Progress 04/01/23 to 03/31/24
Outputs
Target Audience:The target audiences included professionals, scientists, researchers, students (graduate and undergraduate), consumer advocates, commodity groups interested in the field of foods for health, nutrition, inflammatory diseases and obesity. Changes/Problems:Some of the challenges encountered had to do with delays in some supplies, supplies changes, and unexpected delays in the hiring of personnel. We had some challenges with the control corn P-ww diet. The formulation developed by the nutritionist had to be discontinued. Thus, some of the experiments using the corn diet will need to be repeated. What opportunities for training and professional development has the project provided?During this period the project contributed to the training of a graduate student, a lab aid, and two senior scientists. How have the results been disseminated to communities of interest?Results have been communicated by several means including oral presentations, posters, and publications: Oral Presentations Doseff, A.I. Invited Speaker Gordon Conference. Metabolic Engineering in Plants: Sustainability Through Innovation (June 11-16). À La Carte: Dietary Flavones Reprogramming Aberrant Splicing in Cancer and Obesity. Session: Making Medicines in Plants. Barcelona, Spain Doseff, A.I. Targeting cancer and immune cell fate with dietary phytochemicals. Arkansas State University. Departmentof Biology and Arkansas Biosciences Institute, Jonesboro, Arkansas.(October 21). Doseff, A.I. Plenary speaker. Plenary speaker. 2022 (October 18-20). Flavone apigenin triggers transcriptome reprogramming reducing inflammation through its association with novel protein target. 12th American Council of Medicinally Active Plants (ACMAP). West Virginia State University, Institute, West Virginia. Doseff, A.I. Reprogramming tumor driven transcriptome and immune landscape by dietary flavonoids and its impact on chronic inflammatory diseases. West Virginia University Cancer Institute. Morgantown, West Virginia.(October 3-4). Doseff, A.I. Targeting immune cell fate with dietary phytochemicals. University of Northern Texas, Denton, Texas.(April 4-6, 2024). Posters Kariagina, A., Donado Pestana, Carlos, Guzior, D.V., Hernandez, C.M., Quinn, M., Quinn, R.A., and Doseff, A.I. 2022 (October 20th). Flavone-rich celery-based apigenin rich diet reduces obesity-associated inflammation and microbial dysbiosis. Physiology Research Symposium. Michigan State University. Publications 1. Kariagina, A. and Doseff, A.I. (2022). Anti-Inflammatory mechanisms of dietary flavones: Tapping into nature to control chronic inflammation in obesity and cancer. Int. J. Mol. Sci. 23:(24): 15753-15780. 2. Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. (2022). Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants. J. Medicinally Active Plants. 10 (4): 74-81. An additional publication is under review What do you plan to do during the next reporting period to accomplish the goals?We will analyze the metabolomic data. We will continue the quantitative studies to evaluate the effect of celery-based whole foods rich in apigenin in the microbiome and integrate with the metabolomic results. We will do some of the experiments related with aim 2.
Impacts
What was accomplished under these goals?
We demonstrated that consumption of HFD-supplemented with CEBAR significantly reduced adipocyte size in all three adipose depots studied. These effects were accompanied by a reduction of leptin and an increase in adiponectin. In addition, we found that mice fed with HFD-supplemented with CEBAR showed a significant reduction of macrophages in adipose tissues compared to mice fed with HFD alone, reaching a number found in mice fed with the control diet. Since the last report we found that the reduction of macrophages did not result in a switch from pro-inflammatory M1 to M2 but rather reduced infiltration into adipose tissues, results that can be explained by the significant decrease in the levels of macrophage chemoattractant factor (MCP-1) observed. A significant decrease in inflammatory cytokines Interleukin 1b (IL-1b) and Tumor Necrosis Factor (TNF) were observed in adipose tissues of mice fed with HFD-supplemented with CEBAR compared to HFD alone, reaching levels similar to those found in the control diet. These results suggest that the CEBAR diet reduces HDF-induced inflammation in adipose tissues and restores the number of macrophages to levels found in lean animal controls. In addition, we found that the CEBAR diet increases the expression of lipolytic genes in white adipose tissues, results that may explain the significant reduction of body weight observed in mice fed with HFD-supplemented with CEBAR compared with HFD alone. These results suggest that the CEBAR diet reduces obesity possibly by altering lipid homeostasis. We conducted microbiome analyses from cecum and feces of mice fed with control diet, HFD alone or supplemented with CEBAR. We found that CEBAR supplementation increased the presence of fecal Bacteroidetes, lowering the high ratio Firmicutes/Bacteroidetes ratio significantly reduced in HFD-supplemented with CEBAR compared to HFD, reaching levels indistinguishable from the control diet. The Lachnospiraceae family was the most significantly impacted by the CEBAR supplementation, showing distinct regulation of various genera. Among the critical results, we found CEBAR significantly increases the levels of the genus Blautia compared to mice fed with HFD alone. These results are significant since Blautia has been shown to decrease inflammation and HFD-induced obesity in mice and humans (Hosomi et al., Nat. Communications, 2022). Our results revealed that the CEBAR diet alters the HFD-induced microbiome composition increasing the levels of additional genera that have been associated with reduced obesity. In addition, we started the metabolome analyses. Preliminary results show large changes in the fecal metabolome.
