Exploring the “gene–protein–metabolite” network of coronary heart disease with phlegm and blood stasis syndrome by integrated multi-omics strategy

Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteom...

Full description

Saved in:
Bibliographic Details
Published inFrontiers in pharmacology Vol. 13; p. 1022627
Main Authors Yang, Guang, Zhou, Siyuan, He, Haoqiang, Shen, Zinuo, Liu, Yongmei, Hu, Jun, Wang, Jie
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 29.11.2022
Subjects
Online AccessGet full text
ISSN1663-9812
1663-9812
DOI10.3389/fphar.2022.1022627

Cover

Abstract Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a “gene–protein–metabolite” network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Results: Our findings revealed that the “gene–protein–metabolite” network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 ( Mirzaei et al., 2009 , 95, 740–746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) ( Katus et al., 2017 ; Knuuti, 2019 ). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina ( Rousan et al., 2017 ). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy ( Shaw et al., 2008 ; Antman and Braunwald, 2020 ). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations ( Teng et al., 2016 ). TCM has become a principal complement in western countries ( Wieland et al., 2013 ). Like “disease” is used in western medicine, “syndrome” is used in TCM to comprehend anomalous human conditions on the basis of patients’ symptoms, tongue, and pulse ( Li et al., 2012 ). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome ( Ren et al., 2020 ; Liu et al., 2021 ; Zheng et al., 2022 ). The concept of “omics” originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources ( Dai and Shen, 2022 ). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode ( Pan et al., 2022 ). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals ( Singh et al., 2016 ; Lal et al., 2018 ; Mohler et al., 2020 ). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine ( Zhou et al., 2019 ). Li’s metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome ( Zheng et al., 2022 ). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other’s research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the “gene–protein–metabolite” network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the “gene–protein–metabolite” network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules ( Figure 1) .
AbstractList Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a "gene-protein-metabolite" network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Results: Our findings revealed that the "gene-protein-metabolite" network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 (Mirzaei et al., 2009, 95, 740-746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) (Katus et al., 2017; Knuuti, 2019). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina (Rousan et al., 2017). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy (Shaw et al., 2008; Antman and Braunwald, 2020). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations (Teng et al., 2016). TCM has become a principal complement in western countries (Wieland et al., 2013). Like "disease" is used in western medicine, "syndrome" is used in TCM to comprehend anomalous human conditions on the basis of patients' symptoms, tongue, and pulse (Li et al., 2012). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome (Ren et al., 2020; Liu et al., 2021; Zheng et al., 2022). The concept of "omics" originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources (Dai and Shen, 2022). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode (Pan et al., 2022). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals (Singh et al., 2016; Lal et al., 2018; Mohler et al., 2020). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine (Zhou et al., 2019). Li's metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome (Zheng et al., 2022). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other's research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the "gene-protein-metabolite" network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the "gene-protein-metabolite" network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules (Figure 1).Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a "gene-protein-metabolite" network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Results: Our findings revealed that the "gene-protein-metabolite" network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 (Mirzaei et al., 2009, 95, 740-746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) (Katus et al., 2017; Knuuti, 2019). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina (Rousan et al., 2017). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy (Shaw et al., 2008; Antman and Braunwald, 2020). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations (Teng et al., 2016). TCM has become a principal complement in western countries (Wieland et al., 2013). Like "disease" is used in western medicine, "syndrome" is used in TCM to comprehend anomalous human conditions on the basis of patients' symptoms, tongue, and pulse (Li et al., 2012). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has re
Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a “gene–protein–metabolite” network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Results: Our findings revealed that the “gene–protein–metabolite” network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 ( Mirzaei et al., 2009 , 95, 740–746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) ( Katus et al., 2017 ; Knuuti, 2019 ). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina ( Rousan et al., 2017 ). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy ( Shaw et al., 2008 ; Antman and Braunwald, 2020 ). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations ( Teng et al., 2016 ). TCM has become a principal complement in western countries ( Wieland et al., 2013 ). Like “disease” is used in western medicine, “syndrome” is used in TCM to comprehend anomalous human conditions on the basis of patients’ symptoms, tongue, and pulse ( Li et al., 2012 ). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome ( Ren et al., 2020 ; Liu et al., 2021 ; Zheng et al., 2022 ). The concept of “omics” originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources ( Dai and Shen, 2022 ). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode ( Pan et al., 2022 ). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals ( Singh et al., 2016 ; Lal et al., 2018 ; Mohler et al., 2020 ). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine ( Zhou et al., 2019 ). Li’s metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome ( Zheng et al., 2022 ). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other’s research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the “gene–protein–metabolite” network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the “gene–protein–metabolite” network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules ( Figure 1) .
Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD.Methods: Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a “gene–protein–metabolite” network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay.Results: Our findings revealed that the “gene–protein–metabolite” network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome.Conclusion: PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 (Mirzaei et al., 2009, 95, 740–746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) (Katus et al., 2017; Knuuti, 2019). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina (Rousan et al., 2017). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy (Shaw et al., 2008; Antman and Braunwald, 2020). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations (Teng et al., 2016). TCM has become a principal complement in western countries (Wieland et al., 2013). Like “disease” is used in western medicine, “syndrome” is used in TCM to comprehend anomalous human conditions on the basis of patients’ symptoms, tongue, and pulse (Li et al., 2012). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome (Ren et al., 2020; Liu et al., 2021; Zheng et al., 2022). The concept of “omics” originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources (Dai and Shen, 2022). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode (Pan et al., 2022). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals (Singh et al., 2016; Lal et al., 2018; Mohler et al., 2020). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine (Zhou et al., 2019). Li’s metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome (Zheng et al., 2022). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other’s research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the “gene–protein–metabolite” network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the “gene–protein–metabolite” network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules (Figure 1).
