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Open AccessArticle

Network Pharmacology Analysis and Experimental Study of Yinchen Against Neuroinflammation in Ischemic Stroke

by Minmin Guo, Yijie Ma, Linlin Wang, Ruipeng Ge, You Wang, Gefei Ma, Guanhua Du and Li Li

Pharmaceuticals 2025, 18(12), 1852; https://doi.org/10.3390/ph18121852 - 4 Dec 2025

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Abstract

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains [...] Read more.

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains unclear. In this study, we aimed to investigate the therapeutic potential of Yinchen for IS and the material basis of this potential. Methods: The main active components in Artemisia scoparia extract (ASE, the extract of Yinchen), were identified by HPLC and MS. The targets of Yinchen and IS were obtained from public databases. Network pharmacology, molecular docking, and experimental investigation were further applied to acquire the core constituents in Yinchen that work against the neuroinflammation that occuring during IS. The neurological outcomes were evaluated in a transient Middle Cerebral Artery Occlusion (tMCAO) rat model. Additionally, the changes in the inflammatory responses in both the ischemic brain and in lipopolysaccharide (LPS)-treated microglial cells were examined using real-time qPCR. Results: Four active compounds of ASE, including isochlorogenic acid C (ICGA-C), isochlorogenic acid B (ICGA-B), isochlorogenic acid A (ICGA-A), and chlorogenic acid (CGA), were identified by HPLC and MS. Network pharmacology predicted that 103 compounds of Yinchen had 198 intersection targets with IS. The top five of these targets were TNF, STAT3, IL1B, AKT1, and SRC. Molecular docking results demonstrated that the abovementioned four compounds detected in ASE showed good interaction with all of the above five core targets. Moreover, both the four compounds and ASE were observed to attenuate NO release and suppress the release of various inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1) in a dose-dependent manner in LPS-induced BV2 microglial cells. ASE was further found to exert neuroprotective effects against ischemia–reperfusion (I/R) injury and inhibit the production of inflammatory factors in tMCAO rats. Conclusions: Yinchen exerts an anti-neuroinflammatory effect on IS, and its constituents with high scores binding to five core targets contribute to this effect. This supports its potential as an anti-inflammatory agent for the treatment of IS. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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20 pages, 4100 KB

Open AccessArticle

Therapeutic Potential of Gynostemma pentaphyllum (Thunb.) Makino Against COVID-19 Identified Through Network Pharmacology

by Min Ho Kim, Jin Ah Won, Jun Sang Yu, Su Min Kim, Dong Keun Lee, Xiang-Lan Piao and Hye Hyun Yoo

Pharmaceuticals 2025, 18(12), 1851; https://doi.org/10.3390/ph18121851 - 4 Dec 2025

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Abstract

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and [...] Read more.

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and cardiovascular effects. In this study, we investigated the potential of G. pentaphyllum as a complementary treatment for COVID-19 using a network pharmacology approach combined with molecular docking analysis. Methods: To delve into the therapeutic mechanisms of G. pentaphyllum, we identified 59 active compounds and predicted 408 protein targets, of which 19 overlapped with COVID-19-associated genes, including IL1B, IL6, TNF, ACE, and REN. GO and KEGG enrichment analyses were conducted to determine relevant biological processes and pathways, focusing on cytokine signaling, inflammatory responses, and the renin–angiotensin system. Network analyses evaluated interactions of flavonoids and triterpenoid saponins with immunological, inflammatory, renin–angiotensin system, and host entry pathways. Molecular docking was performed to validate the binding affinities of key compounds to their predicted targets. Results: The compound–target–pathway network revealed class-specific patterns: flavonoids primarily mapped to immuno-inflammatory nodes, whereas triterpenoid saponins were enriched for renin–angiotensin system/host-entry–related targets. Docking energies spanned −6.1 to −11.9 kcal/mol, with six compound–target pairs ≤ −10.0 kcal/mol. Notably, NOS2–rutin (−11.9 kcal/mol), NOS2–gypenoside LI (−11.6 kcal/mol), and ACE–gypenoside LI (−11.3 kcal/mol) showed the strongest affinities. Conclusions: These findings provide evidence that G. pentaphyllum exerts therapeutic effects through the complementary actions of flavonoid and saponin components, each modulating distinct molecular pathways. This dual mechanistic potential underscores the value of G. pentaphyllum as a versatile therapeutic for COVID-19 therapy. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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31 pages, 25829 KB

Open AccessArticle

The Hepatoprotective Properties of the Revised Formulation of Dahuang Xiaoshi Tang, an Ancient Chinese Herbal Decoction, Are Probed by Integrated Metabolomics and Network Pharmacology

by Xiangpeng Kong, Xiaoyang Wang, Haiqin Ren, Yajun Yao, Hui Zhang, Huifeng Li, Huifang Li, Yangang Cheng, Zhuqing Song, Miaorong Pei and Karl Wah Keung Tsim

Pharmaceuticals 2025, 18(10), 1534; https://doi.org/10.3390/ph18101534 - 13 Oct 2025

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Abstract

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble [...] Read more.

