New insight into the mechanisms of Ginkgo biloba leaves in the treatment of cancer.

BACKGROUND: Ginkgo biloba leaves (GBLs), as an herbal dietary supplement and a traditional Chinese medicine, have been used in treating diseases for hundred years. Recently, increasing evidence reveals that the extracts and active ingredients of GBLs have anti-cancer (chemo-preventive) properties. However, the molecular mechanism of GBLs in anti-cancer has not been comprehensively summarized. PURPOSE: To systematically summarize the literatures for identifying the molecular mechanism of GBLs in cellular, animal models and clinical trials of cancers, as well as for critically evaluating the current evidence of efficacy and safety of GBLs for cancers. METHODS: Employing the search terms "Ginkgo biloba" and "cancer" till July 25, 2023, a comprehensive search was carried out in four electronic databases including Scopus, PubMed, Google Scholar and Web of Science. The articles not contained in the databases are performed by manual searches and all the literatures on anti-cancer research and mechanism of action of GBLs was extracted and summarized. The quality of methodology was assessed independently through PRISMA 2020. RESULTS: Among 84 records found in the database, 28 were systematic reviews related to GBLs, while the remaining 56 records were related to the anticancer effects of GBLs, which include studies on the anticancer activities and mechanisms of extracts or its components in GBLs at cellular, animal, and clinical levels. During these studies, the top six cancer types associated with GBLs are lung cancer, hepatocellular carcinoma, gastric cancer, breast cancer, colorectal cancer, and cervical cancer. Further analysis reveals that GBLs primarily exert their anticancer effects by stimulating cancer cell apoptosis, inhibiting cell proliferation, invasion and migration of cancers, exhibiting anti-inflammatory and antioxidant properties, and modulating signaling pathways. Besides, the pharmacology, toxicology, and clinical research on the anti-tumor activity of GBLs have also been discussed. CONCLUSIONS: This is the first paper to thoroughly investigate the pharmacology effect, toxicology, and the mechanisms of action of GBLs for anti-cancer properties. All the findings will reinforce the need to explore the new usage of GBLs in cancers and offer comprehensive reference data and recommendations for future research on this herbal medicine.

Systematic investigation of the mechanism of herbal medicines for the treatment of prostate cancer.

Due to various unpleasant side effects and general ineffectiveness of current treatments for prostate cancer (PCa), more and more people with PCa try to look for complementary and alternative medicine such as herbal medicine. However, since herbal medicine has multi-components, multi-targets and multi-pathways features, its underlying molecular mechanism of action is not yet known and still needs to be systematically explored. Presently, a comprehensive approach consisting of bibliometric analysis, pharmacokinetic assessment, target prediction and network construction is firstly performed to obtain PCa-related herbal medicines and their corresponding candidate compounds and potential targets. Subsequently, a total of 20 overlapping genes between DEGs in PCa patients and the target genes of the PCa-related herbs, as well as five hub genes, i.e., CCNA2, CDK2, CTH, DPP4 and SRC were determined employing bioinformatics analysis. Further, the roles of these hub genes in PCa were also investigated through survival analysis and tumour immunity analysis. Moreover, to validate the reliability of the C-T interactions and to further explore the binding modes between ingredients and their targets, the molecular dynamics (MD) simulations were carried out. Finally, based on the modularization of the biological network, four signaling pathways, i.e., PI3K-Akt, MAPK, p53 and cell cycle were integrated to further analyze the therapeutic mechanism of PCa-related herbal medicine. All the results show the mechanism of action of herbal medicines on treating PCa from the molecular to systematic levels, providing a reference for the treatment of complex diseases using TCM.

Systematic investigation of the multi-scale mechanisms of herbal medicine on treating ventricular remodeling: Theoretical and experimental studies.

