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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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the systemic circulation after 4 weeks of successive applications. Once the compounds
reached the uterus, a target organ, they bound to ERs, resulting in increased uterine growth.
However, the use of positively charged niosomes with particle sizes of approximately 200
nm may increase the risk of systemic side effects on the uterus compared to those from
conventional creams in an ovariectomized rat model. Future studies could investigate the
effects of this plant extract on hormonal levels and the potential implications for hormonal
replacement therapy in rats.
FIGURE 15.17 Macrophotographs of the uterus isolated from rats that underwent a 28-day treatment with
various creams: (a) Base cream, (b) cream containing empty niosomes, (c) cream containing 1% P. candollei
var. mirifica extract, (d) cream containing 1% P. candollei var. mirifica extract-loaded niosomes, and (e)
cream containing 0.1% 17β-estradiol-loaded niosomes. The experimental groups were imaged to analyze the
morphological changes induced by the treatments.
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FIGURE 15.18 The relative wet weight of the uterus (mg/100 g bodyweight) of ovariectomized rats after
28 days of treatment with various creams: A, Base cream; B, cream containing empty niosomes; C, cream
containing free 1% P. candollei var. mirifica extract; D, cream containing 1% P. candollei var. mirifica extract-
loaded niosomes, and E, cream containing 0.1% 17β-estradiol-loaded niosomes. The results indicate mean ±
standard deviation values (n = 5). The symbol ††P<0.001 indicates statistically significant differences from
negative controls.
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Finally, this study conducted an assessment of primary skin irritation in male New
Zealand white rabbits. The results showed no signicant difference in primary skin
irritation between different dosages of plant extracts incorporated into the formulation. The
skin at the test sites displayed minimal erythema, with a Draize dermal score of 1 after 24
and 48 hours, which diminished to 0 after 72 hours of patch testing. There were no signs of
eschar or edema at the treatment sites during the observation period. Based on ISO 1099310:1996, the skin irritation indexes of the tested creams were lower than 0.3, indicating
that they could be classied as nonirritating products. The presence of surfactants in the
formulations was believed to cause erythema by disturbing the skin’s barrier function.
In the study’s negative and positive controls, normal saline solution did not elicit skin
irritation, while sodium lauryl sulfate (SLS) caused mild skin erythema, with a primary
irritation index of 0.5. SLS is an anionic surfactant known to induce skin irritation in both
laboratory settings and living organisms and was chosen as the positive control for testing
primary skin irritation in this study due to its established mechanism of action.
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Overall, the study demonstrated that PME-loaded niosomes and free plant extract both
exhibited estrogenic properties by enhancing vaginal cornication and increasing uterine
weight in an ovariectomized rat model. Additionally, the presence of niosomes resulted in
better efcacy compared with conventional cream. These results support the potential of
phytoestrogenic extracts as an alternative to traditional hormone replacement therapy for
menopause-related symptoms caused by estrogen deciency. PME-loaded niosome-based
creams have shown promise as a safe and effective hormone replacement therapy , but further
research is necessary to validate these ndings in larger animal models or clinical trials.
15.9 CURRENT TRENDS IN PHYTOESTROGEN RESEARCH
Bibliometric analysis is a valuable method for identifying current research trends and
emerging topics across various fields. In phytoestrogen research, bibliometric analysis
proves particularly useful in identifying productive authors, institutions, and countries, as
well as the most cited articles and journals, alongside popular topics and research areas. This
information serves as a guide for future research and offers insights into the present state of
the field. Within this chapter, the author conducts a bibliometric analysis of phytoestrogen
research utilizing Scopus, a comprehensive bibliographic database containing peer-reviewed
literature. The study focuses on publications related to phytoestrogens over the past decade (1
January 1960 to 25 May 2023), examining publication counts, citation metrics, top authors,
institutions, countries, journals, and research areas. Furthermore, the study explores the
implications of these findings for future research in the field. By providing a comprehensive
overview of current trends and emerging topics in phytoestrogen research, this analysis
functions as a beneficial tool, guiding future investigations in this vital field of study .
