this combination is effective because it acts simultaneously on more than 50 pathways involved in cancer without side effects, while chemotherapy drugs only work on one pathway at a time with very bad side effects. This combination prevents cancer cells from dividing because it deprives those cells of fats to make new membranes and proteins to keep them alive. They also increase the expression of tumor SUPPRESSOR genes to keep cells from dividing, and kills existing cells by increasing the signals for the cells to commit suicide (called apoptosis). Inflammation increases the risk of cancer and supports the growth of cancer. This combination of herbs attacks multiple signaling pathways involved in inflammation, and it down regulates the signaling of growth hormones that would otherwise promote cancer growth. Furthermore, we demonstrated that when provided along with standard therapies, the therapy with Zyflamend was more effective in fighting cancer and less variable. As a side issue that seems to be related to the same signaling pathways, this combination also appears to do the same thing to fat cells. It tells pre-fat cells not to divide or to be converted to "mature" fat cells, and signals them to kill themselves prematurely (apoptosis). With mature fat cells, it tells them to breakdown existing fat. We show that when mice consume human equivalent doses of Zyflamend, they have 40% less adipose tissue and are otherwise healthy. This may lead to additional therapies to combat obesity.
Publications
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2018
Citation:
Whelan, J., Puckett, D., Frankel, V.D., Alani, D., Chahed, S., Donohoe, D.R. and Bettaieb, A. Zyflamend Attenuates High Fat Diet-Induced Obesity in Mice. Am Soc Nutr, Boston, MA June 2018
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2018
Citation:
Whelan, J., MacDonald, A., Bettaieb, A., Donohoe, D., Han, A., and Zhao, Y. Cancer regulatory proteins LKB1 and CaMKK2 are antithetically regulated via the activation of PKCzeta and DAPK, respectively, by a well-defined polyherbal blend, Zyflamend. Am Soc Nutr, Boston, MA June 2018
|
Progress 10/01/17 to 09/30/18
Outputs
Target Audience:The general public, food scientists, nutritionists, physicians, researchers in the biomedical field, dietitians, pharmacologists, ethnobotonists, policy makers, and government agencies, and government representatives Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The project resulted in a Thesis published in 2017. This project provided the necessary training of a graduate student to pursue a career in research investigating the health-promoting effects of diet. How have the results been disseminated to communities of interest?Presentations at Scientific Meetings: 1. Whelan, J., Puckett, D., Frankel, V.D., Alani, D., Chahed, S., Donohoe, D.R. and Bettaieb, A. Zyflamend Attenuates High Fat Diet-Induced Obesity in Mice. Am Soc Nutr, Boston, MA June 2018. 2. Whelan, J., MacDonald, A., Bettaieb, A., Donohoe, D., Han, A., and Zhao, Y. Cancer regulatory proteins LKB1 and CaMKK2 are antithetically regulated via the activation of PKCzeta and DAPK, respectively, by a well-defined polyherbal blend, Zyflamend. Am Soc Nutr, Boston, MA June 2018. Pesentation to a Prostate Cancer Survival group at the University of Tennessee Medical Center, titled "The Power of "Z": What role can dietary bioactives play in cancer survival?' What do you plan to do during the next reporting period to accomplish the goals?I plan to continue some efforts related to Specific Aim #1: Establish human equivalent levels of select bioactive compounds for proper translation from experimental models to humans. We have confirmed in a pre-clinical rodent model that combinations of food components can have beneficial health effects at hunman equivalent dosing. Buckley, M.R., Grandas, O.H., Bools, L.M., Kirkpatrick, S.S., Whelan, J., Terry, P.D., Freeman, M.B., Mountain, D.J.H. 2018. Zyflamend, a Poly-Herbal Dietary Supplement, Inhibits Intimal Hyperplasia Development in a Rodent Model of Vascular Injury. J. Vascul Surg (in review). In this case, the endpoint is vascular injury, The endpoint is not so much as important as the fact that the dosing we are using can have significant health promoting prroperties and the dosing is based on the synergistic effects of "food" components. People eat food, not purified compounds. We are testing tranlational validity in an equivalent human situation, thus allowing us to further address Specific Aim #1.
Impacts
What was accomplished under these goals?
