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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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- •About the Editor
- •Contents
- •Contributors
- •Abbreviations
- •Preface
- •1. Natural Products as Drug Candidates
- •1.1 Introduction
- •1.2 An array of natural products
- •1.2.1 Plant-derived natural products
- •1.2.2 Microbial natural products
- •1.3 Importance of analytical techniques
- •1.3.1 A glance at extraction techniques
- •1.3.2 Microbial culturing techniques
- •1.3.3 Outlook and perspectives in nanoparticles
- •1.4 Natural products as a guide in drug design and synthesis
- •1.5 Natural products as promising drug candidates
- •1.5.1 Antiviral drug candidates
- •1.5.2 Antiparasitic drug candidates
- •1.5.3 Neuroprotective agents
- •1.6 Conclusion
- •Keywords
- •References
- •2. Traditional Knowledge for Drug Discovery
- •2.1 Introduction
- •2.2 Databases on indian remedial flora, indigenous medicines, and phytochemicals
- •2.2.1 Cultural preservation
- •2.2.2 Sustainable practices
- •2.2.3 Biodiversity conservation
- •2.2.4 Health and medicine
- •2.2.5 Climate change adaptation
- •2.2.6 Interconnectedness and wisdom
- •2.3 History of traditional knowledge
- •2.3.1 Indigenous healing practices
- •2.3.2 Aboriginal dreamtime
- •2.3.3 Traditional agriculture
- •2.3.4 Traditional crafts
- •2.3.5 Indigenous cosmologies
- •2.3.6 Traditional music and dance
- •2.3.7 Traditional navigation
- •2.4 Traditional medicine in plant formulations
- •2.4.1 Ayurveda
- •2.4.2 Traditional chinese medicine
- •2.4.3 Indigenous healing practices
- •2.5 Drug discovery
- •2.6 Aspects of developing plant-based drugs
- •2.6.1 Selection criteria for plants
- •2.6.2 Plant material authentication
- •2.6.3 Extraction methods
- •2.6.4 Isolation and structure elucidation of bioactive components
- •2.6.5 Standardization of plant formulations
- •2.7 Conclusions
- •References
- •3. Herbal Healing: Plant-Based Natural Products
- •3.1 Introduction
- •3.2 Classification of secondary metabolites
- •3.2.1 Phenolic compounds
- •3.2.2 Terpenes
- •3.2.3 Alkaloids
- •3.3 History of natural products
- •3.4 Drug discovery from natural products
- •3.5 Drugs derived from the plants
- •3.6 Conclusions
- •Keywords
- •References
- •4. Natural Products with Antimicrobial Properties
- •4.1 Introduction
- •4.2 Plants as antimicrobial agents
- •4.3 Marine sources as antimicrobial agents
- •4.4 Antimicrobial products derived from microorganisms
- •4.5 Conclusions and future trends
- •Keywords
- •References
- •5. Natural Products with Immunomodulatory Properties
- •5.1 Introduction
- •5.2.1 Aloe vera (l.) burm.f. (family: asphodelaceae)
- •5.2.2 Andrographis paniculata (burm. f.) wall.ex.nees. (family: acanthaceae)
- •5.2.3 Acorus calamus l. (family: araceae)
- •5.2.4 Allium sativum l. (family: alliaceae)
- •5.2.5 Azadirachta indica a. juss. (family: meliaceae)
- •5.2.6 Argyreia speciosa (l.f.) sweet (family: convolvulaceae)
- •5.2.7 Bidens pilosa l. (family: asteraceae)
- •5.2.8 Baliospermum montanum (willd.) müll.arg. (family: euphorbiaceae)
- •5.2.9 Boerhaavia diffusa l. (family: nyctaginaceae)
- •5.2.10 Boswellia serrata roxb. excolebr. (family: burseraceae)
- •5.2.11 Camellia sinensis (l.) kuntze (family: theaaceae)
- •5.2.12 Capparis zeylanica l. (family: capparidaceae)
- •5.2.13 Calendula officinalis l. (family: asteraceae)
- •5.2.14 Chelidonium majus l. (family: papaveraceae)
- •5.2.15 Carica papaya l. (family: caricaceae)
- •5.2.26 Glycyrrhiza glabra l. (family: leguminosae)
- •5.2.27 Hypericum perforatum l. (family: hypericaceae)
- •5.2.28 Hippophae rhamnoides l. (family: elaeagnaceae)
- •5.2.29 Hydrastis canadensis l. (family: ranunculaceae)
- •5.2.30 Jatropha curcas l. (family: euphorbiaceae)
- •5.2.31 Mangifera indica l. (family: anacardiaceae)
- •5.2.32 Mollugo verticillata l. (family: molluginaceae)
- •5.2.33 Matricaria chamomilla l. (family: asteraceae)
- •5.2.34 Momordica charantia l. (family: cucurbitaceae)
- •5.2.35 Morinda citrifolia l. (family: rubiaceae)
- •5.2.36 Nigella sativa l. (family: ranunculaceae)
- •5.2.37 Nelumbo nucifera gaertn. (family: nymphaeceae)
- •5.2.38 Nerium oleander l. (family: apocynaceae)
- •5.2.39 Ocimum tenuiflorum l. (family: labiatae)
- •5.2.40 Premna tomentosa willd. (family: verbanaceae)
- •5.2.41 Plantago sp. (plantago major l. and plantago asiatica l.) (family: plantaginaceae)
- •5.2.42 Psoralea corylifolia l. (family: fabaceae)
- •5.2.43 Prunella vulgaris l. (family: lamiaceae)
- •5.2.44 Punica granatum l. (family: punicaceae)
- •5.2.45 Rhinacanthus nasutus (l.) kurz (family: acanthaceae)
- •5.2.46 Salvia officinalis l. (family: lamiaceae)
- •5.2.47 Tamarindus indica l. (family: leguminosae)
- •5.2.48 Tinospora cordifolia (willd.) miers (family: menispermaceae)
- •5.2.16 Centella asiatica (l.) urb. (family: umbelliferae)
- •5.2.17 Cichorium intybus l. (family: asteraceae)
- •5.2.18 Cryptolepis dubia (burm.f.) m.r. almeida (family: apocynaceae)
- •5.2.19 Citrus aurantiifolia (christm.) swingle (family: rutaceae)
- •5.2.20 Curcuma longa l. (family: zingiberaceae)
- •5.2.21 Desmodium gangeticum (l.) dc. (family: fabaceae)
- •5.2.22 Eclipta prostrata (l.) (family: asteraceae)
- •5.2.23 Phyllanthus emblica l. (family: euphorbiaceae)
- •5.2.24 Evolvulus alsinoides (l.) (family: convolvulaceae)
- •5.2.25 Ficus benghalensis l. (family: moraceae)
- •5.2.49 Terminalia chebula retz. (family: combretaceae)
- •5.2.51 Urtica dioica l. (family: urticaceae)
- •5.2.52 Withania somnifera (l.) dunal (cultivated var.) (family: solanaceae)
- •5.3 Traditional importance of research to society and researchers
- •5.4 Conclusion
- •Keywords
- •References
- •6. Natural Products with Anticancerous Properties
- •6.1 Introduction
- •6.2 Plant-derived anticancer compounds
- •6.2.1 Polyphenols
- •6.2.2 Flavanoids
- •6.2.3 Brassinosteroids
- •6.2.4 Vinca alkaloids
- •6.2.5 Taxanes
- •6.2.6 Campothecin derivatives
- •6.3 Microorganisms-based anticancer compounds
- •6.3.1 Primary metabolites
- •6.3.2 Secondary metabolites
- •6.4 Selected medicinal plants with anticancerous activities
- •6.4.1 Curcuma longa l.