The author conducted a search in the Scopus database using the keywords “phytoestrogen”
OR “phytoestrogens.” The search encompassed scientic literature containing any of these
terms in their title, abstract, or keywords. Full texts meeting the established eligibility criteria
based on certain inclusion and exclusion rules were subject to analysis. The criteria for
inclusion involved literature sourced from the Scopus database, comprising original articles
written exclusively in English. Scientic literature failing to meet these criteria, such as those
containing unrelated terms, unavailable full texts, or repetitive content, were excluded. The
literature that met the criteria and was extracted from the database was saved as “.CVS” and
subsequently transferred to VOSViewer 1.6.16 (https://www.vosviewer.com/) for further
bibliometric analysis. The analysis encompassed several parameters to evaluate the results,
including trends in publication, analysis of contributions from countries, institutions, and
publishers, evaluation of authors and their bibliographical coupling network, examination
of the most cited papers and their cocitation networks, keyword cooccurrence network and
overlay , and an exploration of toxicological aspects (Van Eck and Waltman, 2017).
15.9.1 PUBLICATION TRENDS
The systematic literature search was conducted meticulously, carefully selecting relevant
documents to effectively demonstrate the development and changes in research over
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an extensive period. A thorough analysis of the past 60 years was performed to gain a
comprehensive understanding of the evolution of phytoestrogen-related research, with
insightful results depicted in Figure 15.19. Within the vast Scopus database, an impressive total of 10,111 documents were recorded, encompassing a diverse range of scholarly
works: 6642 articles, 2020 reviews, 499 conference papers, 268 book chapters, 186
editorials, 171 notes, 152 short surveys, 124 letters, 25 errata, 18 books, and 5 other types
of publications. However, for meticulous bibliometric analysis, only the research articles
(6642 papers) were considered, refining the dataset. Scrutinizing the overall development
trend reveals that research progress in the field of phytoestrogens can be conveniently
divided into three stages. The initial stage, predating 2000, had a notably low number of
publications on the topic, indicating limited interest within the research community, with
research articles falling short of 200. The subsequent period from 2001 to 2010 witnessed
a substantial increase in publications, reaching a peak in 2006 with an impressive 342
studies published, reflecting a surge in research efforts on phytoestrogens. Following
this remarkable peak, the number of research articles remained relatively stable in subsequent years, averaging 247 documents published annually. This sustained level of output
demonstrates a consistent commitment to advancing the understanding of phytoestrogens
and their implications.
FIGURE 15.19 Publishing trends of phytoestrogens—all types of documents vs. research articles (1 January
1960–25 May 2023) based on the Scopus database.
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15.9.2 ANALYSIS OF CONTRIBUTING COUNTRIES AND CONTRIBUTING INSTITUTIONS
Phytoestrogens have been extensively researched, and conducting a bibliometric analysis
offers insights into countries making notable contributions. Figure 15.20 illustrates the
results of the analysis conducted to identify the top 20 countries and institutions making
significant contributions to phytoestrogen research. The analysis covered a comprehensive
range of publications from 1960 to 2023. The top contributing countries were identified
by the quantity of their publications and citations, with the United States leading the list
(1646 publications), followed by China (861), Germany (438), the United Kingdom (386),
and Japan (381). Among the contributing institutions, notable universities and research
organizations emerged, including Helsingin Yliopisto (146 documents) in Finland, the
National Institutes of Health (75 documents) and the National Institute of Environmental
Health Science (74 documents) in the United States, and the Ministry of Education China
(73 documents), Chulalongkorn University (68 documents), and Mahidol University (59
documents) in Thailand. This analysis provides valuable insights into the global distribution of research contributions in the field of phytoestrogens and highlights the leading
countries and institutions driving advancements in this area of study. Furthermore, the
analysis demonstrated the increasingly interdisciplinary nature of phytoestrogen research,
with contributions from various fields such as medicine (3330 documents, 29.4%);
biochemistry, genetics, and molecular biology (2604 documents, 23.0%); pharmacology,
toxicology, and pharmaceutics (1592 documents, 14.0%); agriculture and biological
sciences (897 documents, 7.9%); chemistry (713 documents, 6.3%); and other fields.
