INTRODUCTION:

Phytoestrogens and Hypertension:

Natural products play an important role as nutritional supplements and provide potential health benefits in cardiovascular diseases (CVD)¹. Recent evidence by various epidemiological, experimental and clinical studies proved that herbal and natural products in the form of neutraceuticals improve cardiovascular events, as compared to the synthetic drugs.

These studies also indicate that dietary supplements and food nutrients have profound cardioprotective effects in the primary as well as secondary coronary heart disease and hence they are considered as cardiovascular friendly natural products². The mechanism of cardioprotection produced by dietary nutritional supplements such as phytoestrogens (soy and soy protein), flavonoids (citrus fruits, pulses, red wine, tea and cocoa), olive oil, omega-3 fatty acids (fish oil and fish-based products), lycopene (tomato and tomato-based products), resveratrol (grapes and red wine), coffee, and soy in the prevention and treatment of cardiovascular disorders have been discussed in the following review (in parenthesis) with the emphasis of epidemiological and clinical studies. Based on the intriguing results of various studies, prophylactic and therapeutic potential of cardiovascular friendly natural products have been suggested. The supplementation of cardiovascular friendly natural products needs to be considered in all populations who have high prevalence of CVD³.

METHODS:

Materials:

A literature search for articles published in peer-reviewed journal articles based on phytoestrogen and hypertension, as well as electronic database searches using PubMed, Scopus, ScienceDirect, Google Scholar. Were used to gather the information on various plants based lignans and neolignans that have historically been used for pharmacological based hypertension treatment, ethnomedicinal, phytochemical, and the treatment of other cardiovascular disorders.

Pharmacological mechanism of phytoestrogen based medicinal antihypertensive agents:

Phytoestrogens are plant derived dietary estrogens having diverse group of naturally occurring nonsteroidal plant compounds that, because of their structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects, by sitting in and blocking receptor sites against estrogen. The estrogens and phytoestrogens are similar at molecular levels to allow them mildly mimic and sometimes act as antagonists of estrogen. So, the researcher are exploring the role of phytoestrogens in human biological estrogen system including protective action against prostate, breast, bowel, and other cancers, cardiovascular disease, brain function disorders and osteoporosis⁴.

They are mainly belonging to a large group of substituted natural phenolic compounds, the coumestans, prenylflavonoids and isoflavones are three of the most active in estrogenic effects in this class are presented in figure no 2. The best-researched are isoflavones, which are commonly found in soy and red clover. Lignans have also been identified as phytoestrogens, although they are not flavonoids. Phytoestrogens are defined functionally as substances that promote estrogen actions in mammals and their structures are similar to mammalian estrogen 17β-estradiol (E2)⁵.

The cardiovascular potential of plant phytoestrogens is evident from a number of important observations describing protective effects of natural isoflavones, flavonoids, terpenoids, polyphenols etc and is consistent with several epidemiological studies demonstrating the beneficial effects of isoflavones in cardiovascular diseases⁶. Soy based isoflavones have been found to increase expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of NO, increased plasma nitrate/nitrite and decreased endothelin-1 levels, systemic arterial compliance in men and postmenopausal women; increased brachial artery flow-mediated dilatation etc⁷.

Recent studies shown that the data of clinical, experimental and epidemiological studies indicates that dietary phytoestrogens, flavonoids and polyphenolic compounds have shown most potent activities for prevention in CVDs⁸. The major class of compounds found in phytoestrogen. These phytoestrogens are sub-classified into coumestans, prenylflavonoids and isoflavones. These class having the most active class in estrogenic effects, polyphenols (also known as polyhydroxyphenols includes tannic acid, ellagitannin⁹.

Secondary metabolites of plant, based on their biosynthetic origins can be further divided into three major groups: Flavonoids and allied phenolic and polyphenolic compounds, Terpenoids and nitrogen-containing alkaloids and sulphur-containing compounds¹⁰. These plant secondary metabolites such as phytoestrogens, flavonoids and polyphenols are used for their several potential health benefits likes as antioxidant, antiinflammatory, anticancer and antihypertensive, antibacterial, antifungal, antiviral and other biological activities¹¹.

Plant derived estrogens or phytoestrogens are xenoestrogens, a diverse group of naturally occurring nonsteroidal plant derived compounds that have 2-phenylnaphthalene-type chemical structures similar to those of estrogens¹². Because of their structural similarity with estradiol structure (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects, by sitting in and blocking receptor sites against estrogen¹³. Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER) and formed hormone receptor complex which in turn binds with DNA and induce transcription of mRNA¹⁴. There are two variants of the estrogen receptor, alpha (ER-α) found in uterus, heart, liver, kidney and beta (ER-β) found in ovaries and other tissues¹⁵.

