scholarly journals A Network Pharmacology Study on the Molecular Mechanisms of FDY003 for Breast Cancer Treatment

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Ho-Sung Lee ◽  
In-Hee Lee ◽  
Kyungrae Kang ◽  
Sang-In Park ◽  
Seung-Joon Moon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Herbal Medicines ◽  
Enrichment Analysis ◽  
Estrogen Signaling ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Anticancer Efficacy ◽  
Artemisia Capillaris

Herbal medicines have drawn considerable attention with regard to their potential applications in breast cancer (BC) treatment, a frequently diagnosed malignant disease, considering their anticancer efficacy with relatively less adverse effects. However, their mechanisms of systemic action have not been understood comprehensively. Based on network pharmacology approaches, we attempted to unveil the mechanisms of FDY003, an herbal drug comprised of Lonicera japonica Thunberg, Artemisia capillaris Thunberg, and Cordyceps militaris, against BC at a systemic level. We found that FDY003 exhibited pharmacological effects on human BC cells. Subsequently, detailed data regarding the biochemical components contained in FDY003 were obtained from comprehensive herbal medicine-related databases, including TCMSP and CancerHSP. By evaluating their pharmacokinetic properties, 18 chemical compounds in FDY003 were shown to be potentially active constituents interacting with 140 BC-associated therapeutic targets to produce the pharmacological activity. Gene ontology enrichment analysis using g:Profiler indicated that the FDY003 targets were involved in the modulation of cellular processes, involving the cell proliferation, cell cycle process, and cell apoptosis. Based on a KEGG pathway enrichment analysis, we further revealed that a variety of oncogenic pathways that play key roles in the pathology of BC were significantly enriched with the therapeutic targets of FDY003; these included PI3K-Akt, MAPK, focal adhesion, FoxO, TNF, and estrogen signaling pathways. Here, we present a network-perspective of the molecular mechanisms via which herbal drugs treat BC.

scholarly journals A network pharmacology-based study on Alzheimer disease prevention and treatment of Qiong Yu Gao

2020 ◽  
Author(s):  
Jieshu You ◽  
Chen-yue Li ◽  
Wei Chen ◽  
Xia-lin Wu ◽  
Li-jie Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Kegg Pathway ◽  
Herbal Medicines ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Resistance Pathway ◽  
Prevention And Treatment ◽  
Ad Prevention

Abstract Background and objective: As the pathological mechanisms of AD are complex, increasing evidence have demonstrated Chinese Medicine with multi-ingredients and multi-targets may be more suitable for the treatment of diseases with complex pathogenesis. Therefore, the study was to preliminarily decipher the bioactive compounds and potential mechanisms of Qiong Yu Gao (QYG) for AD prevention and treatment by an integrated network pharmacology approach. Methods: Putative ingredients of QYG and significant genes of AD were retrieved from public database after screening. Then QYG ingredients target proteins/genes were obtained by target fishing. Compound-target-disease network was constructed using Cytoscape to decipher the mechanism of QYG for AD. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to QYG for AD treatments. Results: Finally, 70 compounds and 511 relative drug targets were collected. In which, 17 representative direct targets were found. Gene ontology enrichment analysis revealed that the adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway was the key biological processes and were regulated simultaneously by the 17 direct targets. The KEGG pathway enrichment analysis found that three signaling pathways were closely related to AD prevention and treatment by QYG, including PI3K-Akt signaling pathway, regulation of actin cytoskeleton pathway and insulin resistance pathway. Conclusion: This study demonstrated that QYG exerted the effect of preventing and treating AD by regulating multi-targets with multi-components. Furthermore, the study demonstrated that a network pharmacology-based approach was useful for elucidation of the interrelationship between complex diseases and interventions of Chinese herbal medicines.

A Network Pharmacology Analysis of the Systems-Perspective Anticancer Mechanisms of the Herbal Drug FDY2004 for Breast Cancer

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110491
Author(s):  
Ho-Sung Lee ◽  
In-Hee Lee ◽  
Kyungrae Kang ◽  
Sang-In Park ◽  
Tae-Wook Kwon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Herbal Drugs ◽  
Apoptosis Pathway ◽  
Anticancer Properties ◽  
Systems Perspective