According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study aimed to explore the biological basis of PBS syndrome in CHD. Using a strategy that integrated RNA-seq, DIA-based proteomics, and untargeted metabolomics on 90 clinic samples, we constructed a "gene-protein-metabolite" network for CHD-PBS syndrome. We expanded the sample size and validated the differential genes and metabolites in the network through enzyme-linked immunosorbent assay. Our findings revealed that the "gene-protein-metabolite" network of CHD-PBS syndrome included 33 mRNAs, four proteins, and 25 metabolites. JNK1, FOS, CCL2, CXCL8, PTGS2, and CSF1 were all poorly expressed in the PBS group during the sequencing stage, whereas arachidonic acid (AA) was highly expressed. During the validation stage, JNK1, AP-1, CCL2, and CXCL8 were poorly expressed, whereas PTGS2, CSF1, and AA were highly expressed. The area under the receiver operating curve was as follows: CSF1 [0.9635, 95%CI (0.9295, 0.9976)] >JNK1 [0.9361, 95% CI (0.8749, 0.9972)] >CXCL8 [0.8953, 95% CI (0.8222, 0.9684)] > CCL2 [0.8458, 95% CI (0.7676, 0.9241)] >AP-1 [0.7884, 95%CI (0.6869, 0.8899)]. The logistic regression model composed of CSF1 and JNK1 showed the greatest diagnostic value and significance for PBS syndrome. PBS syndrome is characterized by low levels of FOS, AP-1, CCL2, CXCL8, and JNK1 and elevated levels of PTGS2 and CSF1, implying that the AA metabolism is abnormal and that the JNK/AP-1 pathway is inhibited. PBS syndromes, as a subtype of CHD, may have unique molecular changes. Background. Globally, coronary heart disease (CHD) is the leading cause of death, and this would likely continue until 2030 (Mirzaei et al., 2009, 95, 740-746). According to the disease course, CHD can be classified as chronic stable CHD (or chronic coronary syndrome) and acute coronary syndrome (ACS) (Katus et al., 2017; Knuuti, 2019). Although stable CHD is not as lethal as ACS, it has a varied incidence range and patients with CHD have prolonged angina. Some symptoms of stable angina are alleviated with pharmacological therapy, but it cannot eliminate recurrent angina (Rousan et al., 2017). The clinical outcomes were not significantly improved in patients who underwent revascularization compared with those who received optimal pharmacological therapy (Shaw et al., 2008; Antman and Braunwald, 2020). A bottleneck appears to exist in CHD treatment, and traditional Chinese medicine (TCM) can act as a favorable complement. Because of its individualized treatment approach, TCM is widely practiced in eastern civilizations (Teng et al., 2016). TCM has become a principal complement in western countries (Wieland et al., 2013). Like "disease" is used in western medicine, "syndrome" is used in TCM to comprehend anomalous human conditions on the basis of patients' symptoms, tongue, and pulse (Li et al., 2012). On the basis of disease-syndrome diagnose, a TCM doctor can subclassify CHD patients into various categories, such as phlegm and blood stasis (PBS) syndrome, cold congealing and Qi stagnation syndrome, and Qi stagnation and blood stasis syndrome. PBS syndrome has recently emerged as a hot research topic in the TCM field. Objective diagnosis, expert consultations, and efficacy evaluation scales have been developed for PBS syndrome (Ren et al., 2020; Liu et al., 2021; Zheng et al., 2022). The concept of "omics" originates from the genome. It refers to the vocabulary generated by biological molecules at different levels to describe high-sequence molecular biological data resources (Dai and Shen, 2022). RNA, protein, and metabolites decipher the essence of complex etiologies, and the integration of transcriptomics, proteomics, and metabolomics are becoming a promising research mode (Pan et al., 2022). Multi-omics studies have revealed the biological characteristics of APOE transgenic mice, bronchopulmonary dysplasia, and plant tolerant to heavy metals (Singh et al., 2016; Lal et al., 2018; Mohler et al., 2020). Over the past few years, many academic achievements related to CHD-PBS syndrome have been accrued in the single-omic area. For example, Zhou identified the differential metabolites between PBS syndrome and Qi and Yin deficiency syndrome by using the urine samples of 1072 volunteers. Some of the specific metabolites of PBS syndrome are pyroglutamic acid, glutaric acid, glucose, mannitol, and xanthine (Zhou et al., 2019). Li's metabolomic study suggested that valine, leucine, isoleucine, and glycerol phospholipid metabolism could represent PBS syndrome (Zheng et al., 2022). Although some progress has been made in the understanding of PBS syndrome in CHD through the studies conducted, some issues still exist, such as a single-omics level, a lack of in-depth research, an inability to verify each other's research results, and a lack of validation of research conclusions. Overall, a systematic description of the biological foundation of PBS syndrome is lacking. Thus, the present study utilizes system biology methodologies and constructs a multi-omics network by integrating differential genes, proteins, and metabolites to systematically and comprehensively reveal the biological basis of CHD-PBS syndrome. The current study explored 1) the characteristics of the transcriptome, proteome, and metabolome for CHD-PBS syndrome; 2) the "gene-protein-metabolite" network based on differential genes (DGs), differential proteins (DPs), and differential metabolites (DMs); 3) the key biological process and metabolic pathway most related to PBS syndrome; and 4) quantitative results and the diagnostic potential of biomarkers for PSB syndrome. Materials and methods. Multi-omics sequencing, bioinformatics analysis, and clinical validation research strategy. We collected the blood samples from healthy subjects as well as CHD patients with PBS and non-phlegm and blood stasis (NPBS) syndrome to compare the differences between them by subjecting the samples to the transcriptome, proteome, and metabolomics analyses. Bioinformatics analysis identified differential molecules as well as related biological processes and pathways. Next, the "gene-protein-metabolite" network was constructed using the MetaboAnalyst database, String database, and Cytoscape software. We selected molecules with strong centrality and biological association as potential PBS syndrome biomarkers and recruited more volunteers for further validation by enzyme-linked immunosorbent assay (ELISA). Finally, the ROC curve was utilized to assess the level and diagnostic efficacy of various molecules (Figure 1).
