scholarly journals Network Pharmacology-Based Strategy for the Investigation of the Anti-Osteoporosis Effects and Underlying Mechanism of Zhuangguguanjie Formulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Wang Gong ◽  
Xingren Chen ◽  
Tianshu Shi ◽  
Xiaoyan Shao ◽  
Xueying An ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Signaling Pathway ◽  
Osteoclast Differentiation ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Network Pharmacology ◽  
Biological Processes

As the society is aging, the increasing prevalence of osteoporosis has generated huge social and economic impact, while the drug therapy for osteoporosis is limited due to multiple targets involved in this disease. Zhuangguguanjie formulation (ZG) is extensively used in the clinical treatment of bone and joint diseases, but the underlying mechanism has not been fully described. This study aimed to examine the therapeutic effect and potential mechanism of ZG on postmenopausal osteoporosis. The ovariectomized (OVX) mice were treated with normal saline or ZG for 4 weeks after ovariectomy following a series of analyses. The bone mass density (BMD) and trabecular parameters were examined by micro-CT. Bone remodeling was evaluated by the bone histomorphometry analysis and ELISA assay of bone turnover biomarkers in serum. The possible drug–disease common targets were analyzed by network pharmacology. To predict the potential biological processes and related pathways, GO/KEGG enrichment analysis was performed. The effects of ZG on the differentiation phenotype of osteoclasts and osteoblasts and the predicted pathway were verified in vitro. The results showed that ZG significantly improved the bone mass and micro-trabecular architecture in OVX mice compared with untreated OVX mice. ZG could promote bone formation and inhibit bone resorption to ameliorate ovariectomy-induced osteoporosis as evidenced by increased number of osteoblast (N.Ob/Tb.Pm) and decreased number of osteoclast (N.Oc/Tb.Pm) in treated group compared with untreated OVX mice. After identifying potential drug–disease common targets by network pharmacology, GO enrichment analysis predicted that ZG might affect various biological processes including osteoblastic differentiation and osteoclast differentiation. The KEGG enrichment analysis suggested that PI3K/Akt and mTOR signaling pathways could be the possible pathways. Furthermore, the experiments in vitro validated our findings. ZG significantly down-regulated the expression of osteoclast differentiation markers, reduced osteoclastic resorption, and inhibited the phosphorylation of PI3K/Akt, while ZG obviously up-regulated the expression of osteogenic biomarkers, promoted the formation of calcium nodules, and hampered the phosphorylation of 70S6K1/mTOR, which can be reversed by the corresponding pathway activator. Thus, our study suggested that ZG could inhibit the PI3K/Akt signaling pathway to reduce osteoclastic bone resorption as well as hamper the mTORC1/S6K1 signaling pathway to promote osteoblastic bone formation.

scholarly journals Investigation of Pharmacological Mechanisms of Schisandrin a for the Treatment of Asthma Determined by Network Pharmacology and Experimental Validation

2021 ◽  
Author(s):  
Qing Qiu ◽  
Fangfang Huang ◽  
Jiating Su ◽  
Qianwen Lin ◽  
Yuge Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Airway Remodeling ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Network Pharmacology ◽  
Dependent Manner ◽  
Mice Model ◽  
Epithelial Barrier Function ◽  
Cox 2

Abstract Traditional Chinese medicines (TCM) are increasingly applied and accepted in asthma prevention and treatment. In the present investigation, we aimed to evaluate the effects of schisandrin A against asthma and examine its underlying mechanism. Here, 68 intersection targets between schisandrin A and asthma were identified by network pharmacology. Further enrichment analysis demonstrated that the nuclear factor-kappaB (NF-κB) signaling pathway may be a major signaling pathway and cyclooxygenase 2 (COX-2/PTGS2) may be a key target in the anti-asthmatic mechanism of schisandrin A. Then, the relevant mechanisms were verified. In vitro, we found that schisandrin A knock down the expression of COX-2 and iNOS (inducible nitric oxide synthase) in 16 HBE cells and RAW264.7 cells in a dose-dependent manner. While, it ameliorated the epithelial barrier function injury, and reduced the activation of NF-κB signaling pathway effectively. Additionally, OVA-induced asthma mice model showed that inflammatory cell infiltration, mucus secretion as well as airway remodeling could be availably suppressed by schisandrin A treatment. In conclusion, our data suggested that schisandrin A can reduce asthma symptoms by inhibiting inflammation production, including lowering the Th2 cell ratio, which provides a basis for further understanding of the treatment of asthma with schisandrin A.