Breast cancer is a malignant tumor with high incidence, prevalence, and mortality rates in women. In recent years, herbal drugs have been assessed as anticancer therapy against breast cancer, owing to their promising therapeutic effects and reduced toxicity. However, their pharmacological mechanisms have not been fully explored at the systemic level. Here, we conducted a network pharmacology analysis of the systems-perspective molecular mechanisms of FDY2004, an anticancer herbal formula that consists of Moutan Radicis Cortex, Persicae Semen , and Rhei Radix et Rhizoma, against breast cancer. We determined that FDY2004 may contain 28 active compounds that exert pharmacological effects by targeting 113 breast cancer-related human genes/proteins. Based on the gene ontology terms, the FDY2004 targets were involved in modulating biological processes such as cell growth, cell proliferation, and apoptosis. Pathway enrichment analysis identified various breast cancer-associated pathways that may mediate the anticancer activity of FDY2004, including the PI3K-Akt, MAPK, TNF, HIF-1, focal adhesion, estrogen, ErbB, NF-kappa B, p53, and VEGF signaling pathways. Thus, our analysis offers novel insights into the anticancer properties of herbal drugs for breast cancer treatment from a systemic perspective.

scholarly journals Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Lang Yang ◽  
Liuyi Fan ◽  
Kexin Wang ◽  
Yupeng Chen ◽  
Lan Liang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Antibody Therapy ◽  
Enrichment Analysis ◽  
Estrogen Signaling ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Mechanism Analysis ◽  
Erxian Decoction

Osteoporosis (OP) is a highly prevalent orthopedic condition in postmenopausal women and the elderly. Currently, OP treatments mainly include bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody therapy, selective estrogen receptor modulators, teriparatide (PTH1-34), and menopausal hormone therapy. However, increasing evidence has indicated these treatments may exert serious side effects. In recent years, Traditional Chinese Medicine (TCM) has become popular for treating orthopedic disorders. Erxian Decoction (EXD) is widely used for the clinical treatment of OP, but its underlying molecular mechanisms are unclear thanks to its multiple components and multiple target features. In this research, we designed a network pharmacology method, which used a novel node importance calculation model to identify critical response networks (CRNs) and effective proteins. Based on these proteins, a target coverage contribution (TCC) model was designed to infer a core active component group (CACG). This approach decoded the mechanisms underpinning EXD’s role in OP therapy. Our data indicated that the drug response network mediated by the CACG effectively retained information of the component-target (C-T) network of pathogenic genes. Functional pathway enrichment analysis showed that EXD exerted therapeutic effects toward OP by targeting PI3K-Akt signaling (hsa04151), calcium signaling (hsa04020), apoptosis (hsa04210), estrogen signaling (hsa04915), and osteoclast differentiation (hsa04380) via JNK, AKT, and ERK. Our method furnishes a feasible methodological strategy for formula optimization and mechanism analysis and also supplies a reference scheme for the secondary development of the TCM formula.

scholarly journals A Network Pharmacology-Based Study on Alzheimer disease prevention and treatment of Qiong Yu Gao

2020 ◽  
Author(s):  
Jieshu You ◽  
Chen-yue Li ◽  
Wei Chen ◽  
Xia-lin Wu ◽  
Li-jie Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Kegg Pathway ◽  
Herbal Medicines ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Integrated Network ◽  
Resistance Pathway ◽  
Prevention And Treatment

Abstract Background and objective: As the pathological mechanisms of AD is complex, increasing evidence have demonstrated Chinese Medicine with multi-ingredients and multi-targets may be more suitable for the treatment of diseases with complex pathogenesis. Therefore, the study was to preliminarily decipher the bioactive compounds and potential mechanisms of Qiong Yu Gao (QYG) for AD prevention and treatment by an integrated network pharmacology approach. Methods: Putative ingredients of QYG and significant genes of AD were retrieved from public database after screening. Then QYG ingredients target proteins/genes were obtained by target fishing. Compound-target-disease network was constructed using Cytoscape to decipher the mechanism of QYG for AD. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to QYG for AD treatments. Results: Finally, 70 compounds and 511 relative drug targets were collected. In which, 17 representative direct targets were found. Gene ontology enrichment analysis revealed that the adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway was the key biological processes and were regulated simultaneously by the 17 direct targets. KEGG pathway enrichment analysis found that three signaling pathways were closely related with AD treatment by QYG, including PI3K-Akt signaling pathway, regulation of actin cytoskeleton pathway and insulin resistance pathway. Conclusion: This study demonstrated that QYG exerted the effect of treating AD by regulating multi-targets with multi-components. Furthermore, the study demonstrated that a network pharmacology-based approach was useful for elucidation of the interrelationship between complex diseases and interventions of Chinese herbal medicines.

