CELLMED (셀메드)

Cellmed Orthocellular Medicine and Pharmaceutical Association (셀메드 세포교정의약학회)
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Anew formula CPC22 regulates bone loss, hot flashes, and dysregulated lipid metabolism in ovariectomized postmenopausal mice

  • Hee-Yun Kim (BioChip Research Center, Hoseo University) ;
  • Hyunwoo Jee (Department of Science in Korean Medicine, Graduate School, Kyung Hee University) ;
  • Hosong Cho (LG Household &Healthcare Research Park) ;
  • Dongjun Park (LG Household &Healthcare Research Park) ;
  • Hyun-Ja Jeong (BioChip Research Center, Hoseo University)
  • Received : 2023.11.03
  • Accepted : 2023.11.20
  • Published : 2023.11.30
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Abstract

Background and objective: A new formular CPC22 consists of Cynanchum wilfordii root, Pueraria thomsonii flower, and Citrus unshiu peel and has been developed to improve the postmenopausal symptoms. The research intended to evaluate whether CPC22 would regulate bone loss, hot flashes, and dysregulated lipid metabolism in ovariectomized (OVX) postmenopausal mice. Method: The OVX mice were orally administered with CPC22 daily for 7 weeks. Results: CPC22 regulated OVX-induced bon loss by enhancing serum osteoprotegerin, alkaline phosphatase, and osteocalcin levels and diminishing serum receptor-activator of the NF-κB ligand (RANKL), collagen type 1 cross-linked N-telopeptide, and tartrate-resistant acid phosphatase levels. As a result of CPC22 treatment, notable decreases in tail skin temperature and rectal temperature were observed, along with diminishment in hypothalamic RANKL and monoamine oxidase A levels and enhancement in hypothalamic serotonin (5-HT), norepinephrine, dopamine, 5-HT2A, and estrogen receptor-β levels. CPC22 enhanced levels of serum estrogen and diminished levels of serum follicle-stimulating hormone and luteinizing hormone. CPC22 regulated levels of serum lipid metabolites, including total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Furthermore, CPC22 diminished levels of serum blood urea nitrogen, creatine kinase, alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase and restored vaginal dryness without affecting uterus atrophy index and vagina weights. Conclusion: Therefore, these results indicated that CPC22 improves OVX-induced bone loss, hot flashes, and dysregulated lipid metabolism by compensating for estrogen deficiency without side effects, suggesting that CPC22 may be used for the prevention and treatment of post menopause.

