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Network Pharmacology of Natural Products, 2nd Edition
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Network Pharmacology of Natural Products, 2nd Edition

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: 25 December 2025 | Viewed by 3187

Special Issue Editors

Prof. Dr. Alexander George Panossian

E-Mail Website
Guest Editor
Phytomed AB, 58344 Vastervick, Sweden
Interests: network pharmacology; neuroendocrine-immune system; stress; ageing; infalmmation; adaptogens
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Karl Wah-Keung Tsim

E-Mail Website
Guest Editor
Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China
Interests: agricultural and domestic animal services; cellular and molecular mechanisms; food science and technology; molecular and cellular neuroscience
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to highlight recent findings on the relationship between natural products (purified compounds, plant extracts, herbal medicines, complex formulations) and pharmacological activity, including specific and pleiotropic action.

We encourage authors to submit studies on a wide range of topics, including molecular mechanisms of multitarget action based on network pharmacology approaches and clinical trials.

Prof. Dr. Alexander George Panossian
Prof. Dr. Karl Wah-Keung Tsim
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural compounds
  • plant extracts
  • structure-activity relationship
  • network pharmacology
  • multitarget effects
  • synergy of complex preparations
  • pleiotropic activity

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Published Papers (6 papers)

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Research

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17 pages, 7071 KB  
Article
Oligomeric Proanthocyanidins Reverse Lenvatinib Resistance in Hepatocellular Carcinoma Through ITGA3-Mediated Pathway
by Takayuki Noma, Yuan Li, Yuma Wada, Yuji Morine, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, Hiroki Teraoku, Mitsuo Shimada and Ajay Goel
Pharmaceuticals 2025, 18(9), 1361; https://doi.org/10.3390/ph18091361 - 12 Sep 2025
Abstract
Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness [...] Read more.
Background: Oligomeric proanthocyanidins (OPCs) are natural polyphenolic compounds with strong antitumor properties and have gained attention as potential agents to overcome drug resistance. Hepatocellular carcinoma (HCC) remains a major cause of cancer deaths worldwide, and although Lenvatinib is widely used, its effectiveness is limited by acquired resistance. This study explores the potential of OPCs to overcome Lenvatinib resistance in HCC. Methods: To evaluate the potential of OPCs to overcome Lenvatinib resistance in HCC, we established Lenvatinib-resistant Huh-7 and PLC-PRF-5 cell lines and conducted systematic cell culture experiments to assess their antitumor effects. Furthermore, genome-wide transcriptomic profiling, network pharmacology approaches, and pathway enrichment analysis were performed to identify resistance-associated signaling pathways that could serve as therapeutic targets. Results: The combination of OPCs and Lenvatinib demonstrated a significant synergistic anti-proliferative effect in resistant hepatocellular carcinoma cells, with the most synergistic dose combinations showing Bliss synergy scores exceeding 10. Transcriptomic profiling revealed that the adhesion molecule ITGA3 is a key factor in Lenvatinib resistance and contributes to the acquisition of anoikis resistance. The combination treatment suppressed ITGA3–EGFR–AKT signaling, restored anoikis sensitivity, significantly reduced spheroid formation (fold change = 0.10–0.12; p < 0.001), and markedly increased apoptosis (fold change = 2.7–5.0; p < 0.001). Conclusions: This study is the first to demonstrate that OPCs can overcome chemotherapy resistance by targeting the integrin pathway, providing scientific evidence for their potential use as an adjunctive therapy for chemotherapy-resistant HCC. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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29 pages, 13368 KB  
Article
Systems Network Integration of Transcriptomic, Proteomic, and Bioinformatic Analyses Reveals the Mechanism of XuanYunNing Tablets in Meniere’s Disease via JAK-STAT Pathway Modulation
by Zhengsen Jin, Chunguo Wang, Yifei Gao, Xiaoyu Tao, Chao Wu, Siyu Guo, Jiaqi Huang, Jiying Zhou, Chuanqi Qiao, Keyan Chai, Hua Chang, Chun Li, Xun Zou and Jiarui Wu
Pharmaceuticals 2025, 18(9), 1266; https://doi.org/10.3390/ph18091266 - 25 Aug 2025
Viewed by 529
Abstract
Background: Meniere’s disease (MD) is a rare inner ear disorder characterized by endolymphatic hydrops and symptoms such as vertigo and hearing loss, with no curative treatment currently available. XuanYunNing tablets (XYN) have been clinically used to treat MD, but their molecular mechanisms remain [...] Read more.