- •6.4.2 Viscum album l.
- •6.4.3 Colchicum autumnale l.
- •6.4.4 Raphanus sativus l.
- •6.4.5 Tinospora cordifolia wild
- •6.4.6 Nigella sativa l.
- •6.5 Therapeutic enzymes
- •6.6 Future perspective
- •6.7 Conclusion
- •Keywords
- •References
- •7. Natural Products with Antiviral Properties
- •7.1 Introduction
- •7.2 Source of natural products with antiviral activity
- •7.3 Main components of natural products
- •7.3.1 Flavonoids
- •7.3.2 Polyphenols
- •7.3.3 Polysaccharides
- •7.3.4 Terpenoids
- •7.4 Mechanisms of action of natural compounds in viral infections
- •7.4.1 Direct antiviral effect
- •7.4.2 Anti-inflammatory effect in viral infections
- •7.4.3 Effect on autophagy process
- •7.6 Conclusions
- •Keywords
- •References
- •8. Approaches to Develop Drugs from Natural Products
- •8.1 Introduction
- •8.2 Scenario of drug discovery
- •8.3 Efficient drug discovery engines
- •8.4 Drug discovery approaches using plants
- •8.4.1 Plant selection for screening purpose
- •8.4.2 Authentication of plants
- •8.4.3 Types of molecular markers
- •8.5.1 Parallel approach
- •8.5.2 Sequential approach
- •8.6 Structure elucidation of isolated compounds
- •8.7 Biological screening of extracts/fraction/isolates
- •8.7.1 Cell culture-based assay
- •8.7.2 Dialysis
- •8.7.3 Microdialysis
- •8.7.4 Ultrafiltration
- •8.7.5 Chromatography
- •8.7.6 Ligand fishing
- •8.8 Limitations
- •8.9 Molecular modelling and np database
- •8.10 Future thrust
- •8.11 Conclusion
- •Keywords
- •References
- •9. Strategies for Isolation and Identification of Bioactive Molecules from Natural Sources
- •9.1 Introduction
- •9.2 Bioactive compounds in natural sources and their pharmacological properties
- •9.3.1 Selection of materials
- •9.3.3 Types and properties of solvent for extraction
- •9.4 Extraction methods (conventional and modern)
- •9.4.1 Conventional methods
- •9.4.2 Novel extraction methods
- •9.5 Concentration and purification of bioactive molecules using chromatographic techniques
- •9.5.1 Separation based on adsorption properties
- •9.5.2 Separation based on partition coefficient
- •9.5.3 Separation based on the molecular size
- •9.5.4 Separation based on ionic strength
- •9.5.5 Other modern separation techniques
- •9.6 Identification and characterization of bioactive molecules
- •9.6.1 Qualitative and quantitative techniques/chromatographic or nonchromatographic techniques
- •9.7 Conclusions
- •Keywords
- •References
- •10. Role of Omics in Natural Product-Based Drug Discovery
- •10.1 Introduction
- •10.2 Genomics and transcriptomics in natural product discovery
- •10.2.1 Case studies and examples of natural product discovery using genomics and transcriptomics
- •10.2.2 Limitations and challenges of using genomics and transcriptomics in natural product discovery
- •10.3 Proteomics and metabolomics in natural product discovery
- •10.3.1 Case studies and examples of natural product discovery using proteomics and metabolomics
- •10.4 Bioinformatics in natural product-based drug discovery
- •10.4.1 Role of bioinformatics in natural product-based drug discovery
- •10.4.2 The use of bioinformatics to predict and annotate natural product biosynthetic pathways, gene clusters, and metabolomics
- •10.7 Future perspectives and potential impact of omics in natural product-based drug discovery
- •10.9 Potential impact on drug discovery and development
- •10.10 Conclusion
- •Keywords
- •References
- •11. Natural Products from Endophytic Microorganisms
- •11.1 Introduction
- •11.1.1 Rational/why endophytes?