Basic research investigating the health promoting effects of "food" has focused exclusively on identifiable bioactive nutrients in the food with the assumption that the primary benefit of that food is derived from a single compound. For example, foods that contain beta-carotene (the major antioxidant in orange and yellow colored vegetables, like carrots) reduce the risk of lung cancer. However, when scientists found that taking beta-carotene supplements increased the risk of lung cancer, they realized that "food" has a different effect than any single nutrient in it. Secondly, when we investigate how dietary components "work", we have to use preclinical models (such as animals) to investigate what genes and proteins are turned on and off to explain the physiological events. To have translational validity between species (i.e., the same results in mice will also occur in humans, in the same way, at the same dose), we need to know how much food or nutrient to give to the mouse so it is equivalent to what people would eat. Unfortunately, we are trained as scientists to identify a "dose that works" in rodents, not a dose that translates to people. The "dose that works" could be thousands of times higher than what could possibly be consumed by a person. In the end, we want to know three things: (1) can we effectively determine a mathematical model that will accurately translate the amounts of nutrients in the diet of rodents to the diet of humans (Specific Aim #1); (2) are the combination of nutrients in foods responsible for the health-promoting effects, or is it due to a single nutrient in that specific food (Specific Aim #2); (3) identify how these combinations work in promoting health (Specific Aim #3). In the last year, we were able to determine a mathematical model that could equate the amount of food or the amount of a nutrient in a rodent diet to the amount in a human diet (Specific Aim #1). (Published in the following mansucript: Whelan, J. 2017. Lost in Translation: Allometric Scaling of Bioactive Dietary n-3 and n-6 Fatty Acids. Functional Foods Health Dis. 7:314-328). This is critical when you want to know how this food works at the cellular and molecular level and be confident that it works the same way in people. If it reduces the growth of cancer in mice by altering the expression of genes, you want to know it will do the same thing in people, in the same way, at the same amount consumed. Previously, this has been a problem and a challenge in research. Our resultsshow that when you scaled up or down the amount of food or nutrient based on the differences in metabolic activity, you would get the same results in mice and people. For example, 3% calories of a fat in the diet of a mouse equals 3% calories of that same fat in a human. This extrapolation is simple, but highly effective and accurate, and the first time scientifically validated. If adopted, this model will lead to better experimental designs by scientists. This was tested in mice with prostate cancer and humans with prostate cancer, where we found that the same comparable dose of a group of plant products reduced the blood levels of prostate specific antigen (PSA) in mice and humans in the same way. PSA is an important biomarker of prostate cancer. (Published in the following mansucript:Tague, E., Voy, B.H., Campagna, S., Lookadoo, M.S., Bourdan, K., MacDonald, A., Kim, E.D., White, W.M., Terry, P.D. and Whelan, J. 2018. Metabolomics Approach in the Study of the Well-defined Polyherbal Preparation Zyflamend J. Med. Food. 21:306-316). We are also testing our mathematical model by conducting similar comparable experiments with mice and humans who have vascular injuries. (Submitted for publication in the following mansucript: Buckley, M.R., Grandas, O.H., Bools, L.M., Kirkpatrick, S.S., Whelan, J., Terry, P.D., Freeman, M.B., Mountain, D.J.H. 2018. Zyflamend, a Poly-Herbal Dietary Supplement, Inhibits Intimal Hyperplasia Development in a Rodent Model of Vascular Injury. J. Vascul Surg (in review).) How and why are food and food products more effective than any individual nutrient in the food in promoting health (Specific Aim #3)? Meaning, is it better to take vitamin E supplements or foods that contain vitamin E? Is it better to take supplements of resveratrol (a phytonutrient found in red wine) or foods that contain resveratrol? We published a paper summarizing how a group of herbs decreases prostate cancer and specifically how they work. If you take a pharmaceutical drug, it is designed to attack a single metabolic pathway important to the cancer cell. However, when you consume a food-derived product with many bioactive nutrients they impact 10, 20, 30 pathways important in cancer growth (Published in the following review: Whelan, J., Zhao, Y., Huang, E.-C., MacDonald, A. and Donohoe, D. 2017. Zyflamend and Prostate Cancer Therapy. In: Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R..; Ed., Harikumar, K.B.) CRC Press. Boca Raton, FL. Chapter 11, Pp. 197-220.) While they may not be able to eradicate the cancer, collectively they lower the defense mechanisms of the cancer cell allowing the cancer treatment to be more effective. (Published in the following mansucripts: Tague, E., Voy, B.H., Campagna, S., Lookadoo, M.S., Bourdan, K., MacDonald, A., Kim, E.D., White, W.M., Terry, P.D. and Whelan, J. 2018. Metabolomics Approach in the Study of the Well-defined Polyherbal Preparation Zyflamend J. Med. Food. 21:306-316; and MacDonald, A.F., Bettaieb, A., Donohoe, D.R. Han, A., Zhao, Y. and Whelan, J. 2018. Concurrent Regulation of LKB1 and CaMKK2 in the Activation of AMPK by Zyflamend, a Polyherbal Mixture with Anticancer Properties. BMC Altern Complem Med, 18:188.) In summary, for health promotion and disease prevention, "food" is better than supplements. The reason is the synergistic action of its bioactive and non-bioactive components that affect multiple signaling pathways at the same time. To better understand how food is health promoting, we needed to accurately translate the amount of food consumed between rodent models and humans so we can design better scientific experiments.