Background: Meniere’s disease (MD) is a rare inner ear disorder characterized by endolymphatic hydrops and symptoms such as vertigo and hearing loss, with no curative treatment currently available. XuanYunNing tablets (XYN) have been clinically used to treat MD, but their molecular mechanisms remain unclear. Objective: This study aimed to systematically evaluate the pharmacological effects of XYN in a guinea pig model of MD and to elucidate the underlying molecular mechanisms of both MD pathogenesis and XYN intervention through integrated multi-omics analyses, including transcriptomics, proteomics, and bioinformatics. Methods: A guinea pig model of endolymphatic hydrops was induced by intraperitoneal injection of desmopressin acetate (dDAVP). Pharmacodynamic efficacy was evaluated via behavioral scoring and histopathological analysis. The differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) modulated by XYN treatment were identified using high-throughput transcriptomic and proteomic sequencing. These data were integrated through multi-omics bioinformatic analysis. Key molecular targets and signaling pathways were further validated using RT-qPCR and Western blotting. Results: Pharmacological evaluations showed that guinea pigs in the model group exhibited a 26% increase in endolymphatic hydrops area, while high-dose XYN treatment reduced this area by 19% and significantly improved functional parameters, including overall physiological condition (e.g., weight and general appearance), auricular reflexes to low-, medium-, and high-frequency sound stimuli, nystagmus, and the righting reflex. High-throughput sequencing combined with integrative omics analysis identified 513 potential molecular targets of XYN. Subsequent network and module analyses pinpointed the JAK-STAT signaling pathway as the central axis. Mendelian randomization (MR) analysis further supported a causal relationship between MD and metabolic, immune, and inflammatory traits, reinforcing the central role of JAK-STAT signaling in both MD progression and XYN-mediated intervention. Mechanistic studies confirmed that XYN downregulated IFNG, IFNGR1, JAK1, p-STAT3/STAT3, and AOX at both mRNA and protein levels, thereby inhibiting aberrant JAK-STAT pathway activation in MD model animals. In addition, a total of 125 chemical constituents were identified in XYN by UHPLC-MS analysis. ZBTB20 and other molecules were identified as potential blood-based biomarkers for MD. Conclusions: This study reveals that XYN alleviates MD symptoms by disrupting a pathological cycle driven by JAK-STAT signaling, inflammation, and metabolic dysfunction. These findings support the clinical potential of XYN in the treatment of Meniere’s disease and may inform the development of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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13 pages, 3190 KB  
Article
Network Pharmacology and Machine Learning Identify Flavonoids as Potential Senotherapeutics
by Jose Alberto Santiago-de-la-Cruz, Nadia Alejandra Rivero-Segura, María Elizbeth Alvarez-Sánchez and Juan Carlos Gomez-Verjan
Pharmaceuticals 2025, 18(8), 1176; https://doi.org/10.3390/ph18081176 - 9 Aug 2025
Viewed by 640
Abstract
Background/Objectives: Cellular senescence is characterised by irreversible cell cycle arrest and the secretion of a proinflammatory phenotype. In recent years, senescent cell accumulation and senescence-associated secretory phenotype (SASP) secretion have been linked to the onset of chronic degenerative diseases associated with ageing. In [...] Read more.
Background/Objectives: Cellular senescence is characterised by irreversible cell cycle arrest and the secretion of a proinflammatory phenotype. In recent years, senescent cell accumulation and senescence-associated secretory phenotype (SASP) secretion have been linked to the onset of chronic degenerative diseases associated with ageing. In this context, the senotherapeutic compounds have emerged as promising drugs that specifically eliminate senescent cells (senolytics) or diminish the damage caused by SASP (senomorphics). On the other hand, computational approaches, such as network pharmacology and machine learning, have revolutionised the identification of novel drugs. These tools enable the analysis of large volumes of compounds and the optimisation of the search for the most promising ones as potential drugs. Therefore, we employed such approaches in the present study to identify potential senotherapeutic compounds. Methods: First, we constructed drug-protein interaction networks related to cellular senescence. Then, using three machine learning models (Random Forest, Support Vector Machine, and K-Nearest Neighbours), we classified these compounds based on their therapeutic potential against senescence. Results: Our results enabled us to identify 714 compounds with potential senescent therapeutic activity, of which 270 exhibited desirable medicinal chemistry properties, and we developed an interactive web tool freely accessible to the scientific community. Conclusions: we found that flavonoids were the most abundant compound class from which 18 have never been reported as senotherapeutics. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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25 pages, 8335 KB  