BACKGROUND: To explore the underlying molecule mechanism of herbal medicine in preventing ventricular remodeling (VR), we take a herbal formula that is clinically effective for preventing VR as an example, which composed of Pachyma hoelen Rumph, Atractylodes macrocephala Koidz., Cassia Twig and Licorice. Due to multi-components and multi-targets in herbal medicine, it is extremely difficult to systematically explain its mechanisms of action. METHODS: An innovative systematic investigation framework which combines with pharmacokinetic screening, target fishing, network pharmacology, DeepDDI algorithm, computational chemistry, molecular thermodynamics, in vivo and in vitro experiments was performed for deciphering the underlying molecular mechanisms of herbal medicine for treating VR. RESULTS: ADME screening and SysDT algorithm determined 75 potentially active compounds and 109 corresponding targets. Then, systematic analysis of networks reveals the crucial active ingredients and key targets in herbal medicine. Additionally, transcriptomic analysis identifies 33 key regulators during VR progression. Moreover, PPI network and biological function enrichment present four crucial signaling pathways, i.e. NF-κB and TNF, PI3K-AKT and C-type lectin receptor signaling pathways involved in VR. Besides, both molecular experiments at animal and cell levels reveal the beneficial effect of herbal medicine on preventing VR. Finally, MD simulations and binding free energy validate the reliability of drug-target interactions. CONCLUSION: Our novelty is to build a systematic strategy which combines various theoretical methods combined with experimental approaches. This strategy provides a deep understanding for the study of molecular mechanisms of herbal medicine on treating diseases from systematic level, and offers a new idea for modern medicine to explore drug interventions for complex diseases as well.

Literature data based systems pharmacology uncovers the essence of "body fire" in traditional Chinese medicine: A case by Huang-Lian-Jie-Du-Tang.

ETHNOPHARMACOLOGY RELEVANCE: Like other concepts in traditional Chinese medical theory, "body fire", a concept that has already been well-known and widely used in describing the symptoms and the treatment of corresponding diseases, is, however, still under suspicions in the western medicine due to its vague essence and symptoms. Presently, Huang-Lian-Jie-Du-Tang (HLJDT), a typical popular TCM formula in cleansing the "body fire", is studied as a probe by a systems pharmacology method we produced, with purpose to explore the mechanisms of the potion, as well as to interpret the essence of "body fire" disease. METHODS: The systematic process includes a pharmacokinetics prescreening, pharmacodynamics targets and pathways identification, and candidate-target-pathway network construction. RESULTS: Through this method, 145 chemicals and 91 proteins are identified as active ingredients and "body fire"-related targets. And we find that the mechanism of HLJDT prescription for cleansing "body fire" lies in three, i.e., anti-OS/NS, anti-inflammation and anti-infection function modules, which are mainly executed through four, i.e., PI3K-AKT, MAPK, VEGF as well as Calcium signaling pathways. CONCLUSIONS: Accordingly, the essence of "body fire" is a gradual process which is an integration of OS/NS, inflammation and infection. This work, we hope, may not only offer a systemic methodology for exploring and elucidating TCM concepts from a multi-scale perspective, but also provide an efficient way for herbal drug discovery.

Systems Pharmacology Dissection of Multiscale Mechanisms of Action for Herbal Medicines in Treating Rheumatoid Arthritis.

As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction of the bone and cartilage. Traditional Chinese Medicine (TCM), with rich history of proper effectiveness in treating the inflammatory joint disease containing RA, has long combated such illness from, actually, an integrative and holistic point of view. However, its "multi-components" and "multi-targets" features make it very difficult to decipher the molecular mechanisms of RA from a systematic perspective if employing only routine methods. Presently, an innovative systems-pharmacology approach was introduced, which combined the ADME screening model, drug targeting, and network pharmacology, to explore the action mechanisms of botanic herbs for the treatment of RA. As a result, we uncovered 117 active compounds and 85 key molecular targets from seven RA-related herbs, which are mainly implicated in four signaling pathways, that is, vascular endothelial growth factor, PI3K-Akt, Toll-like receptor, and T-cell-receptor pathways. Additionally, the network relationships among the active components, target proteins, and pathways were further built to uncover the pharmacological characters of these herbs. Besides, molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area calculations were carried out to explore the binding interactions between the compounds and their receptors as well as to investigate the binding affinity of the ligand to their protein targets. In vitro experiments by ligand binding assays validate the reliability of the drug-target interactions as well as the MD results. The high binding affinities and good inhibitions of the active compounds indicate that the potential therapeutic effects of these herbal medicines for treating RA are exerted probably through the modulation of these relevant proteins, which further validates the rationality and reliability of the drug-target interactions as well as our the network-based analytical methods. This work may be of help for not only understanding the action mechanisms of TCM and for discovering new drugs from plants for the treatment of RA, but also providing a novel potential method for modern medicine in treating complex diseases.