Author Liu, Yongmei
Hu, Jun
Yang, Guang
Shen, Zinuo
Zhou, Siyuan
He, Haoqiang
Wang, Jie
AuthorAffiliation 1 Department of Cardiology , Guang’anmen Hospital , China Academy of Chinese Medical Sciences , Beijing , China
2 School of traditional chinese medicine , Beijing University of Chinese Medicine , Beijing , China
AuthorAffiliation_xml – name: 2 School of traditional chinese medicine , Beijing University of Chinese Medicine , Beijing , China
– name: 1 Department of Cardiology , Guang’anmen Hospital , China Academy of Chinese Medical Sciences , Beijing , China
Author_xml – sequence: 1
  givenname: Guang
  surname: Yang
  fullname: Yang, Guang
– sequence: 2
  givenname: Siyuan
  surname: Zhou
  fullname: Zhou, Siyuan
– sequence: 3
  givenname: Haoqiang
  surname: He
  fullname: He, Haoqiang
– sequence: 4
  givenname: Zinuo
  surname: Shen
  fullname: Shen, Zinuo
– sequence: 5
  givenname: Yongmei
  surname: Liu
  fullname: Liu, Yongmei
– sequence: 6
  givenname: Jun
  surname: Hu
  fullname: Hu, Jun
– sequence: 7
  givenname: Jie
  surname: Wang
  fullname: Wang, Jie
BackLink https://www.ncbi.nlm.nih.gov/pubmed/36523490$$D View this record in MEDLINE/PubMed
BookMark eNp9Ustu1DAUjVARLaU_wAJ5ySZDEjt-bJBQVaBSJTawthznOnFJ7GB7aGfXf2CH4Of6JXg6Q9WywAv76vicc33l87w4cN5BUbysqxXGXLwxy6jCqqmaZlXnjTbsSXFUU4pLwevm4EF9WJzEeFnlhYXAlDwrDjFtG0xEdVT8PLteJh-sG1AaAd3e_BrAwe3NjyX4BNblaoakOj_ZlOHfyEG68uEr8gZpH7xTYYNGUCGh3kZQEdCVTSNaxgmGGSnXo27yvkcxqWgjihvXBz8D6jbIugRDUAl6NK-nZEs_W50paYsNmxfFU6OmCCf787j48v7s8-nH8uLTh_PTdxelJpSnEhNNGG-BClPzjnFgnCpBBeXG0KYzggmmjTBdU0HLK8aJaUTNOsI6qlui8HFxvvPtvbqUS7Bznkl6ZeUd4MMg83hWTyAN0zVudVsxLYiuKi56wEK3LQFDQED2ervzWtbdDL0Gl4eZHpk-vnF2lIP_LgUjhNE6G7zeGwT_bQ0xydlGDdOkHPh1lA1r25ZRgXmmvnrY677J38_NhGZH0MHHGMDcU-pKbkMk70IktyGS-xBlEf9HpG1Syfrte-30P-kfO_jVpA
CitedBy_id crossref_primary_10_1093_bib_bbad518
crossref_primary_10_3389_fpsyt_2024_1361177
crossref_primary_10_1186_s13020_025_01085_2
crossref_primary_10_34172_jlms_2023_59
crossref_primary_10_1002_pca_3518
crossref_primary_10_1007_s00604_024_06312_5
crossref_primary_10_2147_DMSO_S491897
crossref_primary_10_1002_bmc_70047
Cites_doi 10.1016/j.cmet.2021.08.014
10.1111/j.1742-4658.2007.05772.x
10.1021/acs.jproteome.8b00799
10.1136/hrt.2008.154856
10.1007/s11302-022-09856-4
10.3892/ijmm.4.3.223
10.1053/j.semperi.2018.09.004
10.1016/j.imbio.2010.06.003
10.1080/17512433.2016.1195263
10.1007/s11684-014-0349-8
10.3389/fphar.2021.664320
10.3389/fpls.2015.01143
10.4049/jimmunol.2100866
10.1194/jlr.M005215
10.1002/jcp.24939
10.1186/s13020-021-00521-3
10.1056/NEJMc2024008
10.3389/fcvm.2022.871142
10.4049/jimmunol.1601330
10.1093/eurheartj/ehx492
10.1007/s13105-021-00812-1
10.1161/01.RES.0000163017.13772.3a
10.1016/j.jare.2018.03.005
10.1080/15384101.2019.1662678
10.1002/med.21847
10.1177/1933719114549845
10.1089/acm.2020.0008
10.1006/jmcc.2001.1351
10.1016/j.freeradbiomed.2021.05.009
10.1016/j.biopha.2018.10.087
10.1186/1749-8546-7-9
10.21037/apm-21-2332
10.1007/s40265-017-0691-7
10.1016/j.atherosclerosis.2018.07.007
10.3892/mmr.2015.4432
10.1007/978-3-642-77377-8_5
10.1016/j.metabol.2022.155213
10.1016/j.biopha.2018.08.004
10.1016/j.cyto.2019.154923
10.1161/CIRCULATIONAHA.107.743963
10.1002/alz.040533
10.3390/antiox8120620
10.1186/2046-4053-2-51
10.1097/FJC.0000000000000769
10.1016/j.amjcard.2009.06.028
10.1042/CS20110234
10.3389/fmed.2022.911861
10.15829/1560-4071-2020-2-3757
10.1111/sji.12840
10.1096/fj.01-0353fje
10.1007/s12012-011-9135-x
ContentType Journal Article
Copyright Copyright © 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang.