Phytoestrogens are found to mimic response over the estrogenic effects on lower dose and antagonistic effects of estrogenic at higher dose and these antiestrogenic effects are used for possible prevention in cancer therapy¹⁶. Many phytoestrogens display somewhat higher affinity for ER-β compared to ER-α. They include a major class of chemical compounds such as isoflavones, flavones, coumestans and lignans and this group of estrogen-like chemicals used for their chemical structure is similar to that of estrogen in human¹⁷. They are found in many human food stuffs including beans, grains, green, vegetables, fruits, and nuts. And when consumed, depending on their concentration in the diet and concentration of sex hormones in the body, life stage and gender, they have shown estrogenic and antiestrogenic effects. Flavonoids are well known for its antihypertensive activity¹⁸. The vasodilation actions of flavonoids are involved in the mechanism of antihypertensive effect. Flavonoids also cause decrease in plasma concentration of Angiotensin II (vasoconstrictor)¹⁹.

DISCUSSION:

Many medicinal plants and natural products are considered by the public as a safe, natural, and cost-effective alternative to synthetic drugs without unambiguous proof by randomized controlled clinical trials^20-25. On this background, there is an increased interest in the development of products with validated efficacy and safety, similar to the recently FDA-approved botanical drugs Veregen from sinecatechins leaf extract of Camellia sinesis, Fulyzaq extract from the red latex of the Dragon’s blood tree and Grastek Timothy grass (Phleum pretense L.) pollen allergen extract^26-31. Some herbal extracts and pure compounds are currently undergoing clinical trials for cardiometabolic indications; an overview is presented here and data, information retrieved from www.clinicaltrials.gov are as follows: BeneFlax® (Flaxseed (Linumusitatissimum L.) lignans) for Phase 2 of Hypertension, Curcumin for Non-insulin dependent diabetes, Vascular aging, Ginger for Non-alcoholic fatty liver disease, Phyllanthus niruri L. and Sida cordifolia L. (Vedicine) NCT02107469 - Diabetic peripheral, polyneuropathy, Quercetin for Diabetes mellitus, obesity, Resveratrol for Diabetes mellitus type 2, inflammation, insulin resistance, cardiovascular disease (Phase 1 and 2)^27-36.

CONCLUSION:

The phytochemical investigation of different antihypertensive phytoestrogen agents, therapeutic applications, and pharmacological mechanism of natural products. These plants compounds have all been thoroughly explored in this review for their different mechanism to treat hypertension. However, more research on the phytochemistry and the mechanisms of action of isolated substances is required to completely comprehend the phytochemical profile and the intricate pharmacological effects of theseplant-basedphytoestrogen are involved. To further ensure this plant's safety and suitability as a source of modern medicine, clinical and laboratory investigations on the toxicity of all plant part extracts as well as other pure phytochemicals obtained from it are crucial.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

REFERENCES:

1. World Health Organization. WHO Traditional Medicine Strategy: 2014-2023. World Health Organization, 2013.

2. World Health Organization. WHO global report on traditional and complementary medicine 2019. World Health Organization, 2019.

3. Qi, Zhang. Who traditional medicine strategy. 2014-2023. Geneva: World Health Organization. 188 (2013).

4. World Health Organization. The regional strategy for traditional medicine in the Western Pacific (2011-2020). (2012).

5. Kasilo, Ossy MJ, and Jean‐Baptiste Nikiema. World Health Organization perspective for traditional medicine. Novel Plant Bioresources: Applications in Food, Medicine and Cosmetics (2014): 23-42.

6. Preethi Jazna.B, ReetaJebakumari, Nalini JeyavanthaSantha. A Study to Assess the Effectiveness of Benson Relaxation Therapy on Blood Pressure and Stress among Women with Pregnancy Induced Hypertension in Selected Hospitals, Madurai. Asian J. Nur. Edu. and Research. 2016; 6(2): 167-170.

7. John Shine. Effectiveness of Individual Teaching Programme on Knowledge and Practice Regarding Lifestyle Modification among Patients with Hypertension in Selected Urban Community At Mangalore. Asian J. Nur. Edu. and Research.2017; 7(2): 139-146.

8. Lakshmi, K. Effectiveness of Nursing Care of Antenatal Mothers with Gestational Diabetes Mellitus. Asian Journal of Nursing Education and Research. 10, no. 3 (2020): 286.

9. G. Kalaiselvi, K. Savithri. Effectiveness of Yoga Therapy on Mild Pregnancy Induced Hypertension. Asian J. Nursing Education and Research. 2021; 11(1):11-14.