scholarly journals Elucidation of the mechanisms and molecular targets of Qishen Yiqi formula for the treatment of pulmonary arterial hypertension using a bioinformatics/network topology-based strategy

2020 ◽  
Vol 23 ◽  
Author(s):  
Peiliang Wu ◽  
Xiaona Xie ◽  
Mayun Chen ◽  
Junwei Sun ◽  
Luqiong Cai ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Network Topology ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Bioactive Ingredients ◽  
Pulmonary Arterial

Background and Objective: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. Methods: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. Results: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. Conclusion: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.

scholarly journals Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Yun Tang ◽  
Xiaobo Yang ◽  
Huaqing Shu ◽  
Yuan Yu ◽  
Shangwen Pan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Septic Shock ◽  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Kidney Injury ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Blood Samples ◽  
Potential Biomarkers

Abstract Background Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI). Methods Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI. Results We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future. Conclusions Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

scholarly journals Analysis of the Molecular Mechanisms of the Effects of Prunella vulgaris against Subacute Thyroiditis Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Xin Shen ◽  
Rui Yang ◽  
Jianpeng An ◽  
Xia Zhong
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Kegg Pathway ◽  
Enrichment Analysis ◽  
Subacute Thyroiditis ◽  
Network Pharmacology ◽  
Pharmacokinetic Parameters ◽  
Pathway Enrichment Analysis ◽  
Prunella Vulgaris ◽  
Protein Protein Interaction

Prunella vulgaris (PV) has a long history of application in traditional Chinese and Western medicine as a remedy for the treatment of subacute thyroiditis (SAT). This study applied network pharmacology to elucidate the mechanism of the effects of PV against SAT. Components of the potential therapeutic targets of PV and SAT-related targets were retrieved from databases. To construct a protein-protein interaction (PPI) network, the intersection of SAT-related targets and PV-related targets was input into the STRING platform. Gene ontology (GO) analysis and KEGG pathway enrichment analysis were carried out using the DAVID database. Networks were constructed by Cytoscape for visualization. The results showed that a total of 11 compounds were identified according to the pharmacokinetic parameters of ADME. A total of 126 PV-related targets and 2207 SAT-related targets were collected, and 83 overlapping targets were subsequently obtained. The results of the KEGG pathway and compound-target-pathway (C-T-P) network analysis suggested that the anti-SAT effect of PV mainly occurs through quercetin, luteolin, kaempferol, and beta-sitosterol and is most closely associated with their regulation of inflammation and apoptosis by targeting the PIK3CG, MAPK1, MAPK14, TNF, and PTGS2 proteins and the PI3K-Akt and TNF signaling pathways. The study demonstrated that quercetin, luteolin, kaempferol, and beta-sitosterol in PV may play a major role in the treatment of SAT, which was associated with the regulation of inflammation and apoptosis, by targeting the PI3K-Akt and TNF signaling pathways.

scholarly journals A Network Pharmacology Approach to Uncover the Mechanisms of Shen-Qi-Di-Huang Decoction against Diabetic Nephropathy

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Sha Di ◽  
Lin Han ◽  
Qing Wang ◽  
Xinkui Liu ◽  
Yingying Yang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interaction ◽  
Regulation Of Blood Pressure ◽  
Protein Protein Interaction Network

Shen-Qi-Di-Huang decoction (SQDHD), a well-known herbal formula from China, has been widely used in the treatment of diabetic nephropathy (DN). However, the pharmacological mechanisms of SQDHD have not been entirely elucidated. At first, we conducted a comprehensive literature search to identify the active constituents of SQDHD, determined their corresponding targets, and obtained known DN targets from several databases. A protein-protein interaction network was then built to explore the complex relations between SQDHD targets and those known to treat DN. Following the topological feature screening of each node in the network, 400 major targets of SQDHD were obtained. The pathway enrichment analysis results acquired from DAVID showed that the significant bioprocesses and pathways include oxidative stress, response to glucose, regulation of blood pressure, regulation of cell proliferation, cytokine-mediated signaling pathway, and the apoptotic signaling pathway. More interestingly, five key targets of SQDHD, named AKT1, AR, CTNNB1, EGFR, and ESR1, were significant in the regulation of the above bioprocesses and pathways. This study partially verified and predicted the pharmacological and molecular mechanisms of SQDHD on DN from a holistic perspective. This has laid the foundation for further experimental research and has expanded the rational application of SQDHD in clinical practice.

scholarly journals Dissecting the Mechanism of Yuzhi Zhixue Granule on Ovulatory Dysfunctional Uterine Bleeding by Network Pharmacology and Molecular Docking