Publications
- Type:
Book Chapters
Status:
Published
Year Published:
2017
Citation:
Zyflamend and Prostate Cancer Therapy. In:
Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R.; Ed, Harikumar, K.B.)CRC Press. Boca Raton, FL. Chapter 11, Pp. 197-220.
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Whelan, J. 2017. Lost in Translation: Allometric Scaling of Bioactive Dietary n-3 and n-6 Fatty Acids. Functional Foods Health Dis. 7:314-328
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
MacDonald, A.F., Bettaieb, A., Donohoe, D.R. Han, A., Zhao, Y. and Whelan, J. 2018. Concurrent Regulation of LKB1 and CaMKK2 in the Activation of AMPK by Zyflamend, a Polyherbal Mixture with Anticancer Properties. BMC Altern Complem Med, 18:188.
- Type:
Journal Articles
Status:
Published
Year Published:
2018
Citation:
Tague, E., Voy, B.H., Campagna, S., Lookadoo, M.S., Bourdan, K., MacDonald, A., Kim, E.D., White, W.M., Terry, P.D. and Whelan, J. 2018. Metabolomics Approach in the Study of the Well-Defined Polyherbal Preparation Zyflamend J. Med. Food. 21:306-316.
- Type:
Journal Articles
Status:
Under Review
Year Published:
2018
Citation:
Buckley, M.R., Grandas, O.H., Bools, L.M., Kirkpatrick, S.S., Whelan, J., Terry, P.D., Freeman, M.B., Mountain, D.J.H. 2018. Zyflamend, a Poly-Herbal Dietary Supplement, Inhibits Intimal Hyperplasia Development in a Rodent Model of Vascular Injury. J. Vascul Surg (in review)
- Type:
Theses/Dissertations
Status:
Published
Year Published:
2017
Citation:
Amber MacDonald, AMPK Activation by Zyflamend: A novel pathway regulating metabolism and growth in prostate cancer.
|
Progress 10/01/16 to 09/30/17
Outputs
Target Audience:The general public, food scientists, nutritionists, physicians, researchers in the biomedical field, dietitians, pharmacologists, ethnobotonists, policy makers, and government agencies, and government representatives Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?We have trained graduate and undergraduate students from my laboratory and the laboratories of my fellow faculty members. How have the results been disseminated to communities of interest?We have presented our research at area hospitals, to physicians and community groups. We have presented at a variety of scientific meetings. What do you plan to do during the next reporting period to accomplish the goals?We are vigorouly exploring additional mechanisms as to how a polyherbal mixture of natural bioactives combats, not only cancer, but can prove eficacious on cardiovascular outcomes, obesityand pancreeatitis. These experiments are a continuation of Specific Aim #3. Our preliminary experiemnts in a rodent model of arterial injury demonstrates remarkable sucess in inhibiting the process of re-blockage with our polyherbal mixture. Thus, we are interested in the translation of our work: "From the land, to the lab to the clinic".
Impacts
What was accomplished under these goals?
Specific aim #1 was accomplished and these data were reported in the following publications: • Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. • Burke, S.J., Karlstad, M.K., Conley, C.P., Reel, D., Whelan, J. and Collier, J.J., 2015. Dietary Polyherbal Supplementation Decreases CD3+ Cell Infiltration into Pancreatic Islets and Prevents Hyperglycemia in Non-obese Diabetic Mice. Nutr Res 34:328-336. Specific Aim #2 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostatecancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. Whelan, J. 2017. Lost in Translation: Allometric Scaling of Bioactive Dietary n-3 and n-6 Fatty Acids. Functional Foods Health Dis. 7:314-328 Specific Aim #3 was accomplished and these data were reported in the following publications: Zhao, Y., Donohoe, D., Huang, E.-C. and Whelan, J. 2015. Zyflamend, a Polyherbal Mixture, Inhibits Lipogenesis and mTORC1 Signaling via Activation of AMPK. J Funct Foods. 18:147-158. Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Minkin, S., Biggerstaff, J.P., Zhao, Y. and Whelan, J. 2014. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Alternat Med 14:68. Huang, E-C, McEntee, M.F. and Whelan, J. 2012. Zyflamend, a combination of herbal extracts, attenuates tumor growth in murine xenograph models of prostate cancer. Nutr Cancer 64:749-760. Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Collier, J.J., Minkin, S., Biggerstaff, J., and Whelan, J. 2011. Zyflamend Reduces the Expression of Androgen Receptor in a Model of Castrate-Resistant Prostate Cancer. Nutr Cancer 63:1287-1296. Whelan, J., Zhao, Y., Huang, E.-C., MacDonald, A. and Donohoe, D. 2017.Zyflamend and Prostate Cancer Therapy. In: Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R.; Ed., Harikumar, K.B.)CRC Press. Boca Raton, FL. Chapter 11, Pp. 197-220. Tague, E., Voy, B.H., Campagna, S., Lookadoo, M.S., Bourdan, K., MacDonald, A., Kim, E.D., White, W.M., Terry, P.D. and Whelan, J. 2018. Metabolomics Approach in the Study of the Well-defined Polyherbal Preparation Zyflamend J. Med. Food (in press: doi: 10.1089/jmf.2017.0062). MacDonald, A.F., Bettaieb, A., Donohoe, D.R. Han, A., Zhao, Y. and Whelan, J. 2018. Concurrent Regulation of LKB1 and CaMKK2 in the Activation of AMPK by Zyflamend, a Polyherbal Mixture with Anticancer Properties.BMC Altern Complem Med (in review).