10. Somwanshi, Sachin B., Punam D. Bairagi, and Kiran B. Kotade. Study of Gestational Diabetes Mellitus: A Brief Review. Asian Journal of Pharmaceutical Research. 7, no. 2 (2017): 118.

11. Yousaf, Aqsa, and Sammia Shahid. The Study of Anethum Graveolens L. (Dill) in the Case of Diabetes Mellitus (DM). Asian Journal of Research in Pharmaceutical Science. 10, no. 4 (2020): 248–56.

12. Chanda, D., Prieto-Lloret, J., Singh, A., Iqbal, H., Yadav, P., Snetkov, V., Aaronson, P.I., 2016. Glabridin-induced vasorelaxation: Evidence for a role of BKCa channels and cyclic GMP. Life Sciences 165, 26–34.

13. Gautam, Y., Dwivedi, S., Srivastava, A., Hamidullah, Singh, A., Chanda, D., Singh, J., Rai, S., Konwar, R., Negi, A.S., 2016. 2-(3′,4′-Dimethoxybenzylidene)tetralone induces anti-breast cancer activity through microtubule stabilization and activation of reactive oxygen species. RSC Adv. 6, 33369–33379.

14. Hamid, A.A., Hasanain, M., Singh, A., Bhukya, B., Omprakash, Vasudev, P.G., Sarkar, J., Chanda, D., Khan, F., Aiyelaagbe, O.O., Negi, A.S., 2014. Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin. Steroids 87, 108–118.

15. Hamid, A.A., Kaushal, T., Ashraf, R., Singh, A., Chand Gupta, A., Prakash, O., Sarkar, J., Chanda, D., Bawankule, D.U., Khan, F., Shanker, K., Aiyelaagbe, O.O., Negi, A.S., 2017. (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids 119, 43–52.

16. Jain, S., Singh, A., Khare, P., Chanda, D., Mishra, D., Shanker, K., Karak, T., 2017. Toxicity assessment of Bacopa monnieri L. grown in biochar amended extremely acidic coal mine spoils. Ecological Engineering. 108, 211–219.

17. Khwaja, S., Fatima, K., Hasanain, M., Behera, C., Kour, A., Singh, A., Luqman, S., Sarkar, J., Chanda, D., Shanker, K., Gupta, A.K., Mondhe, D.M., Negi, A.S., 2018. Antiproliferative efficacy of curcumin mimics through microtubule destabilization. European Journal of Medicinal Chemistry. 151, 51–61.

18. Kumar, B.S., Ravi, K., Verma, A.K., Fatima, K., Hasanain, M., Singh, A., Sarkar, J., Luqman, S., Chanda, D., Negi, A.S., 2017. Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition. Bioorganic & Medicinal Chemistry. 25, 1364–1373.

19. Mishra, D., Jyotshna, Singh, A., Chanda, D., Shanker, K., Khare, P., 2019. Potential of di-aldehyde cellulose for sustained release of oxytetracycline: A pharmacokinetic study. International Journal of Biological Macromolecules 136, 97–105.

20. Sathish Kumar, B., Kumar, A., Singh, J., Hasanain, M., Singh, A., Fatima, K., Yadav, D.K., Shukla, V., Luqman, S., Khan, F., Chanda, D., Sarkar, J., Konwar, R., Dwivedi, A., Negi, A.S., 2014a. Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization. European Journal of Medicinal Chemistry. 86, 740–751.

21. Sathish Kumar, B., Singh, Aastha, Kumar, A., Singh, J., Hasanain, M., Singh, Arjun, Masood, N., Yadav, D.K., Konwar, R., Mitra, K., Sarkar, J., Luqman, S., Pal, A., Khan, F., Chanda, D., Negi, A.S., 2014b. Synthesis of neolignans as microtubule stabilisers. Bioorganic & Medicinal Chemistry. 22, 1342–1354.

22. Singh, A., Kumar, B.S., Alam, S., Iqbal, H., Shafiq, M., Khan, F., Negi, A.S., Hanif, K., Chanda, D., 2017. Diethyl-4,4ʹ-dihydroxy-8,3ʹ-neolign-7,7ʹ-dien-9,9ʹ-dionate exhibits AH activity in rats through increase in intracellular cGMP level and blockade of calcium channels. European Journal of Pharmacology. 799, 84–93.

23. Singh, A., Kumar, B.S., Iqbal, H., Alam, S., Yadav, P., Verma, A.K., Khan, F., Shanker, K., Hanif, K., Negi, A.S., Chanda, D., 2019. AH activity of diethyl-4,4’-dihydroxy-8,3’-neolign-7,7’-dien-9,9’-dionate: A continuation study in L-NAME treated wistar rats. Eur. J. Pharmacol. 858, 172482.