Copyright © 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang. 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang
Copyright_xml – notice: Copyright © 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang.
– notice: Copyright © 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang. 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang
DBID AAYXX
CITATION
NPM
7X8
5PM
DOA
DOI 10.3389/fphar.2022.1022627
DatabaseName CrossRef
PubMed
MEDLINE - Academic
PubMed Central (Full Participant titles)
DOAJ Directory of Open Access Journals
DatabaseTitle CrossRef
PubMed
MEDLINE - Academic
DatabaseTitleList MEDLINE - Academic
CrossRef


PubMed
Database_xml – sequence: 1
  dbid: DOA
  name: DOAJ Directory of Open Access Journals
  url: https://www.doaj.org/
  sourceTypes: Open Website
– sequence: 2
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
DeliveryMethod fulltext_linktorsrc
Discipline Pharmacy, Therapeutics, & Pharmacology
DocumentTitleAlternate Yang et al
EISSN 1663-9812
ExternalDocumentID oai_doaj_org_article_f7c135c507c94c0089de39c554ef4e9e
PMC9744761
36523490
10_3389_fphar_2022_1022627
Genre Journal Article
GrantInformation_xml – fundername: ;
GroupedDBID 53G
5VS
9T4
AAFWJ
AAKDD
AAYXX
ACGFO
ACGFS
ACXDI
ADBBV
ADRAZ
AENEX
AFPKN
ALMA_UNASSIGNED_HOLDINGS
AOIJS
BAWUL
BCNDV
CITATION
DIK
EMOBN
GROUPED_DOAJ
GX1
HYE
KQ8
M48
M~E
O5R
O5S
OK1
P2P
PGMZT
RNS
RPM
IAO
IEA
IHR
IHW
IPNFZ
NPM
RIG
7X8
5PM
ID FETCH-LOGICAL-c468t-34c4785e69f18b78e786a96968ff62bf9797cf9fb20e580784f2917b47b6c54a3
IEDL.DBID M48
ISSN 1663-9812
IngestDate Wed Aug 27 01:16:00 EDT 2025
Thu Aug 21 18:39:29 EDT 2025
Fri Sep 05 06:27:26 EDT 2025
Thu Jan 02 22:53:16 EST 2025
Tue Jul 01 02:33:49 EDT 2025
Thu Apr 24 22:59:52 EDT 2025
IsDoiOpenAccess true
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Keywords traditional Chinese medicine
coronary heart disease
RNA-seq
proteomics
phlegm and blood stasis syndrome
metabolomics
Language English
License Copyright © 2022 Yang, Zhou, He, Shen, Liu, Hu and Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-c468t-34c4785e69f18b78e786a96968ff62bf9797cf9fb20e580784f2917b47b6c54a3
Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology
Edited by: Sheng Guo, Nanjing University of Chinese Medicine, China
Kunming Qin, Jiangsu Ocean Universiity, China
These authors have contributed equally to this work
Reviewed by: Zhi Yong Du, Beijing Anzhen Hospital, Capital Medical University, China
OpenAccessLink http://journals.scholarsportal.info/openUrl.xqy?doi=10.3389/fphar.2022.1022627
PMID 36523490
PQID 2755576938
PQPubID 23479
ParticipantIDs doaj_primary_oai_doaj_org_article_f7c135c507c94c0089de39c554ef4e9e
pubmedcentral_primary_oai_pubmedcentral_nih_gov_9744761
proquest_miscellaneous_2755576938
pubmed_primary_36523490
crossref_primary_10_3389_fphar_2022_1022627
crossref_citationtrail_10_3389_fphar_2022_1022627
ProviderPackageCode CITATION
AAYXX
PublicationCentury 2000
PublicationDate 2022-11-29
PublicationDateYYYYMMDD 2022-11-29
PublicationDate_xml – month: 11
  year: 2022
  text: 2022-11-29
  day: 29
PublicationDecade 2020
PublicationPlace Switzerland
PublicationPlace_xml – name: Switzerland
PublicationTitle Frontiers in pharmacology
PublicationTitleAlternate Front Pharmacol
PublicationYear 2022
Publisher Frontiers Media S.A
Publisher_xml – name: Frontiers Media S.A
References Dai (B5) 2015; 230
Matsumoto (B22) 2007; 274
Roebuck (B33) 1999; 4
Wu (B43) 2021; 16
Mirzaei (B25) 2009; 95
Nakayama (B27) 2022; 208
Zhuang (B52) 2022
Zhang (B47) 2021; 33
Popova (B31) 2011; 216
Yoshiyama (B45) 2001; 33
An (B2) 2019; 18
Li (B19) 2012; 7
Zhou (B50) 2014; 8
Khambhati (B14) 2018; 276
Yang (B44) 2020; 75
Knuuti (B15) 2019; 25
Dewald (B7) 2005; 96
Chou (B4) 2019; 8
Hernández-Aguilera (B12) 2020; 126
Lin (B20) 2015; 12
Rousan (B35) 2017; 77
Teng (B40) 2016; 9
Katus (B13) 2017; 38
Ren (B32) 2020; 26
Singh (B38) 2016; 6
Zhang (B46) 2012; 12
Miao (B24) 2022; 132
Wang (B41) 2018; 59
Du (B8) 2020; 91
Zheng (B48) 2022; 9
Shaw (B37) 2008; 117
Lal (B16) 2018; 42
Mohler (B26) 2020; 16
Zhou (B49) 2019; 18
Hanna (B10) 2018; 11
Pertynska-Marczewska (B30) 2015; 22
Hannemann (B11) 2017; 198
Li (B18) 2021; 77
Leocádio (B17) 2019; 109
Roth (B34) 1992; 181
Liu (B21) 2021; 10
Zhou (B51) 2021; 171
Orn (B28) 2009; 104
Wieland (B42) 2013; 2
Guo (B9) 2021; 12
Dai (B6) 2022; 9
Meijer (B23) 2012; 122
Shaposhnik (B36) 2010; 51
Antman (B3) 2020; 383
Pan (B29) 2022; 42
Taimor (B39) 2001; 15
Al-Kofahi (B1) 2018; 107
References_xml – volume: 33
  start-page: 2059
  year: 2021
  ident: B47
  article-title: Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species
  publication-title: Cell Metab.