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble complexes, reducing its effectiveness. A revised herbal extract, DXT-M, was developed, and its hepatoprotective properties were demonstrated in animal models using pharmacodynamic, metabolomic, network pharmacological, and toxicological approaches. Methods: The α-naphthalene isothiocyanate was utilised to establish the acute liver injury rat model. The assays of glutamate pyruvate transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, bilirubin, total bile acid, complement 3 (C3) and C4, interleukin-2 (IL-2) and IL-6, tumour necrosis factor α (TNF-α), and pathological morphology were used to evaluate the hepatoprotection of DXT in comparison to DXT-M. The ¹H-NMR-based serum and urine metabolomics were performed to identify potential biomarkers and metabolic pathways of DXT-M in treating hepatitis. The intrinsic regulatory mechanisms of DXT in liver protection, as well as the combination of network toxicology, were elucidated. Statistical analyses included RM two-way ANOVA with Geisser–Greenhouse correction and Dunnett’s post hoc test for longitudinal data, and one-way ANOVA with Dunnett’s post hoc test for group comparisons. Data were shown as mean ± SD. Results: Liver-injured animals exhibited weight loss, ruffled fur, and liver damage, accompanied by elevated liver function indicators. DXT-M effectively improved these symptoms, repaired liver damage, restored liver function, and regulated immune status by modulating complement 3. Metabonomics and other analyses indicated the CYP/GST-ROS axis is key to its hepatoprotective effects. DXT-M outperformed DXT in efficacy. Conclusions: DXT-M demonstrated significant effectiveness in restoring liver pathological damage, correcting abnormal biochemical indicators of liver function, and regulating complement factors. The pathway of CYP/GST-ROS served as the shared regulatory axis and transformation site for DXT-M’s liver protective effects. These findings suggest that DXT-M has potential as a treatment for acute liver injury, highlighting the need for further research into its underlying molecular mechanisms as well as its complete material basis. This study’s main limitation is its focus on acute models; future research should include other liver diseases and clinical observation to evaluate its full potential. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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21 pages, 6905 KB

Open AccessArticle

Schisandrin B Alleviates Lipid Metabolism Disorders and Apoptosis of MAFLD via Modulation of PPARγ-PCK1 and Caspase-3 Signaling Pathways

by Meng Gao, Feilong Liu, Xiyuan Feng, Mengyang Wang, Zhihong Zhang, He Li, Chunmei Wang and Jinghui Sun

Pharmaceuticals 2025, 18(10), 1441; https://doi.org/10.3390/ph18101441 - 25 Sep 2025

Cited by 1 | Viewed by 841

Abstract

Objectives: This study focuses on the regulatory mechanism of Schisandrin B (Sch B) on the lipid metabolism and apoptosis of AML-12 liver cells, with a particular emphasis on its potential therapeutic effect and mechanism of action in preventing and treating metabolic-associated fatty [...] Read more.

Objectives: This study focuses on the regulatory mechanism of Schisandrin B (Sch B) on the lipid metabolism and apoptosis of AML-12 liver cells, with a particular emphasis on its potential therapeutic effect and mechanism of action in preventing and treating metabolic-associated fatty liver disease (MAFLD) by activating the PPARγ signaling pathway. Methods: An MAFLD cell model was established by inducing AML-12 cells with a mixture of oleic acid (OA) and palmitic acid (PA) (2:1). AML-12 cells were divided into a control group, a model group, and 20 μM and 40 μM Sch B groups. The cells were lysed and prepared into the cell suspension, then the cell suspension was centrifuged to obtain its supernatant, and the levels of total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the supernatant were detected according to the instructions of the kits. Effects of Sch B on the pathological changes of AML-12 cells were observed by Oil Red O staining. The key targets were screened through network pharmacology, and relevant targets were verified through molecular docking simulation. The activity of PPARγ was detected using a dual luciferase reporter plasmid, and the level of cell apoptosis was detected using the Annexin V-FITC/PI double staining method. The Western blot method was used to analyze the expression of genes related to lipid metabolism and apoptosis pathways. Results: Sch B could regulate lipid metabolism disorders in OA+PA-induced MAFLD cell model. The activation of PPARγ-PCK1/Aspase is a key step in the action of Sch B, which can effectively block fatty acid synthesis, improve fatty acid oxidation, and reduce lipid droplet aggregation in liver cells, thereby alleviating lipid metabolism abnormalities in the MAFLD cell model and inhibiting cell apoptosis. Conclusions: This finding may lay an important theoretical foundation and open a new research direction for the deep development and application of Schisandra chinensis. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

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17 pages, 7071 KB

Open AccessArticle

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

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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

Open AccessArticle

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

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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

Open AccessArticle

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

Cited by 2 | Viewed by 1591

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

Open AccessArticle

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

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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

Open AccessArticle

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

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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

Open AccessReview

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

Cited by 1 | Viewed by 2640

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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