Publications
- Type:
Book Chapters
Status:
Published
Year Published:
2017
Citation:
Whelan, J., Zhao, Y., Huang, E.-C., MacDonald, A. and Donohoe, D. 2017. Zyflamend and Prostate Cancer Therapy. In: Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R.; Ed., Harikumar, K.B.) CRC Press. Boca Raton, FL. Chapter 11, Pp. 197-220
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Johnstone, M., Bennett, N., Standifer, C., Smith, A., Han, A., Bettaieb, A., Whelan, J. and Donohoe, D.R. 2017. Characterization of the Pro-inflammatory Cytokine IL-1? on Butyrate Oxidation in Colorectal Cancer Cells. J Cell Biochem 118:1614-1621.
- Type:
Journal Articles
Status:
Published
Year Published:
2017
Citation:
Whelan, J. 2017. Lost in Translation: Allometric Scaling of Bioactive Dietary n-3 and n-6 Fatty Acids. Functional Foods Hlth Dis. 7:314-328.
- Type:
Journal Articles
Status:
Accepted
Year Published:
2017
Citation:
Tague, E., Voy, B.H., Campagna, S., Lookadoo, M.S., Bourdan, K., MacDonald, A., Kim, E.D., White, W.M., Terry, P.D. and Whelan, J. 2018. Metabolomics Approach in the Study of the Well-defined Polyherbal Preparation Zyflamend J. Med. Food (in press: doi: 10.1089/jmf.2017.0062).
- Type:
Journal Articles
Status:
Under Review
Year Published:
2017
Citation:
MacDonald, A.F., Bettaieb, A., Donohoe, D.R. Han, A., Zhao, Y. and Whelan, J. 2018. Concurrent Regulation of LKB1 and CaMKK2 in the Activation of AMPK by Zyflamend, a Polyherbal Mixture with Anticancer Properties. BMC Altern Complem Med (in review).
- Type:
Journal Articles
Status:
Under Review
Year Published:
2018
Citation:
Butyrate Regulates Its Own Metabolic Fate Through Inhibition of HDAC1 Activity in Colorectal Cancer Cells. Han, A., Bettaieb, A., Whelan, J. and Donohoe, D.R. 2018. Oncotarget (in final revision).
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2017
Citation:
Whelan, J. Allometric scaling of bioactive dietary n-3 and n-6 fatty acids. Presented at a Symposium on Translating Human Diets and Nutrients to Rodent Diets for Research. Experimental Biology 17 Meeting (FASEB), Chicago, IL, 2017.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2017
Citation:
MacDonald, A., Donohoe, D., Bettaieb, A., Han, A., Zhao, Y., and Whelan, J. Combination of herbal extracts targets prostate cancer by upregulating AMPK thru the tumor suppressor protein LKB1. Experimental Biology 17 Meeting (FASEB), Chicago, IL, 2017.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2017
Citation:
Whelan, J. Lost in Translation: Allometric scaling of bioactive dietary n-3 and n-6 fatty acids. 21st Functional Foods Center International Conference, San Diego, CA, 2017.