- •11.2 Diversity of endophytic microorganisms
- •11.2.1 Endophytic bacteria and endophytic actinomycetes
- •11.2.2 Endophytic fungi
- •11.3.1 ISolation methods
- •11.3.1.1.1 Dilution Plating
- •11.3.1.1.2 Direct Plating
- •11.3.2 Identification methods
- •11.4 Bioactive compounds from endophytic microorganisms
- •11.4.1 Antibiotics
- •11.4.2 Antifungal agents
- •11.4.3 Antimalarial agents
- •11.4.4 Antiviral agents
- •11.4.5 Anticancer agents
- •11.4.6 Antioxidants
- •11.5 Stepwise methods for natural product discovery from endophytic microorganisms
- •11.5.1 Plant selection rationale
- •11.5.2 Isolation and cultivation of endophytes
- •11.5.3 Characterization of endophytes
- •11.5.4 Extraction of natural products
- •11.5.5 Purification of natural products
- •11.6 Biosynthesis and strategies for the optimization of natural product discovery from endophytic microorganisms
- •11.6.1 Exploration of novel microbial sources
- •11.6.2 Metabolomics-guided discovery
- •11.6.3 Coculture
- •11.6.4 Genome mining
- •11.6.5 Modulation by ultraviolent irradiation
- •11.7 Future directions and challenges
- •11.7.1 Improving the efficiency and accuracy of screening methods
- •11.7.2 Enhancing the scalability and affordability of production methods
- •11.7.3 Ensure natural product safety and efficacy
- •11.8 Conclusions
- •References
- •12. Natural Products with Antidiabetic Properties
- •12.1 Introduction
- •12.2 Natural products that regulate glucose absorption
- •12.2.1 Serotonin-derived products
- •12.2.2 Butyl-isobutyl-phthalate from laminaria japonica
- •12.2.3 Bioactive compounds of allium cepa and allium sativum
- •12.2.4 Elatosides E and F of aralia elata
- •12.2.5 Bioactive compounds of bauhinia candicans and bauhinia forficate
- •12.3 Natural products that enhance insulin sensitivity
- •12.3.1 Astragalus membranaceus polysaccharides
- •12.3.2 Bioactive compounds of litchi chinensis
- •12.3.3 Bioactive compounds of fenugreek
- •12.3.4 Bioactive compounds of cinnamon
- •12.3.5 Bioactive compounds of gastrodia elata
- •12.3.6 Polysaccharides of dioscorea
- •12.3.7 Anthocyanins of blueberries
- •12.3.8 Bioactive compounds of psidium guajava
- •12.4.1 Gingerol from zingiber officinale
- •12.4.2 Curcumin from curcuma longa
- •12.4.3 Berberine
- •12.4.4 Capsaicin of pepper
- •12.4.5 Bioactive compounds of bitter melon
- •12.4.6 Ginsenosides of ginseng
- •12.4.7 Bioactive compounds of aloe vera
- •12.4.8 Quinides of coffee
- •12.4.9 Bioactive compounds of tinospora cordifolia
- •12.4.10 Bioactive compounds of pterocarpus marsupium
- •12.4.11 Eugenol of ocimum sanctum
- •12.4.12 Bioactive compounds of syzygium densiflorum
- •12.5 Clinical trials based on antidiabetic effects of natural products derived from plants
- •12.5.1 Gymnema sylvestre (gurmar)
- •12.5.2 Fenugreek (trigonella foenum-graecum)
- •12.5.3 Tea catechins
- •12.5.4 Coffee
- •12.5.5 Rosemary (rosmarinus officinalis)
- •12.6 Conclusion
- •12.7 Future scope
- •Keywords
- •References
- •13. Marine-Derived Natural Products with Anticancer Properties
- •13.1 Introduction
- •13.2 Marine bioactive compounds
- •13.3 Anticancer activity of marine plants
- •13.4 Anticancer agents from marine floras
- •13.5.1 Antioxidants
- •13.5.2 Immunomodulation and apoptosis
- •13.5.3 Nutritional values and anticancer effects
- •13.6 Nature and cancer chemotherapy
- •13.7 Marine organisms and cancer chemotherapy
- •13.8 Anticancer agents from marine floras
- •13.9 Marine plants
- •13.9.1 Macro algae (seaweed)
- •13.9.2 Mangroves and other higher plants
- •13.9.3 Cyanobacteria
- •13.9.4 Bacteria
- •13.9.5 Proteobacteria
- •13.9.6 Cyanobacteria
- •13.9.7 Actinomycetes
- •13.9.8 Marine fungi
- •13.9.9 Soft corals
- •13.9.10 Marine sponges
- •13.10 Anticancer bioactive antibiotics derived from marine sources
- •13.10.1 Polyphenols
- •13.10.2 Polysaccharides
- •13.10.3 Alkaloids
- •13.11 Other marine sources for anticancer compounds
- •13.11.1 Peptides
- •13.11.2 Plitidepsin
- •13.11.3 Trabectedin
- •13.11.4 Lurbinectedin
- •13.12 Marine natural products as anticancer drugs
- •13.13.1 Aquaculture/cultivation
- •13.13.2 Genetic engineering
- •13.13.3 Synthesis/semisynthesis/modification
- •13.14 Conclusions and future prospects
- •References
- •14. Natural Products as Novel Opportunities for Cathepsin Inhibitors
- •14.1 Introduction
- •14.2 Cysteine proteases (CPs)
- •14.2.1 Cathepsin
- •14.2.2 Structure and mechanism of action of cathepsins
- •14.3 NPs as cathepsins inhibitors
- •14.3.1 NPs From bacteria as cathepsin inhibitors
- •14.3.2 NPs from fungus as cathepsin inhibitors
- •14.3.3 NPs from marine organism as cathepsin inhibitors
- •14.3.4 NPs from plants as cathepsin inhibitors
- •14.4 Conclusion and future pespectives
- •Keywords
- •References
- •15. Phytoestrogens in Drug Discovery: A Focus on Mechanisms of Action and Safety Assessment
- •15.1 Introduction
- •15.2 Phytoestrogens and estrogen receptors
- •15.3 Nonestrogen receptor-mediated effects of phytoestrogens
- •15.3.1 Mitogen-activated protein kinase (MAPK) pathway
- •15.3.2 PI3K/AKT pathway
- •15.3.3 WNT pathway
- •15.3.4 G-protein-coupled estrogen receptor (GPER)
- •15.4 Structure–activity relationship (SAR) of phytoestrogens
- •15.4.1 Isoflavones
- •15.4.2 Lignans
- •15.4.3 Coumestans
- •15.4.4 Stilbenes
- •15.4.5 Diarylheptanoids
- •15.5 Comparing potency and efficacy of phytoestrogens on various pathways
- •15.5.1 Potency and efficacy of phytoestrogens on different pathways
- •15.5.2 Possible synergistic effects of phytoestrogens with other drugs
- •15.6 Effects of phytoestrogens on the human organs
- •15.7 Safety Assessment of phytoestrogens
- •15.7.1 Toxicity assays used to evaluate the safety of phytoestrogens