Publications
- Type:
Journal Articles
Status:
Accepted
Year Published:
2022
Citation:
Kariagina, A. and Doseff, A.I. (2022). Anti-Inflammatory mechanisms of dietary flavones: Tapping into nature to control chronic inflammation in obesity and cancer. Int. J. Mol. Sci. 23:(24): 15753-15780.
- Type:
Journal Articles
Status:
Accepted
Year Published:
2022
Citation:
Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. (2022). Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants. J. Medicinally Active Plants. 10 (4): 74-81.
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Progress 04/01/22 to 03/31/23
Outputs
Target Audience:The target audiences included professionals, scientists, researchers, students (graduate and undergraduate), consumer advocates, commodity groups interested in the field of foods for health, nutrition, inflammatory diseases and obesity. Changes/Problems:Recently a non-cost extension has been approved. Some of the challenges encountered had to do with delays in some supplies, supplies changes, and unexpected delays in the hiring of personnel. These challenges, triggered by COVID, continue to affect some of our experiments. For example, the mice showed some changes in responding to the growth environment. During the PD meeting taken place on July 5-6, other PD reported observing changes in the response of commercially purchased mice. We also found some challenges with the control P-ww diet from corn. The formulation developed by the nutritionist affected the mice and had to be discontinued. The experiments including with the new P-ww formulation will need to be repeated. Interesting, the food prepared with the flavone rich P-rr maize line showed very encouraging results with mice fed with HFD+P-rr losing weight. These impactful results warrant further experiments using the two different maize lines. What opportunities for training and professional development has the project provided?During this period the project contributed to the training of a graduate student, a lab aid, and a senior scientist. How have the results been disseminated to communities of interest?Results have been communicated by several means including oral presentations, poster, and publications: Oral Presentations Doseff, A.I. Invited Speaker Gordon Conference. Metabolic Engineering in Plants: Sustainability Through Innovation (June 11-16). Session: Making Medicines in Plants. Barcelona, Spain Doseff, A.I. Targeting cancer and immune cell fate with dietary phytochemicals. Arkansas State University. Departmentof Biology and Arkansas Biosciences Institute, Jonesboro, Arkansas.(October 21). Doseff, A.I. Plenary speaker. 2022 (June 30th). Targeting chronic inflammatory diseases with flavonoid-rich diets: impact in cancer and obesity. 11th American Council of Medicinally Active Plants. Barranquitas, Puerto Rico. Posters Sudhakaran, M. and Doseff, A.I. 2022 (Selected Podium Presentation, June 28 - July 1). Flavone apigenin regulates inflammation through high affinity target RNA binding protein hnRNPA2. 11th American Council of Medicinally Active Plants. Barranquitas, Puerto Rico. Kariagina, A., Donado Pestana, Carlos, Quinn, R.A., and Doseff, A.I. 2022 (September 30th). Flavone-rich celery-based diet reduces obesity-induced inflammation and microbiome dysbiosis. Publications 1. Kariagina, A. and Doseff, A.I. (2022). Anti-Inflammatory mechanisms of dietary flavones: Tapping into nature to control chronic inflammation in obesity and cancer. Int. J. Mol. Sci. 23:(24): 15753-15780. 2. Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. (2022). Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants. J. Medicinally Active Plants. 10 (4): 74-81. Meeting Organizer Dr. Doseff was one of the organizers of the 11th American Council of Medicinally Active Plants hosted by Barranquitas, Puerto Rico. I chaired the Scientific Committee. This committee was responsible for deciding the session, reviewing the abstracts, and selecting oral presentations. What do you plan to do during the next reporting period to accomplish the goals?We will continue the quantitative studies to evaluate the effect of celery-based whole foods rich in apigenin in the microbiome. We will perform the metabolomic analyses. The experiments conducted so far were targeted to study the effect of CEBAR in the presence of HFD. The experiments to study the potential effect of flavone-rich diets in the prevention of obesity will be done.
