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1

Puckett, Dexter, Mohammed Alquraishi, Samah Chahed, Dina Alani, Victoria Frankel, Brynn Voy, Dallas Donohoe, Jay Whelan, and Ahmed Bettaieb. "Zyflamend, a Unique Herbal Blend, Inhibits Adipogenesis Through the Coordinated Regulation of PKA and JNK." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 454. http://dx.doi.org/10.1093/cdn/nzaa045_087.

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Abstract Objectives The prevalence of obesity and its comorbidities has sparked a worldwide concern to address rates of adipose tissue accrual. Recent studies have demonstrated a novel role of Zyflamend, a natural herbal extract, in regulating lipid metabolism in several cancer cell lines through the activation of the AMPK signaling pathway. Yet, the role of Zyflamend in adipogenic differentiation and lipid metabolism remains largely unexplored. The objective of this study is to investigate the effects of Zyflamend on white 3T3-MBX pre-adipocyte differentiation and elucidate the molecular mechanisms. Methods 3T3-MBX pre-adipocytes were treated with Zyflamend, and the expression of various key adipogenic and lipolytic regulators was examined. We also investigated the effects of Zyflamend on pre-adipocyte survival, proliferation, and cell cycle. Results Zyflamend treatment altered cell cycle progression, attenuated proliferation, and increased cell death of 3T3-MBX pre-adipocytes. In addition, treatment with Zyflamend inhibited lipid accumulation during the differentiation of 3T3-MBX cells, consistent with decreased expression of lipogenic genes and increased lipolysis. Mechanistically, Zyflamend-induced alterations in adipogenesis were mediated, at least in part, through the activation of AMPK, PKA, and JNK. Inhibition of AMPK partially reversed Zyflamend-induced inhibition of differentiation, whereas the inhibition of either JNK or PKA fully restored adipocyte differentiation and decreased lipolysis. Conclusions Taken together, the present study demonstrates that Zyflamend, as a novel anti-adipogenic bioactive mix, inhibits adipocyte differentiation through the activation of PKA and JNK pathways.Our findings suggest that Zyflamend supplementation might help in developing novel anti-obesity therapeutic strategies. Funding Sources This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.
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2

Bilen, Mehmet Asim, Sue-Hwa Lin, Dean G. Tang, Kinjal Parikh, Mong-Hong Lee, Sai-Ching J. Yeung, and Shi-Ming Tu. "Maintenance Therapy Containing Metformin and/or Zyflamend for Advanced Prostate Cancer: A Case Series." Case Reports in Oncological Medicine 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/471861.

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Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend.
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Ekmekcioglu, Suhendan, Chandrani Chattopadhyay*, Ugur Akar*, Abdul Gabisi, Robert A. Newman, and Elizabeth A. Grimm. "Zyflamend Mediates Therapeutic Induction of Autophagy to Apoptosis in Melanoma Cells." Nutrition and Cancer 63, no. 6 (August 2011): 940–49. http://dx.doi.org/10.1080/01635581.2011.586488.

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4

Tague, Eric D., Allen K. Bourdon, Amber MacDonald, Maggie S. Lookadoo, Edward D. Kim, Wesley M. White, Paul D. Terry, Shawn R. Campagna, Brynn H. Voy, and Jay Whelan. "Metabolomics Approach in the Study of the Well-Defined Polyherbal Preparation Zyflamend." Journal of Medicinal Food 21, no. 3 (March 2018): 306–16. http://dx.doi.org/10.1089/jmf.2017.0062.

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5

Hume, Anne L. "Zyflamend for prevention of prostate cancer: Studies show benefits, but larger trials needed." Pharmacy Today 20, no. 7 (July 2014): 30. http://dx.doi.org/10.1016/s1042-0991(15)30779-9.

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6

Puckett, Dexter L., Mohammed Alquraishi, Samah L. Chahed, Dallas R. Donohoe, Jay Whelan, and AHMED BAETTAIEB. "Zyflamend Induces Apoptosis in Pancreatic Cancer cells via Modulation of the JNK Pathway." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.09714.