- •15.7.2 Potential adverse effects of phytoestrogens
- •15.8 Case study
- •15.8.1 Vaginal cellular differentiation assay
- •15.8.2 Changes in rat body weight
- •15.8.3 Changes in rats’ uterus weight
- •15.9 Current trends in phytoestrogen research
- •15.9.1 Publication trends
- •15.9.2 Analysis of contributing countries and contributing institutions
- •15.9.3 Analysis of contributing publishers and journals
- •15.9.4 Publication evolution and research areas
- •15.9.5 Limitations
- •15.10 Future directions
- •15.10.1 Exploration of unexplored plant sources
- •15.10.2 Understanding mechanisms of action
- •15.10.3 Synthesis of novel compounds
- •15.10.4 Development of SPERMs
- •15.10.5 Safety assessment
- •15.11 Conclusion
- •Keywords
- •References
- •16. Honey Bee Products with Antimicrobial Properties
- •16.1 Introduction
- •16.2 Honey
- •16.3 Bee bread (perga)
- •16.4 Bee pollen
- •16.5 Bee propolis
- •16.6 Conclusion
- •Keywords
- •References
- •17. Natural Products for the Prevention of Leaky Gut
- •17.1 Introduction
- •17.2 The physical and chemical barriers of the intestine
- •17.2.1 Thick mucus layer
- •17.2.2 Intestinal epithelial cells (IECS)
- •17.2.3 Intestinal junctional complexes
- •17.2.4 Lamina propria
- •17.2.5 Intestinal regulatory T cells
- •17.2.6 Intestinal alkaline phosphatase
- •17.2.7 Antimicrobial peptides
- •17.2.8 Lysozyme
- •17.3 Mechanistic view of factors leading to a leaky gut
- •17.3.1 Gut dysbiosis
- •17.3.2 Mucosal inflammation and oxidative stress
- •17.3.3 TJ disruption
- •17.3.4 Genetics
- •17.3.5 Drugs
- •17.4 Pathological implications of a leaky gut
- •17.5 Natural product improving gut microbial dysbiosis
- •17.5.1 Traditional herbs and polyherbal formulations managing gut micro flora
- •17.5.2 Phytocompounds in the management of intestinal barrier integrity through balancing gut microflora
- •17.6.1 Anti-inflammatory traditional medicine and plant extracts ameliorating intestinal mucosal injury
- •17.6.2 Plant active constituents preventing mucosal injury and oxidative damage
- •17.7 Traditional medicine and natural products upregulating the TJ proteins
- •17.7.1 Traditional medicine and herbal extracts promoting junction protein protection
- •17.7.2 Phytocompounds for junction protein protection
- •17.8 Natural products averting pathological conditions through maintaining intestinal barrier function
- •17.9 Conclusion
- •Keywords
- •References
- •18. Role of Natural Products in the Pharmacotherapy of Osteoporosis
- •18.1 Introduction
- •18.1.1 Effect of traditional chinese medicine (TCM)
- •18.1.2 Effect of malay traditional medicine
- •18.1.3 Antiosteoporotic agents extracted from plant sources
- •18.1.4 Treatment by different pigments
- •18.1.5 Other herbal sources
- •18.1.6 Natural plant-based alkaloids
- •18.1.7 Essential markers involved in bone formation and resorption for osteoporosis treatment
- •18.2 Conclusion
- •Keywords
- •References
- •19. Gel-Based Natural Therapeutics: Potential Alternatives to Traditional Drug Delivery Systems in Aquaculture
- •19.1 INtroduction
- •19.2 DDS
- •19.2.1 Water medication
- •19.3 Oral administration
- •19.3.1 Gavage

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Sim et al. (2022) compared the estrogenic activities of 15 phytoestrogens, following
the Organization for Economic Cooperation and Development standardized protocols.
The study evaluated their potency and interactions with ERα using in vitro ER tests with
VM7Luc4E2 cells and in vivo tests on immature rats. The results demonstrated positive
responses in the human ERα dimerization assay for eight test compounds, while seven
compounds showed negative responses. These ndings were consistent with the outcomes
of the luciferase reporter assay , which evaluated the transactivation ability of the ER. Among
the seven compounds that exhibited higher in vitro estrogenic activities, further analysis
was conducted through uterotrophic bioassays. Biochanin A, 8-prenylnaringenin, and
coumestrol signicantly increased uterine weights, indicating uterotrophic effects. These
effects were nullied when animals were treated with an ER antagonist, emphasizing their
ER-dependent uterine impacts. Analysis showed that these phytoestrogens differentially
regulated uterine gene expression compared to endogenous estrogens. The study found
that both in vitro and in vivo testing methods were consistent and effective for evaluating
phytoestrogens’ interactions with ERα.
Warinsiriruk et al. (2022) studied the effects of 6% P. candollei var. mirica vaginal
gel on vascularization in postmenopausal women with genitourinary syndrome. In this
double-blinded, placebo-controlled trial involving 72 participants, measures such as
vaginal blood ow, vaginal health, and endometrial thickness were assessed. After 12
weeks, the P. candollei var. mirica group showed improved vaginal artery circulation
and tissue restoration, outperforming the placebo group in measures such as the vaginal
maturation index and vaginal health index. The gel was deemed safe for 12 weeks of use
in postmenopausal women. In addition, a study by Sritonchai et al. (2020) explored the
effects of a 12-week treatment with 5% P. candollei var. mirica extract (PME) gel versus
a placebo gel on vaginal health in postmenopausal women suffering from genitourinary
syndrome. In this randomized, double-blinded study involving 60 participants, the research
focused on bacterial vaginosis indicators, vaginal pH, and overall vaginal health. After
12 weeks, the P. candollei var. mirica gel group showed signicant improvements in
bacterial vaginosis markers compared with the placebo group. However, the gel did not
signicantly alleviate genitourinary symptoms.