- Type:
Theses/Dissertations
Status:
Published
Year Published:
2017
Citation:
Amber Francis MacDonald. AMPK Activation by Zyflamend: A novel pathway regulating metabolism and growth in prostate cancer
- Type:
Other
Status:
Other
Year Published:
2017
Citation:
Clinical Trial with UTMC and the Vascular Surgeons: Zyflamend and Percutaneous Lower Extremity Arterial Revascularization: A Clinical Trial . Co-PIs: Jay Whelan, PhD and Michael McNally, MD; Co-Is: Deidre Mountain, PhD, Paul terry, PhD, Oscar Grandas, MD, Michael Freeman, MD, Scott Stevens, MD, Joshua Arnold, MD, Ryan Buckley, MD, Mitchell Goldman, MD (in progress)
- Type:
Other
Status:
Other
Year Published:
2017
Citation:
Clinical Trial with UTMC. PIs: Jay Whelan, PhD, MPH and Paul Terry, PhD Zyflamend and Prostate Cancer: A Clinical Trial of Tumor Progression Biomarkers. Completed.
|
Progress 10/01/15 to 09/30/16
Outputs
Target Audience:The general public, food scientists, nutritionists, physicians, researchers in the biomedicalfield, dietitians, pharmacologists, ethnobotonists, policy makers, government agencies and the general public Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?We have trained graduate and undergraduate students form my laboratory and the laboratories of fellow faculty members. How have the results been disseminated to communities of interest?We have presented our research at area hospitals to physicians and community groups. We have presented at a variety of scientific meetings. I have been asked by the Organizers of the 21st International Scientific Meeting on Functional Foods to organize a scientific workshop/session (March 2017, San Diego, CA)on the best way to extrapolate dietary experiments in rodents to their proper application in humans. What do you plan to do during the next reporting period to accomplish the goals?We are vigorouly exploring additional mechanisms as to how a polyherbal mixture combats prostate cancer. These experiments are a continuation of Specific Aim #3. We are also in the initial phases of a clinical trail in patients who have to have stents put in to open up blocked arteries.Our preliminary experiemnts in a rodent model of arterial injury demonstrates remarkable sucess in inhibiting the process of re-blockage with our polyherbal mixture. Thus, we are interested in the translation of opur work: "from the land, to the lab to the clinic".
Impacts
What was accomplished under these goals?
Most of today's cancers are greatly influenced by our environment, particularly by the foods we eat. A day doesn't go by where there isn't something in the news reporting how diet can reduce the risk of getting sick (i.e., cancer) or promote health. While the scientific community is generating data on what foods can influence health, our ability to explain the mechanism of actions is a work in progress primarily because we do not use the foods we eat to try and explain how they work. Instead, we identify an isolated bioactive compound in the food to test, such as a vitamin or a phytochemical (i.e., vitamin C or resveratrol, respectively). We do this because we believe the individual nutrient accounts for most of the beneficial effects of the food. Unfortunately, the research is flawed because when these nutrients are supplemented in the diet, typically their effects are not consistent with the results generated in the laboratory. This research is designed to provide a translational bridge between the results generated in the laboratory and clinical outcomes in humans. This begins with identifying human equivalent doses to help better design the experiments done in the lab. The second is demonstrating that combinations of bioactive compounds (i.e, food) work much better at promoting health and combating disease than any compound in isolation. Third, demonstrate that these combinations work, in part, due to their synergy, working simultaneously in multiple ways. In summary, this research is designed to demonstrate that combinations of bioactive nutrients in found in plants and foods are better in promoting health and combating disease than the individual constituents found within the food. This project was directed by Dr. Jay Whelan with help from students who work in his laboratory. The following summaries provide an overview as to what we accomplished with regards to this project. The major goals of this project To determine that botanicals may be more effective against cancer than individual compounds derived from botanicals and identify mechanisms responsible for these effects. Specific Aim #1: Establish human equivalent levels of select bioactive compounds for proper translation from experimental models to humans. Specific Aim #2: Compare the effectiveness on inhibiting cancer cell viability of botanicals, compounds derived from those botanicals, and their combinations. Specific Aim #3: Identify mechanisms of action for combinations of botanicals at human equivalent doses. What was accomplished under these goals? Specific aim #1 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. Burke, S.J., Karlstad, M.K., Conley, C.P., Reel, D., Whelan, J. and Collier, J.J., 2015. Dietary Polyherbal Supplementation Decreases CD3+ Cell Infiltration into Pancreatic Islets and Prevents Hyperglycemia in Non-obese Diabetic Mice. Nutr Res 34:328-336. Specific Aim #2 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. Specific Aim #3 was accomplished and these data were reported in the following publications: Zhao, Y., Donohoe, D., Huang, E.