15.9.3 ANALYSIS OF CONTRIBUTING PUBLISHERS AND JOURNALS
A bibliometric analysis of fers valuable insights into the publishing landscape of phytoestrogen
research. Analyzing publications from 1960 to 2023, it was found that Elsevier emer ged as the
leading publisher in this field, followed by Wiley and Springer. These publishers accounted
for a significant proportion of the total publications and citations in the field. The analysis
also identified the most productive journals publishing research on phytoestrogens, including
Journal of Steroid Biochemistry and Molecular Biology (115 documents), Menopause (106
documents), Journal of Agricultural and Food Chemistry (99 documents), Nutrition and
Cancer (72 documents), and Journal of Nutrition (71 documents). These journals not only
published a substantial number of articles on phytoestrogens but also demonstrated a high
citation impact. Furthermore, the analysis revealed a steady increase in the number of publications on phytoestrogens over the years, indicating a growing interest in this field.
15.9.4 PUBLICATION EVOLUTION AND RESEARCH AREAS
A comprehensive analysis was conducted to identify the prevailing themes in phytoestrogen research through the application of cooccurrence keyword heatmap analysis within
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FIGURE 15.20 Analysis of (a) the top 20 contributing countries and (b) contributing institutions in phytoestrogen
research.
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the literature. VOSviewer software was employed to provide an exhaustive outlook of
the topics covered in scholarly works. To ensure the representation of relevant articles,
five iterations were performed to identify the least number of articles with the required
keywords. From a pool of 30,611 keywords, 7141 met the criteria, and subsequently,
a selection of 1000 keywords was made based on their overall link strength, resulting
in the classification of these keywords into five distinct groups. Figure 15.21 presents
the results of a cluster analysis conducted in the field of phytoestrogen research using
bibliometric analysis techniques, utilizing these research keywords. The analysis involved
cooccurrence keyword heatmap analysis and VOSviewer software to identify and categorize key research themes within the literature. The figure illustrates five distinct clusters
representing different aspects of phytoestrogen research, each assigned a unique color.
This cluster analysis provides a comprehensive overview of the prevailing research topics
and their interrelationships, shedding light on the breadth and depth of scholarly discourse
in the field of phytoestrogen research. Cluster 1 (red) (310 items) primarily focuses on
clinical studies of phytoestrogens, emerging as the largest cluster in terms of popularity,
albeit with modest internal homogeneity . Cluster 2 (green) (266 items) encompasses studies
on the pharmacological properties of phytoestrogens, employing molecular approaches to
elucidate their mechanisms of action in detail. Cluster 3 (blue) (238 items) explores the
estrogenicity of phytoestrogens through in silico simulation. Cluster 4 (yellow) (132 items)
centers around investigating phytoestrogens in animal models, while Cluster 5 (blue, 53
items) engages in the study of the preventive effects of phytoestrogens against postmenopausal osteoporosis.
A research trend analysis of phytoestrogen research was conducted using bibliometric
analysis, and the ndings are presented in Figure 15.22. The analysis involved examining
a substantial body of scholarly literature to identify patterns and trends in the eld. The
gure visually depicts the evolution of research topics and the emergence of new areas of
interest over time. The size of the bubbles corresponds to the relative volume of research
output, while the color gradient represents the chronological development of the research
themes. This research trend analysis offers valuable insights into the dynamic landscape
of phytoestrogen research, highlighting key areas of focus and potential avenues for future
exploration. Regarding current trends in phytoestrogen research, several notable themes
emerge. First, there is an escalating interest in the health advantages associated with
phytoestrogens, as evidenced by the increasing number of publications in this area. Second,
researchers are focused on identifying novel sources of phytoestrogens and unraveling their
mechanisms of action. This includes exploring phytoestrogens derived from traditional
Chinese medicines and other herbal remedies, as well as investigating the potential health
advantages of phytoestrogens found in seaweed, axseed, and legumes. Third, considerable
emphasis is placed on evaluating the safety and efcacy of phytoestrogens, particularly in
the context of menopause and other estrogen-related conditions. This encompasses studies
on the potential risks and benets of phytoestrogen supplements and other interventions,
as well as research on the mechanisms of action and potential side effects associated with
different phytoestrogen compounds. Finally, advanced research methods and technologies, such as molecular docking and simulations of molecular dynamics, are increasingly
employed to investigate the molecular-level interactions between phytoestrogens and
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ERs. These approaches have contributed to a more comprehensive understanding of how
different phytoestrogens work, offering new prospects for drug discovery and development.
Overall, the research trend analysis provides valuable insights into the evolving landscape
of phytoestrogen research, highlighting key areas of investigation, including health benets,
novel sources, safety and efcacy evaluation, and advanced research methods.
FIGURE 15.21 Cluster analysis of phytoestrogen research using bibliometric analysis.