  doi: 10.1016/j.cmet.2021.08.014
– volume: 274
  start-page: 2376
  year: 2007
  ident: B22
  article-title: Caspase-8- and JNK-dependent AP-1 activation is required for Fas ligand-induced IL-8 production
  publication-title: FEBS J.
  doi: 10.1111/j.1742-4658.2007.05772.x
– volume: 18
  start-page: 1994
  year: 2019
  ident: B49
  article-title: A large-scale, multi-center urine biomarkers identification of coronary heart disease in TCM syndrome differentiation
  publication-title: J. Proteome Res.
  doi: 10.1021/acs.jproteome.8b00799
– volume: 95
  start-page: 740
  year: 2009
  ident: B25
  article-title: Coronary heart disease epidemics: Not all the same
  publication-title: Heart
  doi: 10.1136/hrt.2008.154856
– year: 2022
  ident: B52
  article-title: Purinergic signaling in myocardial ischemia-reperfusion injury
  publication-title: Purinergic Signal.
  doi: 10.1007/s11302-022-09856-4
– volume: 4
  start-page: 223
  year: 1999
  ident: B33
  article-title: Oxidant stress regulation of IL-8 and ICAM-1 gene expression: Differential activation and binding of the transcription factors AP-1 and NF-kappaB (review)
  publication-title: Int. J. Mol. Med.
  doi: 10.3892/ijmm.4.3.223
– volume: 42
  start-page: 425
  year: 2018
  ident: B16
  article-title: Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia
  publication-title: Semin. Perinatol.
  doi: 10.1053/j.semperi.2018.09.004
– volume: 216
  start-page: 164
  year: 2011
  ident: B31
  article-title: Pro- and anti-inflammatory control of M-CSF-mediated macrophage differentiation
  publication-title: Immunobiology
  doi: 10.1016/j.imbio.2010.06.003
– volume: 9
  start-page: 1225
  year: 2016
  ident: B40
  article-title: Herbal medicines: Challenges in the modern world. Part 3. China and Japan
  publication-title: Expert Rev. Clin. Pharmacol.
  doi: 10.1080/17512433.2016.1195263
– volume: 59
  start-page: 539
  year: 2018
  ident: B41
  article-title: Diagnostic criteria for syndrome elements of coronary heart disease angina
  publication-title: J. Tradit. Chin. Med.
– volume: 8
  start-page: 337
  year: 2014
  ident: B50
  article-title: Clinical phenotype network: The underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine
  publication-title: Front. Med.
  doi: 10.1007/s11684-014-0349-8
– volume: 12
  start-page: 664320
  year: 2021
  ident: B9
  article-title: Serum metabolomic analysis of coronary heart disease patients with stable Angina pectoris subtyped by traditional Chinese medicine diagnostics reveals biomarkers relevant to personalized treatments
  publication-title: Front. Pharmacol.
  doi: 10.3389/fphar.2021.664320
– volume: 6
  start-page: 1143
  year: 2016
  ident: B38
  article-title: Heavy metal tolerance in plants: Role of transcriptomics, proteomics, metabolomics, and ionomics
  publication-title: Front. Plant Sci.
  doi: 10.3389/fpls.2015.01143
– volume: 208
  start-page: 1146
  year: 2022
  ident: B27
  article-title: Porphyromonas gingivalis gingipains induce cyclooxygenase-2 expression and prostaglandin E2 production via ERK1/2-activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 cascades
  publication-title: J. I.
  doi: 10.4049/jimmunol.2100866
– volume: 51
  start-page: 1962
  year: 2010
  ident: B36
  article-title: Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis
  publication-title: J. Lipid Res.
  doi: 10.1194/jlr.M005215
– volume: 230
  start-page: 2108
  year: 2015
  ident: B5
  article-title: Epoxyeicosatrienoic acids regulate macrophage polarization and prevent LPS-induced cardiac dysfunction
  publication-title: J. Cell. Physiol.
  doi: 10.1002/jcp.24939
– volume: 16
  start-page: 109
  year: 2021
  ident: B43
  article-title: Exploring biological basis of Syndrome differentiation in coronary heart disease patients with two distinct Syndromes by integrated multi-omics and network pharmacology strategy
  publication-title: Chin. Med.
  doi: 10.1186/s13020-021-00521-3
– volume: 383
  start-page: e66
  year: 2020
  ident: B3
  article-title: Invasive or conservative strategy for stable coronary disease. Reply
  publication-title: N. Engl. J. Med.