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7

Zhao, Yi, Dallas Donohoe, E.-Chu Huang, and Jay Whelan. "Zyflamend, a polyherbal mixture, inhibits lipogenesis and mTORC1 signalling via activation of AMPK." Journal of Functional Foods 18 (October 2015): 147–58. http://dx.doi.org/10.1016/j.jff.2015.06.051.

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8

Katz, A. E., P. M. Pierorazio, P. Masson, E. T. Goluboff, B. A. Stone, J. M. McKiernan, M. C. Benson, and C. A. Olsson. "Results of a phase I trial administering Zyflamend to subjects with high-grade prostatic intraepithelial neoplasia." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 14575. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14575.

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14575 Background: Subjects diagnosed with prostatic intraepithelial neoplasia (PIN) at prostate biopsy are at increased risk of developing prostate cancer on later biopsies. We initiated a phase I clinical trial to asses the safety and efficacy of the novel herbal anti-inflammatory, Zyflamend, to prevent prostate cancer in high-risk subjects with PIN. Methods: Men ages 40–75 diagnosed with high-grade PIN (without prostate cancer) on biopsy within the last six months were enrolled. Patients were assigned to one of eight treatment groups, with successive dose-escalation occurring in each group. Patients were evaluated every three months for 18 months; at which time they had a physical exam and blood samples drawn to monitor for toxicity, to check for fluctuations in PSA and testosterone, and monitor a battery of inflammatory serum. At 6, 12 and 18 months, 12-core transrectal ultrasound guided biopsy of the prostate was performed. Biopsy tissue was evaluated for the presence of PIN and/or prostate cancer then stained for inflammatory biomarkers. A NCI common terminology criteria for adverse events (v3.0) based questionnaire was used to monitor side effects. Endpoints are completion of the 18 month protocol without adenocarcinoma or diagnosis of adenocarcinoma prior to 18 months. Results: To date 25 patients have been enrolled; the expected closure date is March, 2006. The median patient age is 65.1 years with a median PSA level of 6.8. There have been no adverse events reported or toxicities apparent. Five patients (20%) have complained of grade I dyspepsia resolving spontaneously without intervention. Preliminary results include a total of 22 biopsies performed in 19 patients. 18 of the 22 biopsies were performed per protocol at scheduled visits, the remaining four were performed between scheduled visits. Of 22 biopsies completed seven returned positive for PIN (31.8%) and three have returned with adenocarcinoma (13.6%). Conclusions: The novel herbal anti-inflammatory, Zyflamend, appears to be associated with minimal toxicity and no serious adverse events when administered orally. Short term biopsy results indicate a low progression rate, although long-term efficacy awaits further studies. No significant financial relationships to disclose.
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9

Huang, E.-Chu, Guoxun Chen, Seung Joon Baek, Michael F. McEntee, J. Jason Collier, Steven Minkin, John Biggerstaff, and Jay Whelan. "Zyflamend Reduces the Expression of Androgen Receptor in a Model of Castrate-Resistant Prostate Cancer." Nutrition and Cancer 63, no. 8 (November 2011): 1287–96. http://dx.doi.org/10.1080/01635581.2011.606956.

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10

Huang, E. Chu, Michael F. McEntee, and Jay Whelan. "Zyflamend, a Combination of Herbal Extracts, Attenuates Tumor Growth in Murine Xenograft Models of Prostate Cancer." Nutrition and Cancer 64, no. 5 (July 2012): 749–60. http://dx.doi.org/10.1080/01635581.2012.689413.

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11

Buckley, Michael R., Paul D. Terry, Stacy S. Kirkpatrick, Joshua D. Arnold, Michael M. McNally, Oscar H. Grandas, Michael B. Freeman, Mitchell H. Goldman, Jay Whelan, and Deidra JH Mountain. "Dietary supplementation with Zyflamend poly-herbal extracts and fish oil inhibits intimal hyperplasia development following vascular intervention." Nutrition Research 68 (August 2019): 34–44. http://dx.doi.org/10.1016/j.nutres.2019.06.001.