A New Strategy for Deleting Animal drugs from Traditional Chinese Medicines based on Modified Yimusake Formula.

Traditional Chinese medicine (TCM), such as Uyghur Medicine (UM) has been used in clinical treatment for many years. TCM is featured as multiple targets and complex mechanisms of action, which is normally a combination of medicinal herbs and sometimes even contains certain rare animal medicinal ingredients. A question arises as to whether these animal materials can be removed replaced from TCM applications due to their valuable rare resources or animal ethics. Here, we select a classical UM Yimusake formula, which contains 3 animal drugs and other 8 herbs, and has got wealthy experience and remarkable achievements in treating erectile dysfunction (ED) in China. The active components, drug targets and therapeutic mechanisms have been comprehensively analyzed by systems-pharmacology methods. Additionally, to validate the inhibitory effects of all candidate compounds on their related targets, in vitro experiments, computational analysis and molecular dynamics simulations were performed. The results show that the modified, original and three animal materials display very similar mechanisms for an effective treatment of ED, indicating that it is quite possible to remove these three animal drugs from the original formula while still keep its efficiency. This work provides a new attempt for deleting animal materials from TCM, which should be important for optimization of traditional medicines.

Systematic Investigation of Ginkgo Biloba Leaves for Treating Cardio-cerebrovascular Diseases in an Animal Model.

Globally, cardio-cerebrovascular diseases (CCVDs) are the leading cause of death, and thus the development of novel strategies for preventing and treating such diseases is in urgent need. Traditional Chinese medicine (TCM), used for thousands of years in Asia and other regions, has been proven effective in certain disorders. As a long-time medicinal herb in TCM, Ginkgo biloba leaves (GBLs), have been widely used to treat various diseases including CCVDs. However, the underlying molecular mechanisms of medicinal herbs in treating these diseases are still unclear. Presently, by incorporating pharmacokinetic prescreening, target fishing, and network analysis, an innovative systems-pharmacology platform was introduced to systematically decipher the pharmacological mechanism of action of GBLs for the treatment of CCVDs. The results show that GBLs exhibit a protective effect on CCVDs probably through regulating multiple pathways and hitting on multiple targets involved in several biological pathways. Our work successfully explains the mechanism of efficiency of GBLs for treating CCVDs and, meanwhile, demonstrates that GDJ, an injection generated from GBLs, could be used as a preventive or therapeutic agent in cerebral ischemia. The approach developed in this work offers a new paradigm for systematically understanding the action mechanisms of herb medicine, which will promote the development and application of TCM.

A Methodology for Cancer Therapeutics by Systems Pharmacology-Based Analysis: A Case Study on Breast Cancer-Related Traditional Chinese Medicines.