  doi: 10.1056/NEJMc2024008
– volume: 9
  start-page: 871142
  year: 2022
  ident: B48
  article-title: A landscape of metabonomics for intermingled phlegm and blood stasis and its concurrent syndromes in stable Angina pectoris of coronary heart disease
  publication-title: Front. Cardiovasc. Med.
  doi: 10.3389/fcvm.2022.871142
– volume: 198
  start-page: 3605
  year: 2017
  ident: B11
  article-title: The AP-1 transcription factor c-jun promotes arthritis by regulating cyclooxygenase-2 and arginase-1 expression in macrophages
  publication-title: J. Immunol.
  doi: 10.4049/jimmunol.1601330
– volume: 38
  start-page: 3049
  year: 2017
  ident: B13
  article-title: Early diagnosis of acute coronary syndrome
  publication-title: Eur. Heart J.
  doi: 10.1093/eurheartj/ehx492
– volume: 77
  start-page: 451
  year: 2021
  ident: B18
  article-title: MiR-137 regulates low-intensity shear stress-induced human aortic endothelial cell apoptosis via JNK/AP-1 signaling
  publication-title: J. Physiol. Biochem.
  doi: 10.1007/s13105-021-00812-1
– volume: 96
  start-page: 881
  year: 2005
  ident: B7
  article-title: CCL2/Monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts
  publication-title: Circ. Res.
  doi: 10.1161/01.RES.0000163017.13772.3a
– volume: 11
  start-page: 23
  year: 2018
  ident: B10
  article-title: Synopsis of arachidonic acid metabolism: A review
  publication-title: J. Adv. Res.
  doi: 10.1016/j.jare.2018.03.005
– volume: 18
  start-page: 2928
  year: 2019
  ident: B2
  article-title: Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages
  publication-title: Cell Cycle
  doi: 10.1080/15384101.2019.1662678
– volume: 42
  start-page: 441
  year: 2022
  ident: B29
  article-title: Association predictions of genomics, proteinomics, transcriptomics, microbiome, metabolomics, pathomics, radiomics, drug, symptoms, environment factor, and disease networks: A comprehensive approach
  publication-title: Med. Res. Rev.
  doi: 10.1002/med.21847
– volume: 22
  start-page: 774
  year: 2015
  ident: B30
  article-title: Relationship of advanced glycation end products with cardiovascular disease in menopausal women
  publication-title: Reprod. Sci.
  doi: 10.1177/1933719114549845
– volume: 26
  start-page: 729
  year: 2020
  ident: B32
  article-title: A quantitative diagnostic method for phlegm and blood stasis syndrome in coronary heart disease using tongue, face, and pulse indexes: An exploratory pilot study
  publication-title: J. Altern. Complement. Med.
  doi: 10.1089/acm.2020.0008
– volume: 33
  start-page: 799
  year: 2001
  ident: B45
  article-title: Angiotensin blockade inhibits increased JNKs, AP-1 and NF- kappa B DNA-binding activities in myocardial infarcted rats
  publication-title: J. Mol. Cell. Cardiol.
  doi: 10.1006/jmcc.2001.1351
– volume: 171
  start-page: 55
  year: 2021
  ident: B51
  article-title: Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis
  publication-title: Free Radic. Biol. Med.
  doi: 10.1016/j.freeradbiomed.2021.05.009
– volume: 109
  start-page: 1411
  year: 2019
  ident: B17
  article-title: Low serum levels of CCL2 are associated with worse prognosis in patients with acute coronary syndrome: 2-year survival analysis
  publication-title: Biomed. Pharmacother. Biomedecine Pharmacother.
  doi: 10.1016/j.biopha.2018.10.087
– volume: 7
  start-page: 9
  year: 2012
  ident: B19
  article-title: Inquiry diagnosis of coronary heart disease in Chinese medicine based on symptom-syndrome interactions
  publication-title: Chin. Med.
  doi: 10.1186/1749-8546-7-9
– volume: 10
  start-page: 9940
  year: 2021
  ident: B21
  article-title: Study on syndrome differentiation strategy of phlegm and blood stasis syndromes of coronary heart disease based on expert consultation on medical cases
  publication-title: Ann. Palliat. Med.
  doi: 10.21037/apm-21-2332
– volume: 77
  start-page: 265
  year: 2017
  ident: B35
  article-title: Drug therapy for stable Angina pectoris
  publication-title: Drugs
  doi: 10.1007/s40265-017-0691-7
– volume: 276
  start-page: 1
  year: 2018
  ident: B14
  article-title: Immunotherapy for the prevention of atherosclerotic cardiovascular disease: Promise and possibilities
  publication-title: Atherosclerosis
  doi: 10.1016/j.atherosclerosis.2018.07.007
– volume: 12
  start-page: 8193
  year: 2015
  ident: B20
  article-title: Candesartan ameliorates acute myocardial infarction in rats through inducible nitric oxide synthase, nuclear factor-κB, monocyte chemoattractant protein-1, activator protein-1 and restoration of heat shock protein 72
  publication-title: Mol. Med. Rep.
  doi: 10.3892/mmr.2015.4432
– volume: 181
  start-page: 141
  year: 1992
  ident: B34
  article-title: The biology of CSF-1 and its receptor
  publication-title: Curr. Top. Microbiol. Immunol.
  doi: 10.1007/978-3-642-77377-8_5
– volume: 132
  start-page: 155213
  year: 2022
  ident: B24
  article-title: Vascular smooth muscle cell c-Fos is critical for foam cell formation and atherosclerosis
  publication-title: Metabolism.
