ObjectiveTo investigate the effects of Huangqi Jianzhongtang （HQJZ） on macrophage polarization and fat consumption in cancer cachexia （CC） mice. MethodsUltra-performance liquid chromatography-quadrupole/electrostatic field Orbitrap high-resolution mass spectrometry （UPLC-Q-Orbitrap HRMS） was used to control the quality of HQJZ. （1） In vitro experiment： HQJZ-containing serum was prepared， and the optimal concentration was determined by cytotoxicity assay. Mouse monocyte-derived macrophages （RAW264.7） were cultured and randomly divided into six groups， including a blank group， a classically activated macrophages （M1） group， an alternatively activated macrophages （M2） group， a HQJZ + blank group， a HQJZ+M1 group， and a HQJZ + M2 group. The relative expression of macrophage marker genes CD86， inducible nitric oxide synthase （iNOS）， CD206， and arginase-1 （Arg1） was detected by real-time quantitative polymerase chain reaction （Real-time PCR ）. （2） In vivo experiment： Thirty-two BALB/c mice were randomly divided into a control group， a model group， a medroxyprogesterone acetate （MPA） group， and a HQJZ group. Except for the control group， the other mice were injected with CT-26 colon cancer cells to establish a CC model. Mice in the MPA and HQJZ groups were given MPA （0.13 g·kg^-1·d^-1） or HQJZ （13.13 g·kg^-1·d^-1） by gavage， respectively， while mice in the control and model groups were given an equal volume of saline by gavage， with interventions continued for 10 d. Real-time PCR was used to detect the expression of macrophage markers （iNOS， Arg1， CD86， CD206） and fat browning-related genes uncoupling protein 1 （UCP1） and peroxisome proliferator-activated receptor γ （PPARγ） in epididymal adipose tissue. Western blot （WB） was used to detect protein expression levels of UCP1 and PPARγ. Micro-computed tomography （micro-CT） was used to measure residual fat volume， and hematoxylin-eosin （HE） staining was used to assess fat browning and calculate pathological scores. ResultsIn vitro， the dominant effective concentration of HQJZ-containing serum was 12.5%. Real-time PCR results showed that， compared with the blank group， Arg1 expression decreased in the HQJZ+blank group （P<0.05）， CD206 showed a downward trend without statistical significance， while iNOS and CD86 expression were significantly increased （P<0.05）. Compared with the M1 group， Arg1 and CD206 expression decreased in the HQJZ+M1 group （P<0.05）. Compared with the M2 group， CD206 expression decreased in the HQJZ+M2 group （P<0.05）， CD86 expression increased significantly （P<0.01）. In vivo， Real-time PCR results showed that， compared with the control group， CD86 and CD206 expression levels were significantly increased in the model group （P<0.01）. Compared with the model group， CD206 expression in the MPA group was significantly decreased （P<0.01）. In the HQJZ group， CD206 was significantly decreased （P<0.01）. WB results showed that， compared with the model group， protein expression of UCP1 and PPARγ was significantly reduced in the HQJZ group （P<0.05， P<0.01）. micro-CT results showed that the total white fat volume in the HQJZ group was greater than that in the model group （P<0.05）. HE staining results showed that pathological scores in the HQJZ group were lower than those in the model group （P<0.05）. ConclusionHQJZ may inhibit white adipose tissue browning by promoting macrophage M1 polarization and suppressing M2 polarization， thereby delaying fat consumption in CC mice.

Metastasis in gastric cancer is a key factor contributing to poor prognosis. Its pathogenesis is complex， characterized by a combination of underlying deficiency and superficial excess， cold and heat in complexity， and stagnation in collateral Conventional aggressive treatment methods tend to exacerbate the depletion of healthy Qi and Zang-Fu organ dysfunctions. The harmonizing method in traditional Chinese medicine （TCM） emphasizes holistic regulation and reinforcing healthy Qi while expelling pathogenic factors. The blood harmonizing method is grounded in the core TCM theory of blood vessel transmission and Zang-Fu organ accumulation of cancerous toxins. It closely addresses the essence of metastasis-where cancerous toxins spread through the bloodstream and accumulate in the collaterals-thereby providing a unique and feasible diagnostic and therapeutic approach for clinical intervention in gastric cancer metastasis. This paper systematically reviews relevant TCM theories such as transmission and Zang-Fu organ accumulation of cancerous toxins and accumulation-gathering and provides an in-depth explanation of the core pathogenesis of gastric cancer metastasis. Specifically， cancerous toxins circulate throughout the body via the blood vessels and accumulate in the collaterals of target organs such as the liver， peritoneum， lymph nodes， and lungs. The occurrence and development of this process are consistently centered on the key mechanism of disharmony in blood-related syndromes. On this basis， the paper explicitly proposes three major therapeutic approaches centered on harmonizing the blood. The first is harmonizing the blood to restore ascending and descending functions， thereby invigorating the spleen and regulating the middle energizer to restore the