Keywords

References

  1. Hoga L, Rodolpho J, Goncalves B, Quirino B. Women's experience of menopause: a systematic review of qualitative evidence. JBI Database System Rev Implement Rep. 2015;13(8):250-337. https://doi.org/10.11124/01938924-201513080-00018
  2. del Giorno C, Fonseca AM, Bagnoli VR, Assis JS, Soares JM, Jr., Baracat EC. Effects of Trifolium pratense on the climacteric and sexual symptoms in postmenopause women. Rev Assoc Med Bras (1992). 2010;56(5):558-562. https://doi.org/10.1590/S0104-42302010000500017
  3. Kang SJ, Choi BR, Kim SH, Yi HY, Park HR, Song CH, Ku SK, Lee YJ. Anti-climacterium effects of pomegranate concentrated solutions in ovariectomized ddY mice. Exp Ther Med. 2017;13(4):1249-1266. https://doi.org/10.3892/etm.2017.4109
  4. Wolff LP, Martins MR, Bedone AJ, Monteiro IM. [Endometrial evaluation in menopausal women after six months of isoflavones]. Rev Assoc Med Bras (1992). 2006;52(6):419-423. https://doi.org/10.1590/S0104-42302006000600022
  5. Kanis JA, Cooper C, Rizzoli R, Reginster JY. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019;30(1):3-44. https://doi.org/10.1007/s00198-018-4704-5
  6. He B, Yin L, Zhang M, Lyu Q, Quan Z, Ou Y. Causal Effect of Blood Pressure on Bone Mineral Density and Fracture: A Mendelian Randomization Study. Front Endocrinol (Lausanne). 2021;12:716681.
  7. Kling JM, Clarke BL, Sandhu NP. Osteoporosis prevention, screening, and treatment: a review. J Womens Health (Larchmt). 2014;23(7):563-572. https://doi.org/10.1089/jwh.2013.4611
  8. Berin E, Hammar M, Lindblom H, Lindh-Astrand L, Ruber M, Spetz Holm AC. Resistance training for hot flushes in postmenopausal women: A randomised controlled trial. Maturitas. 2019;126:55-60. https://doi.org/10.1016/j.maturitas.2019.05.005
  9. Shen W, Stearns V. Treatment strategies for hot flushes. Expert Opin Pharmacother. 2009;10(7):1133-1144. https://doi.org/10.1517/14656560902868217
  10. Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115-120. https://doi.org/10.1016/j.jsbmb.2013.08.010
  11. Steininger TL, Gong H, McGinty D, Szymusiak R. Subregional organization of preoptic area/anterior hypothalamic projections to arousal-related monoaminergic cell groups. J Comp Neurol. 2001;429(4):638-653. https://doi.org/10.1002/1096-9861(20010122)429:4<638::AID-CNE10>3.0.CO;2-Y
  12. Wang W, Cui G, Jin B, Wang K, Chen X, Sun Y, Qin L, Bai W. Estradiol Valerate and Remifemin ameliorate ovariectomy-induced decrease in a serotonin dorsal raphe-preoptic hypothalamus pathway in rats. Ann Anat. 2016;208:31-39. https://doi.org/10.1016/j.aanat.2016.08.001
  13. Kalkan R, Altarda M, Tosun O. RANKL is a new Epigenetic Biomarker for the Vasomotor Symptom During Menopause. Balkan J Med Genet. 2020;23(1):51-56. https://doi.org/10.2478/bjmg-2020-0001
  14. Huang D, Hu H, Chang L, Liu S, Liang J, Song Y, Wang X, Zhang H, Wei C, Wu Y. Chinese medicine Bazi Bushen capsule improves lipid metabolism in ovariectomized female ApoE-/- mice. Ann Palliat Med. 2020;9(3):1073-1083. https://doi.org/10.21037/apm-20-906
  15. Sima P, Vannucci L, Vetvicka V. Atherosclerosis as autoimmune disease. Ann Transl Med. 2018;6(7):116.
  16. Marchand GB, Carreau AM, Weisnagel SJ, Bergeron J, Labrie F, Lemieux S, Tchernof A. Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women. Am J Physiol Endocrinol Metab. 2018;314(5):E448-456. https://doi.org/10.1152/ajpendo.00293.2017
  17. Thaung Zaw JJ, Howe PRC, Wong RHX. Postmenopausal health interventions: Time to move on from the Women's Health Initiative? Ageing Res Rev. 2018;48:79-86. https://doi.org/10.1016/j.arr.2018.10.005
  18. Jeong HJ, Kim MH, Kim H, Kim HY, Nam SY, Han NR, Lee B, Cho H, Moon PD, Kim HM. PCE17 and its active compounds exert an anti-osteoporotic effect through the regulation of receptor activator of nuclear factor-κB ligand in ovariectomized mice. J Food Biochem. 2018;42(5):e12561.
  19. Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C. Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer. 2003;105(3):408-412. https://doi.org/10.1002/ijc.11083
  20. Mennenga SE, Gerson JE, Koebele SV, Kingston ML, Tsang CW, Engler-Chiurazzi EB, Baxter LC, Bimonte-Nelson HA. Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity. Psychoneuroendocrinology. 2015;54:1-13. https://doi.org/10.1016/j.psyneuen.2015.01.002
  21. Han NR, Nam SY, Hong S, Kim HY, Moon PD, Kim HJ, Cho H, Lee B, Kim HM, Jeong HJ. Improvement effects of a mixed extract of flowers of Pueraria thomsonii Benth. and peels of Citrus unshiu Markovich on postmenopausal symptoms of ovariectomized mice. Biomed Pharmacother. 2018;103:524-530. https://doi.org/10.1016/j.biopha.2018.04.070
  22. Lee H, Kim MH, Choi YY, Hong J, Yang WM. Effects of Cynanchum wilfordii on osteoporosis with inhibition of bone resorption and induction of bone formation. Mol Med Rep. 2018;17(3):3758-3762. https://doi.org/10.3892/mmr.2017.8309
  23. Lim DW, Lee Y, Kim YT. Preventive effects of Citrus unshiu peel extracts on bone and lipid metabolism in OVX rats. Molecules. 2014;19(1):783-794. https://doi.org/10.3390/molecules19010783
