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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Predicting and Exploring the Mechanisms of Erzhi Pill in Prevention and Treatment of Osteoporosis Based on Network Pharmacology and Zebrafish Experiments

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          Abstract

          Background

          Erzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.

          Methods

          By combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.

          Results

          Our study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.

          Conclusion

          Our study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.

          Most cited references44

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

          Jinlong Ru, Peng Li, Jinan Wang … (2014)
          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.
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            Osteoblast-osteoclast interactions.

            Xiao Chen, Zhongqiu Wang, Na Duan … (2018)
            Bone homeostasis depends on the resorption of bones by osteoclasts and formation of bones by the osteoblasts. Imbalance of this tightly coupled process can cause diseases such as osteoporosis. Thus, the mechanisms that regulate communication between osteoclasts and osteoblasts are critical to bone cell biology. It has been shown that osteoblasts and osteoclasts can communicate with each other through direct cell-cell contact, cytokines, and extracellular matrix interaction. Osteoblasts can affect osteoclast formation, differentiation, or apoptosis through several pathways, such as OPG/RANKL/RANK, RANKL/LGR4/RANK, Ephrin2/ephB4, and Fas/FasL pathways. Conversely, osteoclasts also influence formation of bones by osteoblasts via the d2 isoform of the vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2), complement component 3a, semaphorin 4D or microRNAs. In addition, cytokines released from the resorbed bone matrix, such as TGF-β and IGF-1, also affect the activity of osteoblasts. Drugs could be developed by enhancing or restricting some of these interactions. Several reviews have been performed on the osteoblast-osteoclast communication. However, few reviews have shown the research advances in the recent years. In this review, we summarized the current knowledge on osteoblast-osteoclast communication.
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              Prevention and treatment of postmenopausal osteoporosis.

              Sri Harsha Tella, J Christopher Gallagher (2014)
              In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology research showed that osteocytes produces sclerostin an inhibitor of the anabolic WNT signaling pathway. Recent development of a monoclonal antibody against sclerostin has shown remarkable anabolic activity in bone showing large increases in bone density and fracture trials are now underway. The newer treatments for osteoporosis are likely to be based on our understanding of bone biology and the design of new highly specific compounds with fewer side effects. This review summarizes the diagnosis of postmenopausal osteoporosis and various available non-pharmacological and pharmacological therapies available for its management. This article is part of a Special Issue entitled 'Menopause'.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): dddt
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 24 February 2021
                Publication date Collection: 2021
                Volume: 15
                Pages: 817-827
                Affiliations
                [1 ]Traditional Chinese Medicine Department, Affiliated Hospital of Guangdong Medical University , Zhanjiang, 524023, People’s Republic of China
                [2 ]Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University , Zhanjiang, 524023, People’s Republic of China
                [3 ]Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University , Dongguan, 523808, People’s Republic of China
                [4 ]School of Basic Medical Sciences, Guangzhou University of Chinese Medicine , Guangzhou, 510006, People’s Republic of China
                Author notes
                Correspondence: Shiying Luo Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University , No. 2 East Wenming Road, Xiashan District, Zhanjiang, 524023, Guangdong, People’s Republic of ChinaTel +86 13763058766Fax +86 7592388588 Email luosy76@gdmu.edu.cn
                Author information
                http://orcid.org/0000-0001-8235-9057
                Article
                Publisher ID: 293455
                DOI: 10.2147/DDDT.S293455
                PMC ID: 7917472
                SO-VID: 8ba4ca01-e975-4f94-b615-7aa960f9feb1
                Copyright © © 2021 Zhong et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 04 December 2020
                Date accepted : 19 January 2021
                Page count
                Figures: 6, Tables: 4, References: 44, Pages: 11
                Funding
                Funded by: the Natural Science Foundation of Guangdong Province;
                Funded by: the Scientific Research Foundation for PhD of Guangdong Medical University;
                Funded by: the Scientific Research Subject of Traditional Chinese Medicine Bureau of Guangdong Province;
                The study was supported by the Natural Science Foundation of Guangdong Province (No: 2018A030313390), the Scientific Research Foundation for PhD of Guangdong Medical University (No: B2017030), and the Scientific Research Subject of Traditional Chinese Medicine Bureau of Guangdong Province (No: 20171145 & 20191190).
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: erzhi pill,osteoporosis,network pharmacology,mechanisms,zebrafish,quercetin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: erzhi pill, osteoporosis, network pharmacology, mechanisms, zebrafish, quercetin

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