Breast cancer is the most common carcinoma in women. Comprehensive therapy on breast cancer including surgical operation, chemotherapy, radiotherapy, endocrinotherapy, etc. could help, but still has serious side effect and resistance against anticancer drugs. Complementary and alternative medicine (CAM) may avoid these problems, in which traditional Chinese medicine (TCM) has been highlighted. In this section, to analyze the mechanism through which TCM act on breast cancer, we have built a virtual model consisting of the construction of database, oral bioavailability prediction, drug-likeness evaluation, target prediction, network construction. The 20 commonly employed herbs for the treatment of breast cancer were used as a database to carry out research. As a result, 150 ingredient compounds were screened out as active molecules for the herbs, with 33 target proteins predicted. Our analysis indicates that these herbs 1) takes a 'Jun-Chen-Zuo-Shi" as rule of prescription, 2) which function mainly through perturbing three pathways involving the epidermal growth factor receptor, estrogen receptor, and inflammatory pathways, to 3) display the breast cancer-related anti-estrogen, anti-inflammatory, regulation of cell metabolism and proliferation activities. To sum it up, by providing a novel in silico strategy for investigation of the botanical drugs, this work may be of some help for understanding the action mechanisms of herbal medicines and for discovery of new drugs from plants.

A systems pharmacology approach to investigate the mechanisms of action of Semen Strychni and Tripterygium wilfordii Hook F for treatment of rheumatoid arthritis.

ETHNOPHARMACOLOGY RELEVANCE: The angiogenesis control at the initiation of rheumatoid arthritis (RA) that mainly blocks the inflammatory cascades expects to attenuate the action of angiogenic mediators, synovial angiogenesis, and to partially reverse the erosive bone damage. Two typical Chinese herbs, Semen Strychni and Tripterygium wilfordii Hook F (TwHF) have been used as a remedy to treat RA since ancient time. However, their functioning mechanisms are still unknown. Thus it is necessary to exploit their underlying mechanism for the treatment of RA. METHODS: This study was undertaken to analyze their underlying mechanism based on a systems biology platform. Firstly, active components of the two herbs were screened out from TcmSP database based on their OB and DL values. Then their potential targets were predicted by using Random Forest, Support Vector Machine, and validated via docking process. Finally, a network of compound-target was constructed. RESULTS: In this work, 27 and 33 active compounds were screened out from Semen Strychni and TwHF, targeting 28 and 32 potential proteins, respectively. The results show that the two herbs modulate the angiogenesis mediators through both direct and indirect pathways, and 21 common targets shared by Semen Strychni and TwHF bear major responsibility for treating RA. CONCLUSIONS: The underlying mechanism of Semen Strychni and TwHF in treatment of RA is through multiple targets interaction by their blocking of the angiogenesis mediator cascades. This may provide us a better understanding of the function of the two herbs for the treatment of RA, as well as a clue to unveil their possible treatment effects of other systemic diseases, and in this way, hopefully the screening models may facilitate the discovery of novel combined drugs.

Systems pharmacology dissection of the anti-inflammatory mechanism for the medicinal herb Folium eriobotryae.

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations.

TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.

BACKGROUND: Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. DESCRIPTION: The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski's rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. CONCLUSIONS: The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.

Investigation into the mechanism of Eucommia ulmoides Oliv. based on a systems pharmacology approach.

ETHNOPHARMACOLOGY RELEVANCE: Though Traditional Chinese Medicine (TCM) has long been playing a significant role in the maintenance of health for people in Asia as well as many other places, the mechanism of its action still remains ambiguous for most of the plants used in TCM, such as Eucommia ulmoides Oliv., a kind of herb that is widely used to help regulate hypertension and the immune system nowadays. However, its functioning mechanism is still unknown. Thus it is necessary to exploit the mechanism of Eucommia ulmoides Oliv. METHODS: A systems pharmacology approach combining drug-likeness evaluation, oral bioavailability prediction, multiple drug targets prediction as well as network pharmacology techniques has been used. RESULTS: This comprehensive systematic approach helps successfully to identify 41 candidate compounds contained in Eucommia ulmoides Oliv. while 39 potential targets hit by these ingredients and helps to uncover the synergistic mechanism of action on a systematic level. CONCLUSIONS: Our work successfully explains the mechanism of the efficiency of Eucommia ulmoides Oliv. for the treatment of hypertension and enhancing immune. These results not only provide a new insight for the understanding of the chemical and pharmacological basis of Eucommia ulmoides Oliv., but also provide an efficient way for drug discovery from herbal medicine.