15.5.2 POSSIBLE SYNERGISTIC EFFECTS OF PHYTOESTROGENS WITH OTHER DRUGS
When combined with other drugs, phytoestrogens may have synergistic effects, which
means they work together to produce a greater effect than either could achieve alone. There
are some possible synergistic effects of phytoestrogens with other drugs. (1) Tamoxifen is
a drug commonly used to treat breast cancer. Phytoestrogens may enhance the effects of
tamoxifen and reduce the risk of cancer recurrence (Klaab et al., 2023). (2) Some research
suggests that phytoestrogens might amplify the impact of antidepressants, such as selective
serotonin reuptake inhibitors (SSRIs), and alleviate depressive symptoms. (3) Blood-thinning medications: Phytoestrogens may have blood-thinning effects, and when combined
with medications such as aspirin or warfarin, they may increase the risk of bleeding.

374
Therefore, caution should be taken when combining these drugs. (4) Hormone replacement
therapy (HRT): Phytoestrogens may have similar effects to HRT and may enhance the
benefits of HRT while reducing some of the side effects. (5) Regarding diabetes medications, some studies have suggested that phytoestrogens may improve insulin sensitivity and
glucose metabolism, which could enhance the effects of diabetes medications (Hamaura
et al., 2023).
Recent research has investigated the use of biomimetic and estrogenic nanober wound
dressings for tissue repair (Ahn et al., 2020). Estrogen levels play a signicant role in
wound healing, with higher levels promoting faster healing. However, the use of estrogen
as a therapeutic agent is limited due to its associated side effects. In this research, the focus
is on soy phytoestrogens, which have a higher afnity for ERβ. The team developed wound
dressings using soy protein isolate (SPI) combined with hyaluronic acid (HA) to imitate the
natural structure of the dermis and to deliver genistein, a phytoestrogen that activates ERβ.
The dressings were tested on ovariectomized mice and human skin tissues. The results
showed that the HA/SPI dressings outperformed the control groups in promoting tissue
repair. Inhibition of the ERβ pathway prevented improved healing outcomes. The ndings
suggest that estrogenic brous scaffolds activate the ERβ pathway and facilitate skin repair.
15.6 EFFECTS OF PHYTOESTROGENS ON THE HUMAN ORGANS
This section presents a summary of research studies on dietary phytoestrogens aimed at
evaluating potential hormone-related outcomes and health effects. Figure 15.9 illustrates
the impact of phytoestrogens on multiple body parts, such as the uterus, breasts, bones,
cardiovascular system, brain, and skin (Ceccarelli et al., 2022; Khushboo et al., 2023). In
the uterus, phytoestrogens can have diverse effects. They can bind to ERs in the uterus,
leading to increased proliferation and growth of uterine cells. This estrogenic stimulation
contributes to the thickening of the uterine lining, known as the endometrium. Phytoestrogens
can compete with endogenous estrogen for receptor binding sites in the uterus, resulting
in a milder estrogenic effect compared to the body’s natural estrogen. In certain cases, this
can be beneficial, particularly for conditions involving excessive estrogen activity , such as
estrogen dominance or specific types of fibroids. Moreover, phytoestrogens can modulate
hormone levels in the body, including estrogen. They can act as mild estrogen activators
or inhibitors, depending on the specific compound and concentration. This modulation
helps maintain hormonal balance in the uterus. Additionally, some phytoestrogens possess
anti-inflammatory properties that can be advantageous for the uterus. They aid in reducing
inflammation and alleviating symptoms associated with certain uterine conditions, such as
endometriosis or adenomyosis.
Concerning other organs, phytoestrogens can interact with ERs in breast tissue. They
exhibit a potentially protective effect by competing with stronger estrogens, thereby reducing
the risk of certain breast conditions (Tanwar et al., 2021). Moreover, phytoestrogens can
positively impact bone health by improving bone mineral density and lowering the risk of
osteoporosis. Recent studies have investigated the effects of equol, a metabolite of soybean
isoavone, on postmenopausal osteoporosis. The researchers cultured osteoblast-like cells

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and treated them with different doses of equol and 17β-estradiol. In lab tests, equol was
found to stimulate growth and prevent cell death in osteoblasts, impacting the cell cycle. It
also inuenced the OPG/RANK/RANKL pathway, which is crucial for bone metabolism,
primarily through ERβ. In tests on postmenopausal osteoporosis rats, equol enhanced
femur bone health comparably to the effects of 17β-estradiol, affecting various serum and
urinary markers. Ultimately, equol interacts with the ERβ receptor and protects against
postmenopausal osteoporosis by modulating the OPG/RANKL pathway (Ni et al., 2023).
FIGURE 15.9 Effects of phytoestrogens on various organs.
⏎
Phytoestrogens may offer cardiovascular benets by improving lipid proles, reducing
cholesterol levels, and promoting healthy blood vessel function, thereby decreasing
the risk of cardiovascular disease. In a study by Yen et al. (2023), the cardioprotective
effects of puerarin from Pueraria lobata roots were investigated. Puerarin was found to
reduce cytotoxicity and reactive oxygen species (ROS) production in cardiomyoblasts
subjected to lipopolysaccharide (LPS) and H2O2. It exhibited antioxidant properties,
reduced apoptosis, suppressed NADPH oxidase-1 and Bax activation, and restored Bcl-2
expression, effectively attenuating ROS production. Additionally, puerarin inhibited the
expression of inammatory enzymes, decreased NO output, and lessened the hypertrophic
characteristics when exposed to LPS. Furthermore, it countered oxidative stress by
decreasing malondialdehyde levels and restoring glutathione levels. Puerarin exerted its

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effects by suppressing the toll-like receptor 4/NF-κB and MAPK signaling pathways, both
of which are triggered by LPS. Additionally, it countered the LPS-induced reduction in
AKT activation and heme oxygenase-1 (HO-1) expression. The cardioprotective effects of
puerarin hinge on AKT and HO-1; blocking these entities negated the benecial effects.
Through the mediation of AKT and HO-1, ERs are crucial for puerarin’s anti-inammatory
and antioxidant properties. This research emphasizes puerarin’ s potential therapeutic value
in addressing cardiac issues in postmenopausal women, specically through the activation
of the AKT and HO-1 pathways.