Article
Integrative In Silico and In Vivo Analysis of Banhasasim-Tang for Irritable Bowel Syndrome: Mechanistic Insights into Inflammation-Related Pathways
by Woo-Gyun Choi, Seok-Jae Ko, Jung-Ha Shim, Chang-Hwan Bae, Seungtae Kim, Jae-Woo Park and Byung-Joo Kim
Pharmaceuticals 2025, 18(8), 1123; https://doi.org/10.3390/ph18081123 - 27 Jul 2025
Viewed by 638
Abstract
Background/Objectives: Banhasasim-tang (BHSST) is a traditional herbal formula commonly used to treat gastrointestinal (GI) disorders and has been considered a potential therapeutic option for irritable bowel syndrome (IBS). This study aimed to explore the molecular targets and underlying mechanisms of BHSST in IBS [...] Read more.
Background/Objectives: Banhasasim-tang (BHSST) is a traditional herbal formula commonly used to treat gastrointestinal (GI) disorders and has been considered a potential therapeutic option for irritable bowel syndrome (IBS). This study aimed to explore the molecular targets and underlying mechanisms of BHSST in IBS using a combination of network pharmacology, molecular docking, molecular dynamics simulations, and in vivo validation. Methods: Active compounds in BHSST were screened based on drug-likeness and oral bioavailability. Potential targets were predicted using ChEMBL, and IBS-related targets were obtained from GeneCards and DisGeNET. A compound–target–disease network was constructed and analyzed via Gene Ontology and KEGG pathway enrichment. Compound–target interactions were further assessed using molecular docking and molecular dynamics simulations. The in vivo effects of eudesm-4(14)-en-11-ol, elemol, and BHSST were evaluated in a zymosan-induced IBS mouse model. Results: Twelve BHSST-related targets were associated with IBS, with enrichment analysis identifying TNF signaling and apoptosis as key pathways. In silico simulations suggested stable binding of eudesm-4(14)-en-11-ol to TNF-α and kanzonol T to PIK3CD, whereas elemol showed weak interaction with PRKCD. In vivo, eudesm-4(14)-en-11-ol improved colon length, weight, stool consistency, TNF-α levels, and pain-related behaviors—effects comparable to those of BHSST. Elemol, however, showed no therapeutic benefit. Conclusions: These findings provide preliminary mechanistic insight into the anti-inflammatory potential of BHSST in IBS. The integrated in silico and in vivo approaches support the contribution of specific components, such as eudesm-4(14)-en-11-ol, to its observed effects, warranting further investigation. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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16 pages, 1796 KB  
Article
Natural Products for Drug Discovery in Cognitive Disabilities: Bibliometric Hotspots, Research Trends, Conceptual Framework, and Future Directions
by Mohammed Albratty, Maryam Halawi and Ali Mufraih Albarrati
Pharmaceuticals 2025, 18(7), 983; https://doi.org/10.3390/ph18070983 - 30 Jun 2025
Viewed by 489
Abstract
Background: The therapeutic potential of natural products in cognitive disabilities has drawn growing attention, yet a comprehensive analysis of trends and key contributors is lacking. This study provides a bibliometric overview highlighting growth patterns, themes, and future directions. Methods: A comprehensive [...] Read more.
Background: The therapeutic potential of natural products in cognitive disabilities has drawn growing attention, yet a comprehensive analysis of trends and key contributors is lacking. This study provides a bibliometric overview highlighting growth patterns, themes, and future directions. Methods: A comprehensive Scopus search with multistep filtering was conducted by applying keywords related to natural products and cognitive disabilities to titles, abstracts, and keywords, initially retrieving 10,011 documents. Filters for original articles and English language reduced the results to 5688. Data extracted in October 2024 were analyzed using Excel and the R-package, yielding performance and citation indices. Differential proliferation was visualized using a Sankey diagram, while thematic maps highlighted key research themes, geographic trends, and subject clusters. Results: The field exhibited an annual growth rate of 12.36% from 1971 to 2024, with 2021 being the most productive year (497 articles). In recent decades, citation metrics have highlighted significant impacts. Thematic maps and Sankey diagrams revealed the research focus, geographic trends, and collaboration. Alzheimer’s disease dominates the field, alongside topics such as oxidative stress, neuroprotection, and molecular docking. Emerging trends include ferroptosis, UPLC-Q-TOF-MS, and network pharmacology, which have marked advancements in therapeutic and computational approaches. Conclusions: This analysis underscores the dynamic and interdisciplinary nature of this field, highlighting areas for future exploration, particularly underrepresented cognitive disorders and novel therapeutic approaches. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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Review