mediating function of the middle energizer and block the generation of phlegm and blood stasis at the root. The second is harmonizing the blood to balance cold and heat， using pungent herbs to open and bitter herbs to descend to harmonize the Yin-Yang balance and improve the homeostasis of the tumor microenvironment. The third is harmonizing the blood to unblock collaterals and resolve stasis， thereby gradually dissipating stasis and nodules， gently clearing obstructions in the collaterals， and breaking the critical link of collateral stagnation forming masses caused by metastasis. The article further summarizes modern pharmacological research findings on representative formulas such as Banxia Xiexintang， Weichang'an， Yangzheng Sanjie decoction， and Sijunzitang， confirming that they can inhibit the proliferation， invasion， and metastasis of gastric cancer cells， as well as epithelial-mesenchymal transition， through multiple targets and pathways， to regulate angiogenesis and lymphangiogenesis， modulate the immune microenvironment， and induce tumor cell apoptosis and ferroptosis， thereby blocking the metastasis process at multiple levels. This paper discusses the theoretical basis， pathogenetic mechanisms， therapeutic systems， and modern mechanisms of the blood harmonizing method for the diagnosis and treatment of gastric cancer metastasis. It fully embodies the TCM principles of targeting balance， reinforcing healthy Qi without aiding the pathogen， and eliminating the pathogen without harming the healthy Qi， providing a solid theoretical foundation and practical pharmacological references for the prevention and treatment of gastric cancer metastasis with integrated traditional Chinese and Western medicine in clinical practice.

ObjectiveTo investigate the synergistic promotion of malignant phenotypes in gastric cancer cells by tumor-associated bone marrow mesenchymal stem cells （TA-BMSCs） and polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） through crosstalk， and the intervention mechanism of the intestinal absorption solution containing Banxia Xiexintang （BXT）. MethodsGastric cancer MFC cells were treated with conditioned medium （co-culture-CM） prepared from a co-culture system of TA-BMSCs and PMN-MDSCs. Groups included control， co-culture-CM model， stromal cell-derived factor 1 （SDF1） inhibitor （LY2510924）， α₄β₁ inhibitor （BIO5192）， dual inhibitor combination， and different concentrations （55%， 70%， 85%） of BXT-containing intestinal absorption solutions. MFC cell proliferation， migration， invasion， and apoptosis were assessed via cell counting kit-8 （CCK-8） assay， wound-healing assay， Transwell assay， and flow cytometry. The SDF-1， α₄β₁， matrix metalloproteinase-9 （MMP-9）， and vascular endothelial growth factor A （VEGFA） levels in culture supernatants， along with the protein levels of intracellular macrophage migration inhibitory factor （MIF）， chemokine （C-X-C motif） receptor 4 （CXCR4）， CD106， MMP-9， and VEGFA in MFC cells， were measured by enzyme-linked immunosorbent assay （ELISA） and Western blot， respectively. ResultsCompared with the control group， co-culture-CM promoted the proliferation， migration， and invasion of MFC cells （P<0.01）， elevated the levels of SDF-1， α₄β₁， MMP-9， and VEGFA （P<0.01）， and upregulated the protein levels of MIF （P<0.05）， MMP-9 （P<0.01）， and VEGFA （P<0.01）. Compared with co-culture-CM， BXT-containing intestinal absorption solutions at various concentrations significantly reversed the phenotypic effects on cells， inhibited malignant phenotypes， lowered the levels of MMP-9 and SDF1， and reduced the expression of proteins in the crosstalk axis. Compared with the SDF1+α₄β₁ inhibitor group， the SDF1 inhibitor group and the α₄β₁ inhibitor group showed no differences in the inhibition of proliferation， scratch healing， and cytokine levels. The SDF1 inhibitor increased the apoptosis rate and downregulated the protein levels of MIF and CD106， while the α₄β₁ inhibitor increased the number of migrated cells and the expression of various proteins. Compared with the SDF1 inhibitor group， the α₄β₁ inhibitor group showed reduced inhibitory effect on proliferation， decreased apoptosis rate， increased number of invasive cells， decreased α₄β₁ content， and increased expression of various proteins （P<0.01）. The 55%， 70%， and 85% intestinal absorption solutions increased the inhibitory effect on proliferation， decreased the number of invasive cells， and increased the apoptosis rate （P<0.01）. The 55% BXT-containing intestinal absorption solution group showed increased wound healing rate and upregulated protein levels of VEGFA， CD106， and MMP-9 （P<0.05）. The 70% intestinal absorption solution group showed upregulated protein level of MIF （P<0.05）， and the 85% intestinal absorption solution group showed upregulated protein level of VEGFA （P<0.01） and downregulated the protein level of CXCR4 （P<0.01）. ConclusionTA-BMSCs and PMN-MDSCs synergistically activate the MIF/SDF-1/CXCR4 and MMP-9/α₄β₁/CD106 axes through crosstalk， significantly enhancing gastric cancer cell invasion and migration. BXT-containing intestinal absorption fluid effectively inhibits the malignant progression of gastric cancer cells by multi-targeted intervention in this crosstalk process.