Additionally, phytoestrogens can inuence brain health and cognition. They possess
neuroprotective properties and may help maintain cognitive function while reducing the risk
of neurodegenerative diseases (Sekikawa et al., 2022; Yoo et al., 2022; Mitra et al., 2023).
In 2022, Viña et al. reported the effect of genistein on cognition in prodromal Alzheimer’s
disease patients. This study was designed to explore the impact of genistein on individuals
with early-stage Alzheimer’s disease through a double-blind, placebo-controlled clinical
trial. Over a year, 24 participants received a daily oral dose of 120mg of genistein. Amyloid-β
deposition was analyzed using 18F-utemetamol uptake, and neurocognitive tests were
conducted. The ndings indicated that those treated with genistein saw notable progress
in two specic tests (TAVEC and Centil REY copy) and seemed to make strides in the
remaining tests. When assessing amyloid-β accumulation, those on genistein did not show
increased uptake in the anterior cingulate gyrus, in contrast to those on the placebo. This
study suggests that genistein may help postpone the emergence of Alzheimer’ s dementia in
patients with early symptoms of the disease. It is advisable to conduct additional research
involving more participants to conrm these outcomes.
In addition, Fainanta et al. (2022) explored the impacts of dihydrotestosterone (DHT),
17β-estradiol, and PME on learning, memory, and specic gene expression related to
synaptic function and Alzheimer’s disease markers in androgen-decient male rats.
Orchidectomized rats treated with DHT, E2, or PME for 2 months exhibited improved
spatial learning and memory. While E2 and PME enhanced synaptic plasticity in the
hippocampus, DHT and PME better reduced certain tau protein levels than E2. Only DHT
tended to lower amyloid-β precursor expression. Overall, DHT was most effective in
enhancing learning and memory in these rats, with varying mechanisms compared with
E2 and PME.
Furthermore, phytoestrogens play benecial roles in promoting skin health by
stimulating collagen synthesis, improving skin elasticity, and reducing the appearance of
wrinkles (Rungseevijitprapa et al., 2021). They may also protect against damage caused
by ultraviolet radiation (Liu et al., 2020). However, it is important to note that not all
phytoestrogens are effective in combating skin aging. A study by Yusharyahya et al.
(2021) investigated the anti-aging effects of 5% fenugreek cream on postmenopausal
skin in 50 women over 12 weeks. Both the fenugreek and placebo groups saw improved
wrinkle scores in areas such as the forehead and crow’s feet. However, no signicant
differences between the groups were observed. Dermal thickness measurements showed
initial improvements but decreased by week 12. The study suggests that the 5% fenugreek
concentration might not be optimal for antiaging effects. The authors believe that both
orientin and galactomannan in this plant are responsible for this effect. Further research is

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needed to determine the best concentration. It is essential to consider individual variations
and specic factors when evaluating phytoestrogen effects.
15.7 SAFETY ASSESSMENT OF PHYTOESTROGENS
15.7.1 TOXICITY ASSAYS USED TO EVALUATE THE SAFETY OF PHYTOESTROGENS
To evaluate the safety of phytoestrogens, in vitro assays are often used. In vitro assays
involve testing a substance in a laboratory setting using cells or tissues outside of their
normal biological context. Numerous studies have utilized various in vitro assays to showcase the estrogenic activity of natural substances. Each of these assays has its own benefits
and drawbacks when used as a screening method. Nevertheless, there is not a single in
vitro test considered ideal for precisely predicting estrogenic effects within a complex live
system. Some of the commonly used in vitro assays for evaluating phytoestrogen safety
include the following:
1. Cell viability assays: These assays measure the capability of cells to thrive when
exposed to phytoestrogens. Various cell types can be used, such as breast cancer
cells, uterine cells, and prostate cells, which are known to be sensitive to estrogen
and phytoestrogens (Das et al., 2022). If phytoestrogen is toxic to cells, it can
indicate potential harm to human health.
2. Hormone receptor assays: Phytoestrogens can bind to ERs in the body and activate them, leading to estrogen-like effects. In vitr o assays can measure the aptitude
of phytoestrogens to bind with and activate these receptors, offering clues about
their potential to disrupt the endocrine system.
3. Proliferation assays: Estrogen and phytoestrogens can stimulate cell growth and
proliferation, which can be measured using assays that track the number of cells
over time. These assays can provide information on the potential for phytoestrogens
to promote cancer or other diseases.
4. Gene expression assays: Phytoestrogens might influence the expression levels of
genes governed by estrogen. In vitro assays can measure changes in gene expression in response to phytoestrogens, which can provide insights into their potential
effects on human health.
In vivo assays are essential in the evaluation of the safety of phytoestrogens. In vivo assays
refer to experiments conducted on living organisms to study the effects of a substance.
The use of in vivo assays helps to provide valuable information on the safety and efficacy
of phytoestrogens. To evaluate the safety of phytoestrogens in vivo, several assays can be
used. Some of the commonly used assays are as follows:

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1. Acute toxicity assays: These assays are used to determine the toxicity of phytoestrogens after a single exposure. They are typically conducted on small animals,
such as mice or rats, and involve administering a high dose of phytoestrogen to the
animal and then monitoring it for signs of toxicity.
2. Subchronic toxicity assays: These assays are used to evaluate the toxicity of
phytoestrogens over a longer period. They involve administering a lower dose of
phytoestrogen to the animal for several weeks or months and then assessing any
adverse effects.
3. Reproductive toxicity assays: These assays are used to assess the effects of phytoestrogens on reproductive function. They involve administering phytoestrogens to
animals and then monitoring reproductive parameters such as fertility, pregnancy,
and offspring development (Khushboo et al., 2023).
4. Development toxicity assays: These assays are used to assess the effects of phytoestrogens on fetal development. They involve administering phytoestrogens to pregnant
animals and then monitoring fetal development and birth outcomes.
5. Genotoxicity assays: These assays are used to determine whether phytoestrogens
can cause DNA damage. They involve exposing animals to phytoestrogen and then
assessing any genetic damage.