  doi: 10.1016/j.metabol.2022.155213
– volume: 107
  start-page: 1591
  year: 2018
  ident: B1
  article-title: IL-1β reduces cardiac lymphatic muscle contraction via COX-2 and PGE2 induction: Potential role in myocarditis
  publication-title: Biomed. Pharmacother. Biomedecine Pharmacother.
  doi: 10.1016/j.biopha.2018.08.004
– volume: 126
  start-page: 154923
  year: 2020
  ident: B12
  article-title: Chemokine (C-C motif) ligand 2 and coronary artery disease: Tissue expression of functional and atypical receptors
  publication-title: Cytokine
  doi: 10.1016/j.cyto.2019.154923
– volume: 117
  start-page: 1283
  year: 2008
  ident: B37
  article-title: Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: Results from the clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial nuclear substudy
  publication-title: Circulation
  doi: 10.1161/CIRCULATIONAHA.107.743963
– volume: 16
  start-page: e040533
  year: 2020
  ident: B26
  article-title: Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice
  publication-title: Alzheimer's. &amp. Dement.
  doi: 10.1002/alz.040533
– volume: 8
  start-page: 620
  year: 2019
  ident: B4
  article-title: Anti-atherosclerotic effect of Hibiscus leaf polyphenols against tumor necrosis factor-alpha-induced abnormal vascular smooth muscle cell migration and proliferation
  publication-title: Antioxidants
  doi: 10.3390/antiox8120620
– volume: 2
  start-page: 51
  year: 2013
  ident: B42
  article-title: Bibliometric and content analysis of the Cochrane Complementary Medicine Field specialized register of controlled trials
  publication-title: Syst. Rev.
  doi: 10.1186/2046-4053-2-51
– volume: 75
  start-page: 45
  year: 2020
  ident: B44
  article-title: Berberine attenuates cholesterol accumulation in macrophage foam cells by suppressing AP-1 activity and activation of the Nrf2/HO-1 pathway
  publication-title: J. Cardiovasc. Pharmacol.
  doi: 10.1097/FJC.0000000000000769
– volume: 104
  start-page: 1179
  year: 2009
  ident: B28
  article-title: The chemokine network in relation to infarct size and left ventricular remodeling following acute myocardial infarction
  publication-title: Am. J. Cardiol.
  doi: 10.1016/j.amjcard.2009.06.028
– volume: 122
  start-page: 421
  year: 2012
  ident: B23
  article-title: Activator protein-1 (AP-1) signalling in human atherosclerosis: Results of a systematic evaluation and intervention study
  publication-title: Clin. Sci.
  doi: 10.1042/CS20110234
– volume: 9
  start-page: 911861
  year: 2022
  ident: B6
  article-title: Advances and trends in omics technology development
  publication-title: Front. Med.
  doi: 10.3389/fmed.2022.911861
– volume: 25
  start-page: 119
  year: 2019
  ident: B15
  article-title: 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes the Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC)
  publication-title: Russ. J. Cardiol.
  doi: 10.15829/1560-4071-2020-2-3757
– volume: 91
  start-page: e12840
  year: 2020
  ident: B8
  article-title: IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation
  publication-title: Scand. J. Immunol.
  doi: 10.1111/sji.12840
– volume: 15
  start-page: 2518
  year: 2001
  ident: B39
  article-title: Transcription activator protein 1 (AP-1) mediates NO-induced apoptosis of adult cardiomyocytes
  publication-title: FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol.
  doi: 10.1096/fj.01-0353fje
– volume: 12
  start-page: 25
  year: 2012
  ident: B46
  article-title: Toxicological insight from AP-1 silencing study on proliferation, migration, and dedifferentiation of rat vascular smooth muscle cell
  publication-title: Cardiovasc. Toxicol.
  doi: 10.1007/s12012-011-9135-x
SSID ssj0000399364
Score 2.3832517
Snippet Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD)....
According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD). This study...
Background: According to the theory of traditional Chinese medicine, phlegm and blood stasis (PBS) is the pathological basis for coronary heart disease (CHD)....