Impacts
What was accomplished under these goals?
We evaluated the effect of the celery-based apigenin rich food (CEBAR) in adipocyte size in mice fed with high fat diet (HFD). We found that consumption of CEBAR significantly reduced adipocyte size in all the three adipose depots studied. These affects were accompanied by a reduction of leptin and an increase of adiponectin in mice fed with CEBAR and HFD compared with HFD alone. These results demonstrate that whole food rich in flavones reduced HFD-induced adipocyte enlargement and restores metabolic homeostasis. Additionally, we found that mice fed with HFD+CEBAR showed a significant reduction of macrophages in adipose tissues compared to HFD alone, reaching basal numbers found in mice fed with control diet. The reduction of macrophages in HFD+CEBAR mice results in the decrease of inflammatory cytokines in adipose tissues. These results suggest that CEBAR reduces HDF-induced inflammation in adipose tissues. Remarkably, these effects in the macrophage numbers highlight that CEBAR restores the number of macrophages to homeostasis. Cecum and fecal samples were collected. The initial microbiome analyses showed no differences on the cecum microbiome in HFD+CEBAR compared with HFD alone. However, preliminary analyses showed differences between the microbiome of HFD+CEBAR compared with HFD. CEBAR increased the presence of fecal Bacteroidetes, lowering the high ratio Firmicutes/Bacteroidetes observed in HFD fed mice. These results are being further analyzed to gain a better understanding of the microbiome ecosystem.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
Kariagina, A. and Doseff, A.I. (2022). Anti-Inflammatory mechanisms of dietary flavones: Tapping into nature to control chronic inflammation in obesity and cancer. Int. J. Mol. Sci. 23:(24): 15753-15780.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2022
Citation:
3. Sudhakaran, M. and Doseff, A.I. 2022 (Selected Podium Presentation, June 28 July 1). Flavone apigenin regulates inflammation through high affinity target RNA binding protein hnRNPA2. 11th American Council of Medicinally Active Plants. Barranquitas, Puerto Rico.
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2022
Citation:
4. Kariagina, A., Donado Pestana, Carlos, Quinn, R.A., and Doseff, A.I. 2022 (September 30th). Flavone-rich celery-based diet reduces obesity-induced inflammation and microbiome dysbiosis. Physiology Research Symposium. Michigan State University.
- Type:
Journal Articles
Status:
Published
Year Published:
2022
Citation:
4. Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. (2022). Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants. J. Medicinally Active Plants. 10 (4): 74-81.