  24. Lee G, Choi CY, Jun W. Effects of Aqueous Extracts of Cynanchum wilfordii in Rat Models for Postmenopausal Hot Flush. Prev Nutr Food Sci. 2016;21(4):373-377. https://doi.org/10.3746/pnf.2016.21.4.373
  25. Lim JH, Kim HY, Lee JS, Kim HM, Jeong HJ. Dp44mT regulates the levels of inflammatory mediators through blocking NF-κB nuclear translocation in LPS-stimulated RAW 264.7 macrophages. In Vitro Cell Dev Biol Anim. 2021;57(3):332-341. https://doi.org/10.1007/s11626-021-00552-y
  26. Kim MH, Jeong HS, Moon PD. Effect of KH-BaRoKer-SeongJangTang based on traditional medicine theory on longitudinal bone growth. TANG. 2014;4(2):e14.
  27. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360(9348):1851-1861. https://doi.org/10.1016/S0140-6736(02)11774-0
  28. McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev. 1999;20(3):279-307. https://doi.org/10.1210/er.20.3.279
  29. Shuto H, Tominaga K, Yamauchi A, Ikeda M, Kusaba K, Mitsunaga D, Hirabara Y, Egawa T, Takano Y, Kataoka Y. The statins fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Eur J Pharmacol. 2011;651(1-3):234-239. https://doi.org/10.1016/j.ejphar.2010.10.084
  30. Tataryn IV, Meldrum DR, Lu KH, Frumar AM, Judd HL. LH, FSH and skin temperaure during the menopausal hot flash. J Clin Endocrinol Metab. 1979;49(1):152-154. https://doi.org/10.1210/jcem-49-1-152
  31. Zhang Y, Hua F, Ding K, Chen H, Xu C, Ding W. Angiogenesis Changes in Ovariectomized Rats with Osteoporosis Treated with Estrogen Replacement Therapy. Biomed Res Int. 2019;2019:1283717.
  32. Geng Q, Gao H, Yang R, Guo K, Miao D. Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence. Int J Biol Sci. 2019;15(1):58-68. https://doi.org/10.7150/ijbs.25783
  33. Dalal PK, Agarwal M. Postmenopausal syndrome. Indian J Psychiatry. 2015;57(Suppl 2):S222-232. https://doi.org/10.4103/0019-5545.161483
  34. Hildebrandt T, Alfano L, Tricamo M, Pfaff DW. Conceptualizing the role of estrogens and serotonin in the development and maintenance of bulimia nervosa. Clin Psychol Rev. 2010;30(6):655-668. https://doi.org/10.1016/j.cpr.2010.04.011
  35. Charoenphandhu N, Nuntapornsak A, Wongdee K, Krishnamra N, Charoenphandhu J. Upregulated mRNA levels of SERT, NET, MAOB, and BDNF in various brain regions of ovariectomized rats exposed to chronic aversive stimuli. Mol Cell Biochem. 2013;375(1-2):49-58. https://doi.org/10.1007/s11010-012-1527-0
  36. Hanada R, Leibbrandt A, Hanada T, Kitaoka S, Furuyashiki T, Fujihara H, Trichereau J, Paolino M, Qadri F, Plehm R, et al. Central control of fever and female body temperature by RANKL/RANK. Nature. 2009;462(7272):505-509. https://doi.org/10.1038/nature08596
  37. Krause MS, Nakajima ST. Hormonal and nonhormonal treatment of vasomotor symptoms. Obstet Gynecol Clin North Am. 2015;42(1):163-179. https://doi.org/10.1016/j.ogc.2014.09.008
  38. Sicat BL, Brokaw DK. Nonhormonal alternatives for the treatment of hot flashes. Pharmacotherapy. 2004;24(1):79-93. https://doi.org/10.1592/phco.24.1.79.34812
  39. Shumilov M, Touitou E. Buspirone transdermal administration for menopausal syndromes, in vitro and in animal model studies. Int J Pharm. 2010;387(1-2):26-33. https://doi.org/10.1016/j.ijpharm.2009.11.029
  40. Perich T, Ussher J, Meade T. Menopause and illness course in bipolar disorder: A systematic review. Bipolar Disord. 2017;19(6):434-443. https://doi.org/10.1111/bdi.12530
  41. Garcia AN, Depena C, Bezner K, Yin W, Gore AC. The timing and duration of estradiol treatment in a rat model of the perimenopause: Influences on social behavior and the neuromolecular phenotype. Horm Behav. 2018;97:75-84. https://doi.org/10.1016/j.yhbeh.2017.10.018
  42. Kim HY, Jeong HJ, Kim HM. Antidepressant-like effect of Ikwitang involves modulation of monoaminergic systems. Mol Med Rep. 2016;13(3):2815-2820. https://doi.org/10.3892/mmr.2016.4809
  43. Sun B, Yin YZ, Xiao J. An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause. J Vis Exp. 2019(150). doi: 10.3791/59536.
  44. Lin S, Huang J, Fu Z, Liang Y, Wu H, Xu L, Sun Y, Lee WY, Wu T, Qin L, et al. The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats. Calcif Tissue Int. 2015;96(6):541-551. https://doi.org/10.1007/s00223-015-9975-7
  45. Kim JH, Kim YJ. Effects of genistein in combination with conjugated estrogens on endometrial hyperplasia and metabolic dysfunction in ovariectomized mice. Endocr J. 2015;62(6):531-542. https://doi.org/10.1507/endocrj.EJ15-0056
  46. Kang S, Jo H, Kim MR. Safety Assessment of Endocrine Disruption by Menopausal Health Functional Ingredients. Healthcare (Basel). 2021;9(10):1376.
  47. Kamiya T, Takano A, Kido Y, Matsuzuka Y, Sameshima-Kamiya M, Tsubata M, Ikeguchi M, Takagaki K, Kinjo J. Evaluation of the Estrogenic Activity of Pueraria (Kudzu) Flower Extract and Its Major Isoflavones Using ER-Binding and Uterotrophic Bioassays. Pharmacology & Pharmacy. 2013;4(2):255-260. https://doi.org/10.4236/pp.2013.42036
  48. Schlemmer CK, Coetzer H, Claassen N, Kruger MC. Oestrogen and essential fatty acid supplementation corrects bone loss due to ovariectomy in the female Sprague Dawley rat. Prostaglandins Leukot Essent Fatty Acids. 1999;61(6):381-390. https://doi.org/10.1054/plef.1999.0116