6. Carcinogenicity assays: These involve exposing animals to phytoestrogen over a
long period and then assessing any cancerous growth.
Several in vivo assays on the efcacy and safety of phytoestrogens are available in
scholarly articles. For instance, Keiler
et al. (2017) studied the effects of a hops extract
containing 0.42% of the estrogenic avanone 8-prenylnaringenin on mammary tumor
growth in ovariectomized rats. The hops extract did not promote tumor growth and even
reduced tumor incidence compared to controls. No estrogenic effects were observed in the
liver or uterus. The extract also did not impact estrogen-dependent markers in the normal
mammary gland, suggesting its safety for managing menopausal symptoms without
affecting mammary health. Moreover, the possible mode of action of dietary diosgenin as
an emerging environmental contaminant, endocrine disruptor, and reproductive toxicant
was studied by Khushboo et al. (2023). They explored the potential risks associated with
diosgenin, a phytosteroid saponin found in dietary phytoestrogens. This study sought
to assess the impact of diosgenin on the endocrine and reproductive systems of albino
mice using acute toxicity tests, 90-day repeated oral exposure, and extended reproductive
evaluations for the F1 generation. The ndings indicated a modest toxic effect of diosgenin,
with LD50 measurements of 546.26 mg/kg in males and 538.72 mg/kg in females.
Prolonged diosgenin exposure led to oxidative stress, altered reproductive functions, and
affected the reproductive health of F0 and F1 offspring. It also caused transgenerational
reproductive toxicity in these generations. Given these potential adverse effects, caution
is urged when using diosgenin in food or medicine, emphasizing the need for a thorough
risk assessment. In addition, Srasri et al. (2022) studied the effects of P. candollei var.
mirica root (PMR) on the pituitary-ovarian axis and various metabolic indicators in a
model using premenopausal rats. Over a span of 28 days, the rats received different PMR
powder dosages orally. The research delved into aspects such as reproductive hormones,

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lipid proles, thyroid parameters, the estrous cycle, and tissue assessments. The ndings
revealed that PMR did not notably affect the weight of the uterus, vagina, or body, nor did
it alter the levels of circulating estrogen and prolactin. However, it did manifest effects
similar to estrogen, affecting factors such as ovarian and liver weights, blood gonadotropin
levels, lipid concentrations, and estrous patterns. Tissue examinations noted alterations
in areas such as the anterior pituitary and mammary gland, among others. Notably, when
given in high amounts, this plant powder indicated slight liver toxicity. This investigation
underscores the biological impact of this phytoestrogenic plant and how it mirrors estrogen
effects in premenopausal rats.
Clinical trials are one way in which the safety of phytoestrogens can be evaluated. In these
trials, participants are typically given phytoestrogen supplements or foods that are high in
phytoestrogens and are then monitored for any adverse effects. In the Women’s Isoflavone
Soy Health Study , a randomized, double-blind trial involving 350 postmenopausal women,
participants were given either a soy protein supplement with 99 milligrams of isoflavones
or a placebo for 2 years. No significant differences in breast or endometrial cancer
incidence or other adverse effects were observed between the groups (https://aru.usc.edu/
clinical-trials/wish/).
In recent years, Abdi
et al. (2021) reported a systematic review to assess the effects of
phytoestrogens on urogenital symptoms during menopause. They analyzed 33 randomized
clinical trials that evaluated various forms of phytoestrogens, including P. candollei var.
mirica, fennel, hop plant, soy, red clover, black cohosh, ginseng, and others. These
phytoestrogens were administered in various dosage forms, including oral capsules, tablets,
dietary supplements, fortied powders, vaginal gels, creams, and suppositories. The ndings
indicated that phytoestrogens effectively improved menopausal urogenital symptoms, with
greater recovery rates observed with vaginal use. Urogenital atrophy indicators, urinary
disorders, and sexual function showed improvement after phytoestrogen treatment.
Phytoestrogens are considered a safe and accessible method compared to hormone therapy ,
offering relief for urogenital symptoms and enhancing sexual satisfaction and quality of
life for women.
15.7.2 POTENTIAL ADVERSE EFFECTS OF PHYTOESTROGENS
Phytoestrogens can interact with ERs in the body. This interaction can lead to hormonal
imbalances, which may have negative effects on various biological processes, including
reproductive health, development, and metabolism. Phytoestrogen can interfere with the
normal function of the endocrine system by either mimicking or blocking the actions of
estrogen. When phytoestrogens mimic estrogen, they can cause estrogenic effects in the body .

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Similarly, when they block the actions of estrogen, they can cause antiestrogenic effects.
These effects can disrupt the delicate balance of hormones in the body , leading to hormonal
imbalances.
While the potential risks of phytoestrogens to human health are still not fully understood, several studies have reported negative effects, such as reduced sperm quality , altered
thyroid function, and decreased testosterone levels (Khushboo et al., 2023). For instance,
a study conducted on rats showed that a high intake of phytoestrogens led to a decrease in
sperm count and motility (Pool et al., 2023). Similarly , another study showed that phytoestrogen intake caused a reduction in thyroid hormone levels in male Wistar rats (Dal Forno
et al., 2023). These ndings raise concerns about the potential risks of phytoestrogens
to human health. Therefore, further research is needed to evaluate the safety of phytoestrogens and their potential risks for endocrine disruption in the human body. This study
could enhance our comprehension of how phytoestrogens function and their inuence on
the hormonal system. It can also help to identify safe levels of phytoestrogen intake and
provide guidelines for their use in various applications.
In addition, Jin et al. (2023) conducted a narrative review on estrogens, progesterone,
and phytoestrogens in human milk and their effects on infant health outcomes. This review
highlights that limited research has been conducted to explore the inuence of these
hormones on the growth and health of breastfed infants. A comprehensive understanding of
the factors contributing to the presence of these hormones in human milk is crucial for the
development of effective intervention strategies. Regarding phytoestrogens, their ability
to interfere with normal hormone functions by interacting with ERs is acknowledged.