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Progress 04/01/21 to 03/31/22
Outputs
Target Audience:The target audiences included professionals, scientists, researchers, students (graduate and undergraduate), consumer advocates, commodity groups interested in the field of foods for health, nutrition, inflammatory diseases and obesity. Changes/Problems:The unprecedented times derived fromthe global impact of COVID continue to impose a major impact on our outcomes. The labs continue having complications withhiring personnel and people getting sick with COVID. It is hard to plan the timelines as people need time off. There is also a constant turnover of administrative support personnel in our departments. Despite experiencing many adversities, we have been able to continue publishing papers and promoting opportunities for trainees to continue attending, even if virtual, scientific conferences. What opportunities for training and professional development has the project provided?During this period the project contributed to the training of a graduate student, a visiting scholar, and one undergraduate student and a technician no budgeted in the grant. How have the results been disseminated to communities of interest?Results have been communicated by several means including oral presentations and publications: Oral Presentations Doseff, A.I.; Alliances for Graduate Education and the Professoriate (AGEP) at Michigan State University. Raising awareness: underrepresented groups in sciences. Doseff, A.I. Invited Plenary Speaker 10th American Council of Medicinally Active Plants. Rutgers University, New Jersey. Targeting chronic inflammatory diseases with flavonoid-rich diets: impact in cancer and obesity. Posters Sudhakaran, M., Ramirez-Parra, M., and Doseff, A.I. Dietary Flavonoids Targeting Triple Negative Breast Cancer. 10th American Council of Medicinally Active Plants - Rutgers University, New Jersey. Heeringa, Z., Gjidoda, A., and Doseff, A.I. Deglycosylation of Flavones Increases Cellular Absorption and Anti-cancer Efficacy Towards Precision Medicine. Mid-Michigan Symposium for Undergraduate Research Experiences (Mid-SURE). Michigan State University, East Lansing, Michigan. Publications 1. Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. (2021). Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants. In Press. 2. Voss, O., Arango, A., Tossey, J., Villalona Calero, M.A., and Doseff, A.I. (2021). Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis. Cell Death & Disease. 287:(4). 287. PMID: 33731677. 3. Desmet, N.M., Dhusia, K., Qi, W., Doseff, A.I., Bhattacharya, S., and Gilad, A.A. (2021). Bioengineering of genetically encoded gene promoter repressed by flavonoids for constructing intracellular sensor for molecular events. Biosensors. 11(5):137. PMID: 33924783. 4. Shahabipour, F., Aldhaher, A., Doseff, A.I., Elnour, A.A.M., and Ashammakhi. N. (2021) Use of microfluidic Organ-on-A-Chip systems for screening and development of phytopharmaceuticalsandherbaldrugs. In Phytopharmaceuticals and herbal drugs: Prospects and safety issues in the delivery of natural products. Editor: Dr. Deependra Singh. Publisher: Elsevier. Meeting Organizer Dr. Doseff was one of the organizers of the 10th American Council of Medicinally Active Plants hosted by Rutgers University, New Jersey. I chaired the Scientific Committee. This committee was responsible for deciding the session, reviewing the abstracts, and selecting oral presentations. I also organized and was one of the presenters of a Mentorship and Professional Development panel. Other presenters included Dr. Amer Fayad from USDA, members of the private sector. The session was a great success and we thank the participation of USDA in this session. What do you plan to do during the next reporting period to accomplish the goals?We will continue the quantitative studies to evaluate the effect of celery-based whole foods rich in apigenin in macrophage numbers and function. We would expect to start with more gene expression analysis of inflammatory genes in adipose depots.
Impacts
What was accomplished under these goals?
The goal of this project is to investigate the role of whole foods with high content of apigenin on the crosstalk between the gut microbiome and its metabolites with macrophages and adipocytes and their impact in reducing obesity-induced inflammation. We have been collecting specimens and analyzing data including macrophage counts. The first view of the microbiome composition is emerging and there are changes associated with the whole celery diet. We have also designed primers to validate gene expression related to the processes emerging from the data.
Publications
- Type:
Journal Articles
Status:
Accepted
Year Published:
2021
Citation:
1. Heeringa, Z., Sudhakaran, M., Gjidoda, A.M., and Doseff, A.I. Targeting flavone deglycosylation improves formulation of whole celery-based apigenin rich food. J. Medicinally Active Plants
- Type:
Journal Articles
Status:
Accepted
Year Published:
2021
Citation:
2. Voss, O., Arango, A., Tossey, J., Villalona Calero, M.A., and Doseff, A.I. Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis. Cell Death & Disease. 287:(4). 287. PMID: 33731677.
- Type:
Journal Articles
Status:
Accepted
Year Published:
2021
Citation:
3. Desmet, N.M., Dhusia, K., Qi, W., Doseff, A.I., Bhattacharya, S., and Gilad, A.A. Bioengineering of genetically encoded gene promoter repressed by flavonoids for constructing intracellular sensor for molecular events. Biosensors. 11(5):137. PMID: 33924783.