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In addition, as highlighted in yellow, current trends in phytoestrogen research have
shown a signicant emphasis on molecular biology. Several reasons contribute to this
phenomenon. First, molecular biology techniques provide researchers with a powerful
toolkit to investigate the molecular-level mechanisms of action of phytoestrogens.
Understanding the interactions between phytoestrogens and cellular components, such
as receptors and signaling pathways, enables a comprehensive understanding of their
effects on biological systems. Employing molecular approaches allows researchers to
identify specic molecular targets of phytoestrogens and unravel the intricate underlying
mechanisms of their biological activities. Second, advancements in molecular biology
have facilitated the exploration of the structure–activity relationships of phytoestrogens.
T echniques such as molecular modeling, docking studies, and structure–activity relationship
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analysis enable the examination of the three-dimensional structure of phytoestrogens and
the prediction of their interactions with target molecules. This knowledge aids in the design
and development of novel phytoestrogen derivatives with improved potency or selectivity ,
paving the way for potential therapeutic applications. Furthermore, molecular biology
techniques contribute to the understanding of gene expression and regulation in relation
to phytoestrogen exposure. Researchers can investigate the inuence of phytoestrogens
on gene transcription, epigenetic modications, and downstream signaling pathways,
providing insights into the broader impact of phytoestrogens on cellular processes and
health outcomes. Finally, molecular biology approaches enable personalized medicine
and precise targeting of phytoestrogens. By analyzing individual genetic variations and
gene expression proles, researchers can identify subpopulations that may derive greater
benets or experience different responses to phytoestrogen interventions. This information
guides the development of tailored treatment strategies and facilitates the implementation
of personalized approaches in phytoestrogen research.
FIGURE 15.22 Research trend analysis of phytoestrogen research using bibliometric analysis.
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15.9.5 LIMITATIONS
The limitations of this bibliometric analysis of scientific research over the last 60 years
should be acknowledged. First, the database selection was limited to Scopus due to
VOSviewer’s compatibility with specific databases. Thus, other relevant databases were
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not included in this study. Second, only articles written in English were included in the
analysis, which may have resulted in language bias. Third, the cocitation network and
bibliographical coupling network constructed in this chapter are limited to articles and
authors, respectively, and other units of analysis could be considered to broaden the scope
of this study.
15.10 FUTURE DIRECTIONS
To further advance the use of phytoestrogens in drug discovery, several areas of research
are likely to receive attention in the future. These include exploring uncharted plant sources
to identify novel phytoestrogens, gaining a deeper understanding of their mechanisms
of action, synthesizing new compounds with improved properties, developing selective
phytoestrogen receptor modulators (SPERMs) to avoid undesirable side effects, and
conducting comprehensive safety assessments. The following sections provide further
details on each of these areas.
15.10.1 EXPLORATION OF UNEXPLORED PLANT SOURCES
To further expand on the topic of phytoestrogen identification, researchers may also
investigate the potential of combining different phytoestrogens to create more effective
therapeutic agents. Synergistic effects may occur when multiple compounds act together,
resulting in greater potency and efficacy compared to single compounds alone. Additionally ,
new phytoestrogens may be discovered through the modification of existing phytoestrogens
or the creation of synthetic analogs. These novel compounds may have unique biological
activities and could potentially pave the way for the creation of more specialized and potent
phytoestrogen-based drugs. Therefore, it is essential to explore a wide range of sources and
screening methods to identify and develop new phytoestrogens for potential therapeutic use.
15.10.2 UNDERSTANDING MECHANISMS OF ACTION
Comprehending the mechanisms through which phytoestrogens exert their impact is
crucial for creating medications that are both safe and efficacious. This will involve the
use of advanced molecular and cellular techniques to elucidate the signaling pathways and
biological processes involved in their estrogenic activity. Researchers can use techniques
such as CRISPR/Cas9 gene editing, transcriptomics, proteomics, and metabolomics to
identify and study key molecular targets and metabolic pathways. Phytoestrogens have
been found to undergo a thorough metabolic process in the human body, which resembles
the metabolic pathway of steroids. This process involves a series of transformations, such
as reduction, hydroxylation, and conjugation. However, little is known about natural
phytoestrogen metabolites, which could potentially have different or even opposing
biological activities from their parent compounds. Future research should aim to identify