scholarly journals Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4717
Author(s):  
Jin-Young Lee ◽  
Da-Ae Kim ◽  
Eun-Young Kim ◽  
Eun-Ju Chang ◽  
So-Jeong Park ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Map Kinases ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Dual Action ◽  
Dose Dependent ◽  
Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

scholarly journals The Mechanism Study of Xiao-Xian-Xiong Decoction in the Treatment of Atherosclerosis with Network Pharmacology

2020 ◽  
Author(s):  
Liucheng Xiao ◽  
Zonghuan Li ◽  
Chongyuan Fan ◽  
Chenggong Zhu ◽  
Xingyu Ma ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Foam Cells ◽  
Functional Enrichment ◽  
Network Pharmacology ◽  
Mechanism Study ◽  
Ppi Networks

Abstract Background: Xiao-Xian-Xiong decoction is a useful formula in the treatment of atherosclerosis in traditional Chinese medicine. In this study, we aimed to investigate the function of Xiao-Xian-Xiong decoction in the treatment of atherosclerosis. Methods: In this study, we conducted the method of network pharmacology and molecular docking to discover the mechanism of Xiao-Xian-Xiong decoction against atherosclerosis. Then, we validated the function of Xiao-Xian-Xiong decoction in atherosclerosis in vitro. We investigated the function and mechanism of Xiao-Xian-Xiong decoction in RAW264.7 macrophage-derived foam cells.Results: We identified 213 targets of Xiao-Xian-Xiong decoction and 331 targets of atherosclerosis. The PPI networks of Xiao-Xian-Xiong decoction and atherosclerosis were constructed. Furthermore, the two PPI networks were merged and the core PPI network was obtained. Then, functional enrichment analysis was conducted with GO and KEGG signaling pathway analysis. KEGG analysis indicated Xiao-Xian-Xiong decoction was correlated with ubiquitin mediated proteolysis pathway, PI3K-AKT pathway, MAPK pathway, Notch signaling pathway, and TGF-β signaling pathway. At last, we validated the function of Xiao-Xian-Xiong decoction with atherosclerosis in vitro. Xiao-Xian-Xiong decoction reduced lipid accumulation and promoted the outflow of cholesterol in RAW264.7-derived foam cells. Xiao-Xian-Xiong decoction increased the expression of ABCA1 and ABCG1 protein in foam cells. ABCA1 and ABCG1 were related with regulation of the inflammatory pathway and cell proliferation in atherosclerosis.Conclusions: Combined the mechanism of available treatments of atherosclerosis, we inferred Xiao-Xian-Xiong decoction could alleviate atherosclerosis by inhibiting inflammatory response and cell proliferation.

scholarly journals The Underlying Mechanism of Chinese Herb of Regulating Marrow in the Treatment of  Osteonecrosis of the Femoral Head Based on Network Pharmacology and Molecular Docking

2021 ◽  
Author(s):  
Xiaojian Wang ◽  
Rui Wang ◽  
Ting Xu ◽  
Hongting Jin ◽  
Peijian Tong ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Chinese Medicine ◽  
Signaling Pathway ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Chinese Herbs ◽  
Network Pharmacology ◽  
Active Components ◽  
Pathway Enrichment

Abstract Background The lesion of marrow is a crucial factor in orthopedic diseases, which is recognized by orthopedics-traumatology expert from "Zhe-School of Chinese Medicine". The Chinese herbs of regulating marrow has been widely used to treat osteonecrosis of the femoral head (ONFH) in China, while the interaction mechanisms were still elucidated. Thus, we conducted this study to explore the underlying mechanism of the five highest-frequency Chinese herbs of regulating marrow(HF-CHRM) in the treatment of ONFH with the aid of network pharmacology(NP) and molecular docking(MD). Methods The active components and potential targets of HF-CHRM were obtained through several online databases, such as Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), UniProt database. The gene targets related to ONFH were collected with the help of the OMIM and GeneCards disease-related databases. The "drug- component-target-disease" network and protein-protein interaction(PPI) network of the drug and disease intersecting targets were constructed by using Cytoscape software and the STRING database. R software was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The MD of critical components and targets was carried out using Autodock Vina and Pymol to validate the binding affinity. Results A total of 54 active components, 1074 drug targets and 195 gene targets were obtained. There were 1219 ONFH related targets. 39 drug and disease intersection targets(representative genes: IL6, TP53, VEGFA, ESR1, IL1B) were obtained and considered potential therapeutic targets. 1619 items were obtained by the GO enrichment analysis, including 1517 biological processes, 10 cellular components and 92 molecular functions, which is mainly related to angiogenesis, bone and lipid metabolism and inflammatory reaction. The KEGG pathway enrichment analysis revealed 119 pathways, including AGE-RAGE signaling pathway, PI3K-Akt signaling pathway and IL-17 signaling pathway. MD results showed that quercetin, wogonin, and kaempferol active components had good affinity with IL6, TP53, and VEGFA core proteins. Conclusion The HF-CHRM can treat ONFH by multi-component, multi-target, and multi-pathway comprehensive action.