2020 ◽  
Author(s):  
Jialin Li ◽  
Hua Luo ◽  
Xinkui Liu ◽  
Jingyuan Zhang ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Uterine Bleeding ◽  
Functional Enrichment ◽  
Network Pharmacology ◽  
Dysfunctional Uterine Bleeding

Abstract Background: Yuzhi Zhixue Granule (YZG)is a traditional Chinese patent medicine for treating excessive menstrual flow caused by ovulatory dysfunctional uterine bleeding (ODUB) accompanied by heat syndrome. However, the underlying molecular mechanisms, potential targets, and active ingredients of this prescription are still unknown. Therefore, it is imperative to explore the molecular mechanism of YZG.Methods: The active compounds in YZG were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The putative targets of YZG were collected via TCMSP and Search Tool for Interacting Chemicals (STITCH) databases. The Therapeutic Target Database (TTD) and Pharmacogenomics Knowledgebase (PharmGKB) databases were used to identify the therapeutic targets of ODUB. A protein-protein interaction (PPI) network containing both the putative targets of YZG and known therapeutic targets of ODUB was built. Furthermore, bioinformatics resources from the database for annotation, visualization and integrated discovery (DAVID) were utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, molecular docking was performed to verify the binding effect between the YZG screened compounds and potential therapeutic target molecules.Results: The study employed a network pharmacology method, mainly containing target prediction, network construction, functional enrichment analysis, and molecular docking to systematically research the mechanisms of YZG in treating ODUB. The putative targets of YZG that treat ODUB mainly involved PTGS1, PTGS2, ALOX5, CASP3, LTA4H, F7 and F10. The functional enrichment analysis suggested that the produced therapeutic effect of YZG against ODUB is mediated by synergistical regulation of several biological pathways, including apoptosis arachidonic acid (AA) metabolism, serotonergic synapse, complement and coagulation cascades and C-type lectin receptor signaling pathways. Molecular docking simulation revealed good binding affinity of the seven putative targets with the corresponding compounds.Conclusion: This novel and scientific network pharmacology-based study holistically elucidated the basic pharmacological effects and the underlying mechanisms of YZG in the treatment of ODUB.

scholarly journals Network Pharmacology-based Investigation of the Underlying Mechanism of Panax notoginseng Treatment of Diabetic Retinopathy

2020 ◽  
Vol 23 (4) ◽  
pp. 334-344
Author(s):  
Chunli Piao ◽  
Zheyu Sun ◽  
De Jin ◽  
Han Wang ◽  
Xuemin Wu ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Topological Analysis ◽  
Enrichment Analysis ◽  
Panax Notoginseng ◽  
Diabetic Microangiopathy ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Annotation Database ◽  
Cox 2

Background: Panax notoginseng, a Chinese herbal medicine, has been widely used to treat vascular diseases. Diabetic retinopathy (DR) is one of the complications of diabetic microangiopathy. According to recent studies, the application of Panax notoginseng extract and related Chinese patent medicine preparations can significantly improve DR. However, the pharmacological mechanisms remain unclear. Therefore, the purpose of this study was to decipher the potential mechanism of Panax notoginseng treatment of DR using network pharmacology. Methods: We evaluated and screened the active compounds of Panax notoginseng using the Traditional Chinese Medicine Systems Pharmacology database and collected potential targets of the compounds by target fishing. A multi-source database was also used to organize targets of DR. The potential targets as the treatment of DR with Panax notoginseng were then obtained by matching the compound targets with the DR targets. Using protein-protein interaction networks and topological analysis, interactions between potential targets were identified. In addition, we also performed gene ontology-biological process and pathway enrichment analysis for the potential targets by using the Biological Information Annotation Database. Results: Eight active ingredients of Panax notoginseng and 31 potential targets for the treatment of DR were identified. The screening and enrichment analysis revealed that the treatment of DR using Panax notoginseng primarily involved 28 biological processes and 10 related pathways. Further analyses indicated that angiogenesis, inflammatory reactions, and apoptosis may be the main processes involved in the treatment of DR with Panax notoginseng. In addition, we determined that the mechanism of intervention of Panax notoginseng in treating DR may involve five core targets, VEGFA, MMP-9, MMP-2, FGF2, and COX-2. Conclusion: Panax notoginseng may treat diabetic retinopathy through the mechanism of network pharmacological analysis. The underlying molecular mechanisms were closely related to the intervention of angiogenesis, inflammation, and apoptosis with VEGFA, MMP-9, MMP-2, FGF2, and COX-2 being possible targets.

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