-C. and Whelan, J. 2015. Zyflamend, a Polyherbal Mixture, Inhibits Lipogenesis and mTORC1 Signaling via Activation of AMPK. J Funct Foods. 18:147-158. Buckley, M.R., Grandas, O.H., Bools, L.M., Kirkpatrick, S.S., Whelan, J., Terry, P.D., Freeman, M.B., Mountain, D.J.H. 2016. Zyflamend, a Poly-Herbal Dietary Supplement, Inhibits Intimal Hyperplasia Development in a Rodent Model of Vascular Injury. J. Vascul Surg (in review). Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Minkin, S., Biggerstaff, J.P., Zhao, Y. and Whelan, J. 2014. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Alternat Med 14:68. Huang, E-C, McEntee, M.F. and Whelan, J. 2012. Zyflamend, a combination of herbal extracts, attenuates tumor growth in murine xenograph models of prostate cancer. Nutr Cancer 64:749-760. Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Collier, J.J., Minkin, S., Biggerstaff, J., and Whelan, J. 2011. Zyflamend Reduces the Expression of Androgen Receptor in a Model of Castrate-Resistant Prostate Cancer. Nutr Cancer 63:1287-1296. Our overall results are summarized in a book chapter describing how combinations of foods can effectively treat cancer with no side effects. This was published in the follow manuscript to be published on November 2016: Whelan, J., Zhao, Y., Huang, E.-C., MacDonald, A. and Donohoe, D. 2016. Zyflamend and Prostate Cancer Therapy. In: Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R..; Ed., Harikumar, K.B.) CRC Press. Boca Raton, FL. (in press). What have we learned from all of this? Agricultural products are important for health promotion and disease prevention, but also in the treatment of existing conditions. Agricultural products can be used in conjunction with standard therapies to improve their effectiveness, reduce their side effects by sensitizing "bad" cells (i.e, cancer cells) to make the therapies work better. We have done this with cancer, with diabetes and with cardiovascular disease.
Publications
- Type:
Book Chapters
Status:
Awaiting Publication
Year Published:
2016
Citation:
Whelan, J., Zhao, Y., Huang, E.-C., MacDonald, A. and Donohoe, D. 2016. Zyflamend and Prostate Cancer Therapy. In: Complementary and Alternative Medicines in Prostate Cancer: A Comprehensive Approach. (Sr. Ed., Hardman, R..; Ed., Harikumar, K.B.) CRC Press. Boca Raton, FL. (in press).
- Type:
Books
Status:
Accepted
Year Published:
2016
Citation:
Whelan J. Interpretive Summary. In: Omega-3 Fatty Acids: Health Benefits and Dietary Recommendations. (Authors: Beitz, D.C., Banz, W.J., Brenna, T. and Calder, P.C.) Special Publication No. 32. Council for Agricultural Science and Technology, Ames, IA. (in press).
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Han, A., Bennett, N., MacDonald, A., Johnstone, M., Whelan, J. and Donohoe, D.R. 2016. Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells. J. Cell. Physiol. 231:18041813.
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Johnstone, M., Bennett, N., Standifer, C., Smith, A., Han, A., Bettaieb, A., Whelan, J. and Donohoe, D.R. 2016. Characterization of the Pro-inflammatory Cytokine IL-1? on Butyrate Oxidation in Colorectal Cancer Cells. J. Cell Biochem (in press).
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2016
Citation:
MacDonald, A., Zhao, Y., Han, A., Donohoe, D. and Whelan, J. Activation of AMP Kinase by Zyflamend, a Well-defined Blend of Herbal Extracts. Experimental Biology 16 Meeting (FASEB), San Diego, CA, April 2016.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2016
Citation:
Beckford, R., Howard, S., Das, A., Tester, A., Campagna, S., Whelan, J., Wilson, J. and Voy, B. Enriching the Maternal Diet in Long Chain N-3 Polyunsaturated Fatty Acids Alters Lipid Metabolites and Adiposity in Broiler Chicks. Experimental Biology 16 Meeting (FASEB), San Diego, CA, April 2016.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2016
Citation:
Whelan, J., Donohoe, D., Zhao, Y. Huang, E-C., and MacDonald, A. A combination of herbal extracts increases LKB1-dependent activation of AMPK, a result not shared by CaMKK2. 20th Functional Foods Center International Conference, Harvard University, Boston, MA September 2016.