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39 pages, 4081 KB  
Review
Two Sides of the Same Coin for Health: Adaptogenic Botanicals as Nutraceuticals for Nutrition and Pharmaceuticals in Medicine
by Alexander Panossian and Terrence Lemerond
Pharmaceuticals 2025, 18(9), 1346; https://doi.org/10.3390/ph18091346 - 8 Sep 2025
Viewed by 188
Abstract
Background: Adaptogens, commonly used as traditional herbal medicinal products for the relief of symptoms of stress, such as fatigue and exhaustion, belong to a category of physiologically active compounds related to the physiological process of adaptability to stressors. They are used both as [...] Read more.
Background: Adaptogens, commonly used as traditional herbal medicinal products for the relief of symptoms of stress, such as fatigue and exhaustion, belong to a category of physiologically active compounds related to the physiological process of adaptability to stressors. They are used both as pharmaceuticals in medicine and as dietary supplements or nutraceuticals in nutrition, depending on the doses, indications to treat diseases, or support health functions. However, such a dual-faced nature of adaptogens can lead to inconsistencies and contradictory outcomes from Food and Drug regulatory authorities in various countries. Aims: This narrative literature review aimed to (i) specify five steps of pharmacological testing of adaptogens, (ii) identify the sources of inconsistencies in the assessment of evidence the safety, efficacy, and quality of multitarget adaptogenic botanicals, and (iii) propose potential solutions to address some food and drug regulatory issues, specifically adaptogenic botanicals used for prevention and treatment of complex etiology diseases including stress-induced, and aging-related disorders. Overview: This critically oriented narrative review is focused on (i) five steps of pharmacological testing of adaptogens are required in a sequential order, including appropriate in vivo and in vitro models in animals, in vitro model, and mechanisms of action by a proper biochemical assay and molecular biology technique in combination with network pharmacology analysis, and clinical trials in stress-induced and aging-related disorders; (ii) the differences between the requirements for the quality of pharmaceuticals and dietary supplements of botanical origin; (iii) progress, trends, pitfalls, and challenges in the adaptogens research; (iv) inadequate assignment of some plants to adaptogens, or insufficient scientific data in case of Eurycoma longifolia; (v) inconsistencies in botanical risk assessments in the case of Withania somnifera. Conclusions: This narrative review highlights the importance of harmonized standards, transparent methodologies, and a balanced, evidence-informed approach to ensure consumers receive effective and safe botanicals. Future perspectives and proposed solutions include (i) establish internationally harmonized guidelines for evaluating botanicals based on their intended use (e.g., pharmaceutical vs. dietary supplement), incorporating traditional use data alongside modern scientific methods; (ii) encourage peer review and transparency in national assessments by mandating public disclosure of methodologies, data sources, and expert affiliations; (iii) create a tiered evidence framework that allows differentiated standards of proof for traditional botanical supplements versus pharmaceutical candidates; (iv) promote international scientific dialogs among regulators, researchers, and industry to develop consensus positions and avoid unilateral bans that may lack scientific rigor; (v) formally recognize adaptogens a category of natural products for prevention stress induced brain fatigue, behavioral, and aging related disorders. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)
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