SourceID doaj
pubmedcentral
proquest
pubmed
crossref
SourceType Open Website
Open Access Repository
Aggregation Database
Index Database
Enrichment Source
StartPage 1022627
SubjectTerms coronary heart disease
metabolomics
Pharmacology
phlegm and blood stasis syndrome
proteomics
RNA-seq
traditional Chinese medicine
SummonAdditionalLinks – databaseName: DOAJ Directory of Open Access Journals
  dbid: DOA
  link: http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrZ3NbtQwEIAt1BMXxD-hgAYJ9UKjbhLHjo-AqCokUA-t1FvkTGx2pTa76qaH3PYduCF4uX0SZpxsuosQXLhFiaM4mUlmJp75Rog3clKRV6EwTrCexNKiiq0qatpKkEyKsT60e_v8RZ2cy08X-cVWqy_OCevxwP2DO_IakyxHclvQSCSLZWqXGSQr6Lx0xvHXl8zYVjAVvsFsd5Xsq2QoCjNHfjG1zP9MU6YVpIrbyGxZogDs_5OX-Xuy5Jb1Ob4v7g1uI7zrp_tA3HHNQ3Fw2nOnu0M4uy2jWh7CAZzeEqm7R-L7mGkH5O_BevWD1MatV98CpWHW0NaVa0kduCB5vfoJTZ8cDnMPyIgDe90Bt75uYVjQAf5_C4vppft6BbapISTAA7may9kSNhgEqDoYeRQ1hOTFmMugaUhPxe0ei_Pjj2cfTuKhKUOMUhVtnEmUusidMj4pKl04XSgbEDveq7TyRhuN3vgqnbicYfbSpxQSVlJXCnNpsydir5k37pkAimbyymXaIKI0SMcKy92PFUpUdS0jkWwEVOJALOfGGZclRS4s1DIItWShloNQI_F2PGfR8zr-Ovo9y30cyaztsIM0sBw0sPyXBkbi9UZrSno3ecHFNm5-syxTTXfIzSaLSDzttWi8VKbyNJNmEgm9o187c9k90symgf9NIaDUKnn-Pya_L-7yA-HqytS8EHvt9Y17SW5WW70Kb9Qvn5ku1A
  priority: 102
  providerName: Directory of Open Access Journals
Title Exploring the “gene–protein–metabolite” network of coronary heart disease with phlegm and blood stasis syndrome by integrated multi-omics strategy
URI https://www.ncbi.nlm.nih.gov/pubmed/36523490
https://www.proquest.com/docview/2755576938
https://pubmed.ncbi.nlm.nih.gov/PMC9744761
https://doaj.org/article/f7c135c507c94c0089de39c554ef4e9e
Volume 13
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
journalDatabaseRights – providerCode: PRVAFT
  databaseName: Open Access Digital Library
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: KQ8
  dateStart: 20100101
  isFulltext: true
  titleUrlDefault: http://grweb.coalliance.org/oadl/oadl.html
  providerName: Colorado Alliance of Research Libraries
– providerCode: PRVAON
  databaseName: DOAJ Directory of Open Access Journals
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: DOA
  dateStart: 20100101
  isFulltext: true
  titleUrlDefault: https://www.doaj.org/
  providerName: Directory of Open Access Journals
– providerCode: PRVBFR
  databaseName: Free Medical Journals
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: DIK
  dateStart: 20100101
  isFulltext: true
  titleUrlDefault: http://www.freemedicaljournals.com
  providerName: Flying Publisher
– providerCode: PRVFQY
  databaseName: GFMER Free Medical Journals
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: GX1
  dateStart: 0
  isFulltext: true
  titleUrlDefault: http://www.gfmer.ch/Medical_journals/Free_medical.php
  providerName: Geneva Foundation for Medical Education and Research
– providerCode: PRVHPJ
  databaseName: ROAD: Directory of Open Access Scholarly Resources
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: M~E
  dateStart: 20100101
  isFulltext: true
  titleUrlDefault: https://road.issn.org
  providerName: ISSN International Centre
– providerCode: PRVAQN
  databaseName: PubMed Central
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 99991231
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: RPM
  dateStart: 20100101
  isFulltext: true
  titleUrlDefault: https://www.ncbi.nlm.nih.gov/pmc/
  providerName: National Library of Medicine
– providerCode: PRVFZP
  databaseName: Scholars Portal Journals: Open Access
  customDbUrl:
  eissn: 1663-9812
  dateEnd: 20250131
  omitProxy: true
  ssIdentifier: ssj0000399364
  issn: 1663-9812
  databaseCode: M48
  dateStart: 20101201
  isFulltext: true
  titleUrlDefault: http://journals.scholarsportal.info
  providerName: Scholars Portal
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1La9wwEBZpCiWX0ne3jzANJZfGzdqWJetQSlsaQiElhyzkZuyxlF3YeLe7DtR_o7-4M_Ij2ZL0ZmxZtjwjzzfSzDdCvJfjglCFwiDEchzIHFWQq7SkoxDJpJjc-XJvJz_V8UT-OE_Ot0Rf7qj7gOtbXTuuJzVZzT_-_tV8pgn_iT1OsreHbjnNmdozipiIIFKRvifuk2WKWMtPOrjv_8xsjT2jVEiGNjBk3No8mju62REPYkWemuQ_9g2z5dn9b4Ok_0ZW3jBVR4_Eww5jwpdWKR6LLVs9EfunLUl1cwBn1zlX6wPYh9Nr-urmqfgzhOUBgUPYIw2zgadzmFXBpa1JazhveQ-qNoIcFg6QeRDyVQNcH7uGbtcHeJEXltO5vbiEvCrBR8kD4dH1bA09VwIUDQykFSX4CMeAc6WpSUud2zwTk6PvZ9-Og65yQ4BSpXUQS5Q6TawyLkwLnVqdqtzz8DinosIZbTQ644pobBNmvJcuIr-xkLpQmMg8fi62q0VlXwoglycpbKwNIkqDdC3NuUSyQomqLOVIhL1gMuxozbm6xjwj94blmnm5ZizXrJPrSHwY7lm2pB7_bf2V5T20ZEJuf2Kxusi6-Z05jWGcIKFrNBIJWJnSxgYJrFknrbEj8a7XlowmMO_K5JVdXK2zSNMIuSJlOhIvWu0ZHtVr30joDb3aeJfNK9Vs6knCyU-UWoWv7uzztdjhUXJeZWTeiO16dWXfEsCqi12_MLHr585fbkQlcw
linkProvider Scholars Portal
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Exploring+the+%22gene-protein-metabolite%22+network+of+coronary+heart+disease+with+phlegm+and+blood+stasis+syndrome+by+integrated+multi-omics+strategy&rft.jtitle=Frontiers+in+pharmacology&rft.au=Yang%2C+Guang&rft.au=Zhou%2C+Siyuan&rft.au=He%2C+Haoqiang&rft.au=Shen%2C+Zinuo&rft.date=2022-11-29&rft.issn=1663-9812&rft.eissn=1663-9812&rft.volume=13&rft.spage=1022627&rft_id=info:doi/10.3389%2Ffphar.2022.1022627&rft_id=info%3Apmid%2F36523490&rft.externalDocID=36523490
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1663-9812&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1663-9812&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1663-9812&client=summon