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Progress 10/01/14 to 09/30/15
Outputs
Target Audience:The target audience are several. They include scientist in the field of Food Science, physicians, researchers in the biomedical sciences, dietitians, nutritionists, pharmacologists, ethobotonists, and the general public. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?I have graduated 2 doctoral students with their PhD degrees.In addition, learning opportuniites have been realized with co-collaborators from other laboratories, i.e., Dr. Jason Collier, Dr. Guoxun Chen, Dr. Sueng Baek, Dr. Michael Karlstad, Dr. Micahel McEntee, Dr. Steven Minkin, and Dr. John Biggerstaff, Dr. Susan Burke. How have the results been disseminated to communities of interest?I have presented my dataat scientific meetings (I.e., Experimental Biology, Boston MA, 2 oral presntation). I also presented a 4 hour workshop to the heads of Research and Development (National and International), along with the Pharmacology group and the product development group at Procter and Gamble Company, Cincinnati, OH (January 15-16, 2015). I have shared my data with physicians at M D Anderson Cancer Research Center, Houston, TX. What do you plan to do during the next reporting period to accomplish the goals?I plan to write and present a review chapter on the Impact of Zyflamend on Prostate Cancer and explore its effects on intinal:meda remodeling following arterial injury (cardiovascular disease).
Impacts
What was accomplished under these goals?
Specific aim #1 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. Specific Aim #2 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NFkB signaling. J Functional Foods in Health and Disease. 4:312-339. Specific Aim #3 was in part accomplished and these data were reported in the following publications:Zhao, Y., Donohoe, D., Huang, E.-C. and Whelan, J. 2015. Zyflamend, a Polyherbal Mixture, Inhibits Lipogenesis and mTORC1 Signaling via Activation of AMPK. J Funct Foods. 18:147-158. Burke, S.J., Karlstad, M.K., Conley, C.P., Reel, D., Whelan, J. and Collier, J.J., 2015. Dietary Polyherbal Supplementation Decreases CD3+ Cell Infiltration into Pancreatic Islets and Prevents Hyperglycemia in Non-obese Diabetic Mice. Nutr Res 34:328-336. Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Minkin, S., Biggerstaff, J.P., Zhao, Y. and Whelan, J. 2014. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Alternat Med 14:68.
Publications
- Type:
Journal Articles
Status:
Awaiting Publication
Year Published:
2015
Citation:
Dinwiddie, M.T., Terry, P.D., Whelan, J. and Rachel E. Patzer. 2015. Omega-3 Fatty Acid Consumption and Prostate Cancer: A Review of Exposure Measures and Results of Epidemiological Studies. J Am College Nutr (in press).
- Type:
Journal Articles
Status:
Published
Year Published:
2015
Citation:
Burke, S.J., Karlstad, M.K., Conley, C.P., Reel, D., Whelan, J. and Collier, J.J., 2015. Dietary Polyherbal Supplementation Decreases CD3+ Cell Infiltration into Pancreatic Islets and Prevents Hyperglycemia in Non-obese Diabetic Mice. Nutr Res 34:328-336.
- Type:
Journal Articles
Status:
Published
Year Published:
2015
Citation:
Zhao, Y., Donohoe, D., Huang, E.-C. and Whelan, J. 2015. Zyflamend, a Polyherbal Mixture, Inhibits Lipogenesis and mTORC1 Signaling via Activation of AMPK. J Funct Foods. 18:147-158.
- Type:
Journal Articles
Status:
Awaiting Publication
Year Published:
2015
Citation:
Finch, E.R., Kudva, A.K., Quickel, M.D., Kennett. M.J., Whelan, J., Paulson, R.F. and Prabhu, K.S. 2015. The Role of Dietary Eicosapentaenoic Acid Supplementation in Experimental Chronic Myelogenous Leukemia. Cancer Prev. Res (in press).
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2015
Citation:
Whelan, J. Zhao, Y. and Donohoe, D. Polyherbal Supplements can Modify Energetics and Lipid Metabolism in Cancer Cells by Activating AMPK Signaling. Experimental Biology 15 Meeting (FASEB), Boston, MA. April 2015. (Oral presentation)
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2015
Citation:
Polyherbal Supplements can Modify Energetics and Lipid Metabolism in Cancer Cells by Activating AMPK Signaling . Experimental Biology 15, Session Chair: Mechanisms of Action and Molecular Targets of Dietary Bioactive Components , Boston, MA, April 2015.
- Type:
Other
Status:
Other
Year Published:
2015
Citation:
The Aspirations of Zyflamend in Promoting Health
Presented as part of a 4 hour workshop at Procter and Gamble Company, Cincinnati, OH January 15-16, 2015
- Type:
Other
Status:
Other
Year Published:
2015
Citation:
Zyflamend and AMPK Signaling
Presented as part of a 4 hour workshop at Procter and Gamble Company, Cincinnati, OH January 15-16, 2015
- Type:
Other
Status:
Other
Year Published:
2015
Citation:
Translational Research: From the Land, to the Lab, to the Public -
Putting theory into practice
Presented as part of a 4 hour workshop at Procter and Gamble Company, Cincinnati, OH January 15-16, 2015
- Type:
Other
Status:
Other
Year Published:
2015
Citation:
Why does Zyflamend Succeed while Individual Bioactives Fail?