However, there are insufcient available data to investigate the relationship between
phytoestrogen exposure and infant growth parameters. The research team suggests that future
studies should include assessments of infant phytoestrogen intake and compare outcomes
between males and females. This is particularly important given that phytoestrogens have
been associated with dose- and sex-specic effects on sexual development. In contrast,
maternal estrogens and progesterone are endogenous hormones that play signicant roles
in mammary gland development during pregnancy. Although their concentrations decline
rapidly after birth, they can still be detected in human milk throughout lactation.
There are concerns about the potential adverse effects of phytoestrogens, including their
genotoxicity. Genotoxicity refers to the ability of a substance to cause damage to the
genetic material (deoxyribonucleic acid, DNA) of cells. This can lead to mutations or
other changes in the DNA sequence, which can potentially result in the development of
cancer or other diseases (Nasri and Pohjanvirta, 2021). Several studies have suggested
that phytoestrogens may have genotoxic effects, although the results have been somewhat
mixed. For example, some studies have found that phytoestrogens can cause DNA damage
in vitro (in cells grown in a laboratory setting) (Ganai and Farooqi, 2015). In one study,
for instance, researchers exposed human cells to different concentrations of genistein, a
phytoestrogen found in soybeans, and found that the compound caused DNA damage at

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high concentrations (Spagnuolo et al., 2015; Pawlicka et al., 2022). Other studies have
found similar results with other phytoestrogens, such as daidzein and coumestrol (Han
et al., 2015; Zafar et al., 2017).
In vivo studies (in living organisms) have also suggested that phytoestrogens may have
genotoxic effects. For example, a study in rats found that feeding them a high-phytoestrogen
diet caused DNA damage in the cells of their liver (Kim et al., 2005). However, it is important to note that not all studies found genotoxic effects of phytoestrogens. Some studies
have reported insignicant genotoxic effects of phytoestrogens, both in vivo and in vitro
(Tagorti et al., 2023). Furthermore, some investigations even imply that phytoestrogens
could provide protection against genotoxicity (Gorzkiewicz et al., 2021). Therefore, while
there is some evidence to suggest that phytoestrogens may have genotoxic effects, the
results are not entirely consistent. More comprehensive studies are required to fully grasp
the possible negative impacts of phytoestrogens on genotoxicity, as well as their potential
health benets. Importantly, the inuence of phytoestrogens may vary depending on the
dose, duration of exposure, and individual differences in genetics and other factors.
While certain associations suggest that phytoestrogens may lessen the risk for specific
cancers, such as breast and prostate cancer, there is also some evidence indicating that
they may contribute to the initiation and progression of other cancer types. In particular,
some studies have linked high levels of phytoestrogen intake to an increased risk of endometrial cancer, a type of cancer that affects the lining of the uterus. This is thought to be
because phytoestrogens can stimulate the growth of endometrial cells, which may increase
the risk of abnormal cell growth and the development of cancerous tumors. Additionally,
there is some concern that phytoestrogens may interfere with the effectiveness of certain
treatments, such as tamoxifen, which is commonly utilized in managing hormone receptorpositive breast cancer. This is because phytoestrogens can compete with tamoxifen for
binding to ERs, potentially reducing the effectiveness of the drug and increasing the risk
of cancer recurrence.
To evaluate the safety of phytoestrogens in drug discovery, several factors should be
considered:
1. Route of administration: The route of administration can significantly affect the
safety of phytoestrogens. Oral administration may produce different toxicity profiles
than intravenous administration, for example.
2. Dose: The dose of phytoestrogens is a crucial consideration. Higher doses may
increase the risk of toxicity or adverse effects, while lower doses may be less effective in achieving therapeutic outcomes.

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3. Duration of exposure: The length of exposure to phytoestrogens can impact safety .
Short-term exposure may be well tolerated, while long-term exposure may increase
the risk of adverse effects.
4. Pharmacokinetics: Understanding the pharmacokinetics of phytoestrogens can
assist in determining their safety profile. This includes factors such as absorption,
distribution, metabolism, and excretion.
5. Preclinical testing: Preclinical testing is critical for assessing the safety of phytoestrogens before human trials. This may include in vitro studies, animal studies, and
toxicity assessments.
6. Clinical trials: It is imperative to conduct clinical studies to evaluate the safety of
phytoestrogens in humans. This involves evaluating the incidence and severity of
adverse effects, as well as monitoring for any long-term effects.
7. Patient populations: The safety of phytoestrogens may vary depending on the
patient population being treated. For instance, pregnant or breastfeeding women,
children, and elderly individuals may be more susceptible to adverse effects.
8. Potential interactions: Phytoestrogens may interact with other medications or
supplements, which may increase the risk of adverse effects. Potential interactions
should be taken into account when assessing safety.
9. Regulatory considerations: In phytoestrogen drug discovery, regulatory
considerations are essential to ensure the safety and efficacy of these compounds.
Standardization of phytoestrogen extracts is a promising approach to ensure
consistency in the dose and product quality, which is crucial for regulatory
evaluation. Before using phytoestrogens as therapeutic agents, safety evaluation
is necessary to assess potential toxicity, drug interactions, and adverse effects,
including their long-term effects. Efficacy evaluation through clinical trials is
essential to determine optimal dosages, duration of treatment, and patient populations for these compounds using appropriate endpoints such as bone mineral
density, hot flashes, or breast cancer recurrence rates. Once safety and efficacy
have been established, regulatory agencies such as the Food and Drug Administration must approve the compounds based on data from clinical trials and other
studies. Labeling and advertising regulations are crucial to prevent misleading or
inaccurate information, ensuring that consumers have accurate information about
the phytoestrogen products they use.
According to the author’s opinion, the question of whether people with estrogen-related
cancer should consume phytoestrogens is complex and requires careful consideration of
various factors. It is worth noting that phytoestrogens, found in certain plant foods such as
soybeans, axseeds, and chickpeas, have functional properties similar to those of estrogen.
Research has hinted that these compounds could offer health benets, including lowering
the risk of certain types of cancer and heart diseases. However, other studies have raised
concerns that phytoestrogens could potentially stimulate the growth of estrogen-sensitive
cancers, such as breast cancer. It is worth noting that research on this topic is still somewhat inconclusive, and there is not yet a consensus on whether phytoestrogens are safe or
benecial for people with estrogen-related cancers.
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