scholarly journals Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

2020 ◽  
Vol 21 (8) ◽  
pp. 2745
Author(s):  
Yukihiro Kohara ◽  
Ryuma Haraguchi ◽  
Riko Kitazawa ◽  
Yuuki Imai ◽  
Sohei Kitazawa
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Age Related ◽  
Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

scholarly journals A System-Level Investigation into the Mechanisms of Apigenin Against Inflammation

2019 ◽  
Vol 14 (9) ◽  
pp. 1934578X1987860 ◽  
Author(s):  
Ying Xie ◽  
Dongdong Liang ◽  
Qingke Wu ◽  
Xuemei Chen ◽  
Manal Ali Buabeid ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Biological Activities ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
System Level ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Biological Processes ◽  
Go Terms

Apigenin is a natural flavone that possesses excellent biological activities especially against aging and cancer. However, the underlying mode of its action is not yet revealed. The purpose of this study was to examine the pharmacological mechanisms of apigenin using the knowledge of network pharmacology, protein-protein interaction (PPI) databases and biological processes analysis through Cytoscape. Apigenin targets were retrieved through PASS Prediction and STITCH database and the interactive associations between these targets were studied using STITCH, followed by GO (gene ontology) and pathway enrichment analysis. As a result of target search, 125 protein targets were retrieved. Moreover, 216 GO terms related to various biological processes, 16 GO terms for various molecular processes, 5 GO terms for the cellular components, and 52 Kyoto Encyclopedia of Genes and Genomes pathway terms were achieved by analyzing gene functional annotation clusters and abundance values of these targets. Most of these terms are strongly associated with inflammation through various pathways, for example, FOXO, mammalian target of rapamycin, tumor necrosis factor, p53, AMP-activated protein kinase, p13K-AKT, and mitogen-activated protein kinase, which play an important role in inflammation, aging and cancer. Apigenin can be used to treat inflammation, aging, and cancer with an underlying mechanism of inflammation suppression. This study contributed excellent information for a better understanding of the modes of action of apigenin. However, further studies such as docking and MD simulation are required to understand the therapeutic and toxicological roles of these targets of apigenin.

scholarly journals Cimifugin Suppresses NF-κB Signaling to Prevent Osteoclastogenesis and Periprosthetic Osteolysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Duan ◽  
Xuantao Hu ◽  
Tao Li ◽  
Gen Wu ◽  
Pengcheng Dou ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Western Blot ◽  
Signaling Pathway ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Periprosthetic Osteolysis