Presented as part of a 4 hour workshop at Procter and Gamble Company, Cincinnati, OH January 15-16, 2015
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Progress 01/14/14 to 09/30/14
Outputs
Target Audience: The general public, scientists in the field Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? Yi Zhao, a PhD student in my laboratory has been trained to carry out the eork associated with these projects. In addition, learning opportuniites have been realized with co-collaborators from other laboratories, i.e., Dr. Jason Collier, Dr. E-Chu Huang,Dr. GuoxunChen, Dr. Sueng Baek, Dr. Micahel McEntee,Dr. Steven Minkin, and Dr. John Biggerstaff. How have the results been disseminated to communities of interest? We have presented our research at area hospitals to physicians and community groups. We have presented at a variety of scientific meetings, i.e., Conference on Metabolism, Diet and Disease, Washington, DC, May 2014; Experimental Biology ‘14 Meeting (FASEB), San Diego, CA, April 2014; made presentations at other Research I institutions: “The role of phytonutrients in the treatment of prostate cancer", Invited lecture at Penn State University (Department of Veterinary and Biomedical Sciences), February 2014. We have published our data in a variety of scientific journals What do you plan to do during the next reporting period to accomplish the goals? We plan on identifying the molecular mechanisms respopnsible for the anti-caner effects of our botanical mixture (Specific Aim #3)
Impacts
What was accomplished under these goals?
Specific aim #1 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NF-kB signaling. J Functional Foods in Health and Disease. 4:312-339. Specific Aim #2 was accomplished and these data were reported in the following publications: Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NF-kB signaling. J Functional Foods in Health and Disease. 4:312-339. We are currently working on Specific Aim #3.
Publications
- Type:
Book Chapters
Status:
Awaiting Publication
Year Published:
2014
Citation:
Whelan, J., Hardy, R., Wilkes, R.S. and Valentine, H. 2014. Sustainable Production of Omega-3 Fatty Acids. In Convergence of Food Security, Energy Security and Sustainable Agriculture, Springer, Germany (in press).
- Type:
Journal Articles
Status:
Published
Year Published:
2014
Citation:
Huang, E-C, Chen, G., Baek, S.J., McEntee, M.F., Minkin, S., Biggerstaff, J.P., Zhao, Y. and Whelan, J. 2014. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Alternat Med 14:68.
- Type:
Journal Articles
Status:
Published
Year Published:
2014
Citation:
Zhao, Y., Collier, J.J., Huang, E.C. and Whelan, J. 2014. Turmeric and Chinese goldthread synergistically inhibit prostate cancer cell proliferation and NF-kB signaling. J Functional Foods in Health and Disease. 4:312-339.
- Type:
Journal Articles
Status:
Under Review
Year Published:
2014
Citation:
Fritsche, K.L, Jones L.J., Pearson, L.J., and Whelan, J. 2014. Eicosapentaenoic acid supplementation diminishes murine resistance to infection from Listeria monocytogenes J. Nutr Biochem. (in review).
- Type:
Journal Articles
Status:
Under Review
Year Published:
2014
Citation:
Michael T. Dinwiddie, M.T., Terry, P.D., Whelan, J. and Rachel E. Patzer. 2014. Omega-3 Fatty Acid Consumption and Prostate Cancer: the Methodology of Measurement. (in review).
- Type:
Journal Articles
Status:
Under Review
Year Published:
2014
Citation:
Burke, S.J., Karlstad, M.K., Conley, C.P., Reel, D., McEntee, M.F., Whelan, J. and Collier, J.J., 2014. A Polyherbal Dietary Intervention Preserves Functional Islet ?-cell Mass in Non-obese Diabetic Mice. Evidence-based Complementary and Alternative Medicine. (in review)
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2014
Citation:
Zhao, Y. and Whelan, J. The interaction of botanicals and AMPK signaling in the inhibition of castrate-resistant prostate cancer. Conference on Metabolism, Diet and Disease, Washington, DC, May 2014
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2014
Citation:
Zhao, Y. and Whelan, J. Why food matrices are more potent against cancer as compared to their isolated bioactives. Experimental Biology 14 Meeting (FASEB), San Diego, CA, April 2014.
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2014
Citation:
Burke, S.J., Karlstad, M.D., Reel, D., McEntee, M.F., Whelan, J and J. Jason Collier, J.J. A Polyherbal Dietary Intervention Preserves Functional Islet Beta-cell Mass in Non-obese Diabetic Mice. Experimental Biology 14 Meeting (FASEB), San Diego, CA, April 2014.
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