- Type:
Books
Status:
Accepted
Year Published:
2021
Citation:
4. Shahabipour, F., Aldhaher, A., Doseff, A.I., Elnour, A.A.M., and Ashammakhi. N. Use of microfluidic Organ-on-A-Chip systems for screening and development of phytopharmaceuticals and herbal drugs. In Phytopharmaceuticals and herbal drugs: Prospects and safety issues in the delivery of natural products. Editor: Dr. Deependra Singh. Publisher: Elsevier.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
1. Sudhakaran, M., Ramirez-Parra, M., and Doseff, A.I. Dietary Flavonoids Targeting Triple Negative Breast Cancer. 10th American Council of Medicinally Active Plants Rutgers University, New Jersey.
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2021
Citation:
2. Heeringa, Z., Gjidoda, A., and Doseff, A.I. Deglycosylation of Flavones Increases Cellular Absorption and Anti-cancer Efficacy Towards Precision Medicine. Mid-Michigan Symposium for Undergraduate Research Experiences (Mid-SURE). Michigan State University, East Lansing, Michigan.
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Progress 04/01/20 to 03/31/21
Outputs
Target Audience:The target audiences included professionals, scientists, researchers, students (graduate and undergraduate), consumer advocates, commodity groups interested in the field of foods for health, nutrition, inflammatory diseases and obesity. Changes/Problems:The unprecedented times derived for the global impact of COVID had major impact on our products during this period. The closing of the labs for almost 5 months, the freezing of hiring personnel during this period, and the personal problems of some of the lab personnel contributed to a very challenging professional year. Unfortunately, some of animals were lost and supplies for some of our experiments have been in short supply. In the last few months we have been trying to get back to a new normal and experiments are back under way. What opportunities for training and professional development has the project provided?During this period the project contributed to the training of a technician and 1 undergraduate students (no budgeted in the grant), a visiting scholar and a graduate student. How have the results been disseminated to communities of interest?Results have been communicated by several means including oral presentations and publications: Oral Presentations 1. Doseff, A.I.; Alliances for Graduate Education and the Professoriate (AGEP) at Michigan State University. Raising awareness: underrepresented groups in sciences. 2. Doseff, A.I.; Departmentof Immunology. Institute of Biomedical Sciences, University of São Paulo, Brazil. (October, 2020) 3. Doseff, A.I. National Chung-Hsing University, Taichung, Taiwan. (May 13, 2020). Publications Sudhakaran, M. and Doseff, A.I. (2020). The targeted impact of flavones on obesity-induced inflammation and the potential synergistic role in cancer and the gut microbiota. Molecules. 25 (11):2477-2505. Sudhakaran, M., Ramirez-Parra, M., Stoub, H., Gallo, K., and Doseff, A.I. (2020). Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters. Biochem. Pharmacol. Lina Gomez-Cano, Fabio Gomez-Cano, Dillon, F., Alers-Velazquez, R.M., Doseff, A.I., Grotewold, E. and Gray, J. (2020). Modules involved in the biosynthesis and regulation of maize phenolic compounds. Plant Science. 291. ?110364-110382. What do you plan to do during the next reporting period to accomplish the goals?We will pursue the immunohistochemistry studies proposed and evaluate the number of macrophages. We will conduct and analyze the first studies related to the microbiome characterization.
Impacts
What was accomplished under these goals?
Due to COVID and the closing of the laboratories and all facilities for almost 5 months the proposed accomplishments have been significantly impacted. We have been able under this unforeseen circumstances to keep publishing. Few experiments have been started during the last few months and samples have been collected. We are just starting to evaluate the adipose tissues and microbiome of our first experiment.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
3. Lina Gomez-Cano, Fabio Gomez-Cano, Dillon, F., Alers-Velazquez, R.M., Doseff, A.I., Grotewold, E. and Gray, J. (2020). Modules involved in the biosynthesis and regulation of maize phenolic compounds. Plant Science. 291. ?110364-110382
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
1. Sudhakaran, M. and Doseff, A.I. (2020). The targeted impact of flavones on obesity-induced inflammation and the potential synergistic role in cancer and the gut microbiota. Molecules. 25 (11):2477-2505.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
2. Sudhakaran, M., Ramirez-Parra, M., Stoub, H., Gallo, K. and Doseff, A.I. (2020). Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters. Biochem. Pharmacol.
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