Background: Aseptic loosening of prosthesis (ALP) is one of the most common long-term complications of knee and hip arthroplasty. Wear particle-induced osteoclastogenesis and subsequent periprosthetic osteolysis account for the morbidity of ALP. Here, we investigate the potential of cimifugin (CIM), a natural extract from Cimicifuga racemosa and Saposhnikovia divaricata, as a bone-protective drug in the treatment of ALP.Method: First, we performed cell viability and osteoclast formation assays to assess the effect of noncytotoxic CIM on osteoclast differentiation in vitro. Bone slice resorption and F-actin ring immunofluorescence assays were adopted to assess the effects of CIM on bone-resorption function. Then, quantitative real-time polymerase chain reaction (qRT–PCR) analysis was performed to further assess the repressive effects of CIM on osteoclastogenesis at the gene expression level. To elucidate the mechanisms underlying the above findings, Western blot and luciferase reporter gene assays were used to assess the regulatory effects of CIM on the NF-κB and MAPK signaling pathways. Moreover, a Ti particle-induced murine calvarial osteolysis model and subsequent histomorphometric analysis via micro-CT and immunohistochemical staining were used to elucidate the effect of CIM on periprosthetic osteolysis in vivo.Result: CIM dose-dependently inhibited both bone marrow-derived macrophage (BMM)- and RAW264.7 cell-derived osteoclastogenesis and bone resorption pit formation in vitro, which was further supported by the reduced expression of F-actin and osteoclast-specific genes. According to the Western blot analysis, inhibition of IκBα phosphorylation in the NF-κB signaling pathway, not the phosphorylation of MAPKs, was responsible for the suppressive effect of CIM on osteoclastogenesis. Animal experiments demonstrated that CIM alleviated Ti particle-induced bone erosion and osteoclast accumulation in murine calvaria.Conclusion: The current study suggested for the first time that CIM can inhibit RANKL-induced osetoclastogenesis by suppressing the NF-κB signaling pathway in vitro and prevent periprosthetic osteolysis in vivo. These findings suggest the potential of CIM as a therapeutic in ALP.

Osteoprotegerin inhibit osteoclast differentiation and bone resorption by enhancing autophagy via AMPK/mTOR/p70S6K signaling pathway in vitro

2018 ◽  
Vol 120 (2) ◽  
pp. 1630-1642 ◽  
Author(s):  
Xishuai Tong ◽  
Jianhong Gu ◽  
Ruilong Song ◽  
Dong Wang ◽  
Ziqiang Sun ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Signaling Pathway ◽  
Osteoclast Differentiation

scholarly journals Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

2013 ◽  
Vol 200 (4) ◽  
pp. 537-549 ◽  
Author(s):  
Joachim Albers ◽  
Johannes Keller ◽  
Anke Baranowsky ◽  
Frank Timo Beil ◽  
Philip Catala-Lehnen ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Wnt Signaling ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Negative Influence ◽  
Canonical Wnt Signaling ◽  
Mouse Tissues ◽  
Canonical Wnt

Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of β-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Frizzled 8 (Fzd8) as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking β-catenin in the osteoclast lineage. Here, we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and β-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.

scholarly journals Exploring the Antiglioma Mechanisms of Luteolin Based on Network Pharmacology and Experimental Verification

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Renxuan Huang ◽  
Rui Dong ◽  
Nan Wang ◽  
Beiwu Lan ◽  
Hongyang Zhao ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Fruits And Vegetables ◽  
Docking Simulation ◽  
Underlying Mechanism ◽  
Venn Diagram ◽  
Network Pharmacology ◽  
Discovery Studio ◽  
Inorganic Substances

Luteolin, a natural flavone compound, exists in a variety of fruits and vegetables, and its anticancer effect has been shown in many studies. However, its use in glioma treatment is hampered due to the fact that the underlying mechanism of action has not been fully explored. Therefore, we elucidated the potential antiglioma targets and pathways of luteolin systematically with the help of network pharmacology and molecular docking technology. The druggability of luteolin, including absorption, excretion, distribution, and metabolism, was assessed via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The potential targets of luteolin and glioma were extracted from public databases, and the intersecting targets between luteolin and glioma were integrated and visualized by a Venn diagram. In addition, GO and KEGG pathway analysis was engaged in Metascape. The network of the luteolin-target-pathway was visualized by Cytoscape. Ultimately, the interactions between luteolin and predicted key targets were confirmed by Discovery studio software. According to the ADME results, luteolin shows great potential for development into a drug. 4860 glioma-associated targets and 280 targets of luteolin were identified, of which 205 were intersection targets. 6 core targets of luteolin against glioma, including AKT1, JUN, ALB, MAPK3, MAPK1, and TNF, were identified via PPI network analysis of which AKT1, JUN, ALB, MAPK1, and TNF harbor diagnostic value. The biological processes of luteolin are mainly involved in the response to inorganic substances, response to oxidative stress, and apoptotic signaling pathway. The essential pathways of luteolin against glioma involve pathways in cancer, the PI3K-Akt signaling pathway, the TNF signaling pathway, and more. Meanwhile, luteolin’s interaction with six core targets was verified by molecular docking simulation and its antiglioma effect was verified by in vitro experiments. This study suggests that luteolin has a promising potential for development into a drug and, moreover, it displays preventive effects against glioma by targeting various genes and pathways.

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