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Mohebati, Arash, Joseph B. Guttenplan, Amit Kochhar, Zhong-Lin Zhao, Wieslawa Kosinska, Kotha Subbaramaiah, and Andrew J. Dannenberg. "Carnosol, a Constituent of Zyflamend, Inhibits Aryl Hydrocarbon Receptor–Mediated Activation of CYP1A1 and CYP1B1 Transcription and Mutagenesis." Cancer Prevention Research 5, no. 4 (February 28, 2012): 593–602. http://dx.doi.org/10.1158/1940-6207.capr-12-0002.

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13

Yang, Peiying, Carrie Cartwright, Diana Chan, Mary Vijjeswarapu, Jibin Ding, and Robert A. Newman. "Zyflamend®-mediated inhibition of human prostate cancer PC3 cell proliferation: Effects on 12-LOX and Rb protein phosphorylation." Cancer Biology & Therapy 6, no. 2 (February 2007): 228–36. http://dx.doi.org/10.4161/cbt.6.2.3624.

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14

Rafailov, Samuil, Sam Cammack, Brian A. Stone, and Aaron E. Katz. "The Role of Zyflamend, an Herbal Anti-inflammatory, as a Potential Chemopreventive Agent Against Prostate Cancer: A Case Report." Integrative Cancer Therapies 6, no. 1 (March 2007): 74–76. http://dx.doi.org/10.1177/1534735406298843.

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15

Puckett, Dexter, Mohammed Alquraishi, Dina S. Alani, Samah Chahed, Victoria D. Frankel, Dallas Donohoe, Brynn Voy, Jay Whelan, and Ahmed Bettaieb. "Zyflamend, a unique herbal blend, induces cell death and inhibits adipogenesis through the coordinated regulation of PKA and JNK." Adipocyte 9, no. 1 (January 1, 2020): 454–71. http://dx.doi.org/10.1080/21623945.2020.1803642.

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16

Kunnumakkara, Ajaikumar B., Bokyung Sung, Jayaraj Ravindran, Parmeswaran Diagaradjane, Amit Deorukhkar, Sanjit Dey, Cemile Koca, et al. "Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets." International Journal of Cancer 131, no. 3 (November 9, 2011): E292—E303. http://dx.doi.org/10.1002/ijc.26442.

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17

Yan, Jun, Bingxian Xie, Jillian L. Capodice, and Aaron E. Katz. "Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth." Prostate 72, no. 3 (June 8, 2011): 244–52. http://dx.doi.org/10.1002/pros.21426.

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18

Bools, Lindsay, Ryan Buckely, Deidra J. Mountain, Stacy Kirkpatrick, Jay Whelan, Paul Terry, Michael B. Freeman, and Oscar Grandas. "PC218. A Polyherbal Dietary Supplement, Zyflamend, Inhibits Matrix Metalloproteinase Expression and Attenuates Intimal Hyperplasia in a Rodent Model of Vascular Disease." Journal of Vascular Surgery 61, no. 6 (June 2015): 175S. http://dx.doi.org/10.1016/j.jvs.2015.04.332.

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Xue, Yanshi, Lin Yang, Junzun Li, Yilin Yan, Qinghui Jiang, Lan Shen, Shuai Yang, et al. "Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway." OncoTargets and Therapy Volume 11 (July 2018): 4413–29. http://dx.doi.org/10.2147/ott.s162255.

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Bemis, Debra L., Jillian L. Capodice, Aristotelis G. Anastasiadis, Aaron E. Katz, and Ralph Buttyan. "Zyflamend®, a Unique Herbal Preparation With Nonselective OX Inhibitory Activity, Induces Apoptosis of Prostate Cancer Cells That Lack COX-2 Expression." Nutrition and Cancer 52, no. 2 (July 2005): 202–12. http://dx.doi.org/10.1207/s15327914nc5202_10.

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Yang, Peiying, Zheng Sun, Diana Chan, Carrie A. Cartwright, Mary Vijjeswarapu, Jibin Ding, Xiaoxin Chen, and Robert A. Newman. "Zyflamend® reduces LTB 4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[α]anthracene (DMBA)-induced hamster cheek pouch model." Carcinogenesis 29, no. 11 (August 6, 2008): 2182–89. http://dx.doi.org/10.1093/carcin/bgn181.