24. Singh, A., Mohanty, I., Singh, J., Rattan, S., 2020. BDNF augments rat internal anal sphincter smooth muscle tone via RhoA/ROCK signaling and nonadrenergic noncholinergic relaxation via increased NO release. American Journal of Physiology-Gastrointestinal and Liver Physiology. 318, G23–G33.

25. Singh, A., Rattan, S., 2021. BDNF rescues aging-associated internal anal sphincter dysfunction. American Journal of Physiology-Gastrointestinal and Liver Physiology. 321, G87–G97.

26. Singh, A., Singh, J., Rattan, S., 2021. Evidence for the presence and release of BDNF in the neuronal and non‐neuronal structures of the internal anal sphincter. Neurogastroenterology and Motility.

27. Singh, Aastha, Fatima, K., Singh, Arjun, Behl, A., Mintoo, M.J., Hasanain, M., Ashraf, R., Luqman, S., Shanker, K., Mondhe, D.M., Sarkar, J., Chanda, D., Negi, A.S., 2015. Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule. European Journal of Pharmaceutical Sciences 76, 57–67.

28. Singh, Aastha, Fatima, K., Srivastava, A., Khwaja, S., Priya, D., Singh, Arjun, Mahajan, G., Alam, S., Saxena, A.K., Mondhe, D.M., Luqman, S., Chanda, D., Khan, F., Negi, A.S., 2016. Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer. Chem Biol Drug Des . 88, 625–634.

29. Yadav, P., Iqbal, H., Kumar, K., Kumar, P., Mishra, D., Singh, A., Pal, A., Mukhopadhyay, P., Vamadevan, B., Singh, D., Negi, A.S., Chanda, D., 2022. 2-Benzyllawsone protects against polymicrobial sepsis and vascular hyporeactivity in swiss albino mice. European Journal of Pharmacology. 917, 174757.

30. Manmohan, S., Arjun, S., Khan, S. P., Eram, S., &Sachan, N. K., 2012. Green chemistry potential for past, present and future perspectives. International Research Journal of Pharmacy. 3, 31-36.

31. Singh A, Kumar BS, Alam S, Iqbal H, Shafiq M, Khan F, Negi AS, Hanif K, Chanda D. Corrigendum to Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate exhibits AH activity in rats through increase in intracellular cGMP level and blockade of calcium channels. [Eur. J. Pharmacol. 799 (2017) 84-93]. Eur J Pharmacol. 2017 Jul 5;806:111. doi: 10.1016/j.ejphar.2017.04.033. Erratum for: Eur J Pharmacol. 2017 Mar 15;799:84-93. PMID: 28495016.

32. Singh, A., R. Sharma, K. M. Anand, S. P. Khan, and N. K. Sachan. Food-drug interaction. International Journal of Pharmaceutical and Chemical Science 1, no. 1 (2012): 264-279.

33. Devi. S, L N Samaga. Effect of transcendental meditation on stress and blood pressure among patients with systemic hypertension. Asian J. Nur. Edu. and Research. 5(1): Jan.-March 2015; Page151-156.

34. M. Girija, N. Kokilavani. Effectiveness of Structured Teaching Programme on Knowledge, Attitude and Practice among Patients with Hypertension. Asian J. Nur. Edu. & Research. 4(1): Jan.-March 2014; Page 136-139.

35. Arjun Singh. A Review of various aspects of the Ethnopharmacological, Phytochemical, Pharmacognostical, and Clinical significance of selected Medicinal plants. Asian Journal of Pharmacy and Technology. 12(4):349-0. doi: 10.52711/2231-5713.2022.00055

36. Swapna Mary A, Sapam Sofia Devi, Laishram Dabashini Devi. Effectiveness of Structured Teaching Programme on Knowledge regarding Warning Signs and Prevention of Stroke among Hypertensive patients in selected Hospitals at Bangalore. Asian Journal of Nursing Education and Research. 2022; 12(3):313-6.

Received on 16.12.2022 Modified on 01.04.20223

Res. J. Pharma. Dosage Forms and Tech.2023; 15(3):211-214.

DOI: 10.52711/0975-4377.2023.00034

	R₁	R₂
Daidzein Formononetin Genistein Biochanin A	H H OH OH	H CH₃ H CH₃
	R₁	R₂
Coumestrol 4’-methoxycoumestrol Repensol Trifoliol	H H OH OH	H CH₃ H CH₃