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22

Sandur, Santosh K., Kwang Seok Ahn, Haruyo Ichikawa, Gautam Sethi, Shishir Shishodia, Robert A. Newman, and Bharat B. Aggarwal. "Zyflamend, a Polyherbal Preparation, Inhibits Invasion, Suppresses Osteoclastogenesis, and Potentiates Apoptosis Through Down-Regulation of NF-κ B Activation and NF-κ B–Regulated Gene Products." Nutrition and Cancer 57, no. 1 (May 4, 2007): 78–87. http://dx.doi.org/10.1080/01635580701268295.

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23

Kim, Ji Hye, Byoungduck Park, Subash C. Gupta, Ramaswamy Kannappan, Bokyung Sung, and Bharat B. Aggarwal. "Zyflamend Sensitizes Tumor Cells to TRAIL-Induced Apoptosis Through Up-Regulation of Death Receptors and Down-Regulation of Survival Proteins: Role of ROS-Dependent CCAAT/Enhancer-Binding Protein-Homologous Protein Pathway." Antioxidants & Redox Signaling 16, no. 5 (March 2012): 413–27. http://dx.doi.org/10.1089/ars.2011.3982.

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Alquraishi, Mohammed, Dallas Donohoe, Brynn H. Voy, Jay Whelan, and Ahmed Bettaieb. "Decreased adiposity and enhanced glucose tolerance in Zyflamend treated mice." FASEB Journal 33, S1 (April 2019). http://dx.doi.org/10.1096/fasebj.2019.33.1_supplement.754.5.

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Puckett, Dexter L., Mohammed Alquraishi, Dina Alani, Samah Chahed, Dallas Donohoe, Brynn Voy, Jay Whelan, and Ahmed Bettaieb. "Zyflamend induces apoptosis in pancreatic cancer cells via modulation of the JNK pathway." Cell Communication and Signaling 18, no. 1 (August 14, 2020). http://dx.doi.org/10.1186/s12964-020-00609-7.

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Bettaieb, Ahmed Bettaieb, Dexter Puckett, Samah Chahed, and Jay Whelan. "Zyflamend Induces Apoptosis in Pancreatic Cancer Cells via Modulation of the JNK Pathway." FASEB Journal 33, S1 (April 2019). http://dx.doi.org/10.1096/fasebj.2019.33.1_supplement.lb282.

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Bettaieb, Ahmed, Katelin Hubbard, Dexter Puckett, Presley Dowker, Dina Alani, Samah Chahed, Mohammed Alquraishi, and Jay Whelan. "Zyflamend Supplementation Alleviates High‐Fat Diet‐Induced Obesity and Impairment of Skeletal Muscle Insulin Sensitivity." FASEB Journal 35, S1 (May 2021). http://dx.doi.org/10.1096/fasebj.2021.35.s1.03978.

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Puckett, Dexter, Dina Alani, Samah Chahed, Victoria Frankel, Jay Whelan, and Ahmed Bettaieb. "Zyflamend Induces Apoptosis in Pancreatic Cancer cells via modulation of Endoplasmic Reticulum stress and Autophagy." FASEB Journal 32, S1 (April 2018). http://dx.doi.org/10.1096/fasebj.2018.32.1_supplement.664.1.

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Huang, E‐Chu, Michael F. McEntee, Seung J. Baek, and Jay Whelan. "Synergistic effect of Zyflamend® and hormone ablation therapy on prostate cancer regression: adjuvant therapy for standard care." FASEB Journal 23, S1 (April 2009). http://dx.doi.org/10.1096/fasebj.23.1_supplement.902.14.

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Huang, E‐Chu, Michael F. McEntee, and Jay Whelan. "Zyflamend®, a multi‐herb extract with anticancer properties, promotes cell cycle arrest in advanced human prostate cancer cells." FASEB Journal 22, S1 (March 2008). http://dx.doi.org/10.1096/fasebj.22.1_supplement.700.12.

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Huang, E.-Chu, Yi Zhao, Guoxun Chen, Seung Joon Baek, Michael F. McEntee, Steven Minkin, John P. Biggerstaff, and Jay Whelan. "Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells." BMC Complementary and Alternative Medicine 14, no. 1 (February 21, 2014). http://dx.doi.org/10.1186/1472-6882-14-68.

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