ObjectiveTo explore whether the intestinal absorption solution containing Banxia Xiexintang （BXT） can inhibit the invasion and migration of gastric cancer cells by interfering with the stromal cell-derived factor 1 （SDF1）-CXC chemokine receptor 4 （CXCR4） axis in tumor-associated bone marrow mesenchymal stem cells （TA-BMSCs）. MethodsThe intestinal absorption solution containing BXT was prepared， and the optimal intervention concentration and duration for MFC cells were determined through the cell counting kit-8 （CCK-8） assay. A co-culture system was established comprising TA-BMSCs conditioned medium （TA-BMSCs-CM） and gastric cancer MFC cells. The experiment was conducted with a blank control group， a TA-BMSCs-CM group， an SDF1 inhibitor （LY2510924） group， and intervention groups with varying concentrations （55%， 70%， 85%） of the intestinal absorption solution containing BXT. Cell proliferation was assessed by the CCK-8 assay. Horizontal and vertical cell migration were evaluated via scratch and Transwell assays， respectively. Cell invasion was examined by a Transwell assay with Matrigel. Cell apoptosis was detected by flow cytometry. The levels of factors such as SDF1， matrix metalloproteinase-9 （MMP-9）， and vascular endothelial growth factor A （VEGFA）， as well as the protein levels of macrophage migration inhibitory factor （MIF）， CXCR4， VEGFA， and MMP-9， were quantified by ELISA and Western blot， respectively. ResultsThe CCK-8 assay results indicated that compared with the 24 h intervention， the 48 h interventions with all concentrations of the intestinal absorption solution containing BXT increased the inhibition rate on MFC cells （P<0.01）. The half-maximal inhibitory concentration （IC₅₀） of the intestinal absorption solution containing BXT at the time point of 48 h was 68.51%， and subsequent intervention concentrations were selected as 55%， 70%， and 85%. Compared with the TA-BMSCs-CM group， the intestinal absorption solution containing BXT （particularly at concentrations of 70% 85%） suppressed the proliferation， migration， and invasion of MFC cells， promoted the cell apoptosis （P<0.05， P<0.01）， decreased the levels of SDF1， MMP-9， and VEGFA， and downregulated the protein levels of MIF， CXCR4， VEGFA， and MMP-9 （P<0.05， P<0.01）. The inhibitory effects of the intestinal absorption solution containing BXT were comparable to or superior to those of the SDF1 inhibitor （P<0.01）. ConclusionThe intestinal absorption solution containing BXT can inhibit the invasion and migration of gastric cancer cells by interfering with the SDF1-CXCR4 axis in TA-BMSCs. The underlying mechanism may involve the regulation of the MIF/SDF1/CXCR4 signaling pathway and its downstream effector molecules.

Metastasis in gastric cancer is a key factor contributing to poor prognosis. Its pathogenesis is complex， characterized by a combination of underlying deficiency and superficial excess， cold and heat in complexity， and stagnation in collateral Conventional aggressive treatment methods tend to exacerbate the depletion of healthy Qi and Zang-Fu organ dysfunctions. The harmonizing method in traditional Chinese medicine （TCM） emphasizes holistic regulation and reinforcing healthy Qi while expelling pathogenic factors. The blood harmonizing method is grounded in the core TCM theory of blood vessel transmission and Zang-Fu organ accumulation of cancerous toxins. It closely addresses the essence of metastasis-where cancerous toxins spread through the bloodstream and accumulate in the collaterals-thereby providing a unique and feasible diagnostic and therapeutic approach for clinical intervention in gastric cancer metastasis. This paper systematically reviews relevant TCM theories such as transmission and Zang-Fu organ accumulation of cancerous toxins and accumulation-gathering and provides an in-depth explanation of the core pathogenesis of gastric cancer metastasis. Specifically， cancerous toxins circulate throughout the body via the blood vessels and accumulate in the collaterals of target organs such as the liver， peritoneum， lymph nodes， and lungs. The occurrence and development of this process are consistently centered on the key mechanism of disharmony in blood-related syndromes. On this basis， the paper explicitly proposes three major therapeutic approaches centered on harmonizing the blood. The first is harmonizing the blood to restore ascending and descending functions， thereby invigorating the spleen and regulating the middle energizer to restore the mediating function of the middle energizer and block the generation of phlegm and blood stasis at the root. The second is harmonizing the blood to balance cold and heat， using pungent herbs to open and bitter herbs to descend to harmonize the Yin-Yang balance and improve the homeostasis of the tumor microenvironment. The third is harmonizing the blood to unblock collaterals and resolve stasis， thereby gradually dissipating stasis and nodules， gently clearing obstructions in the collaterals， and breaking the critical link of collateral stagnation forming masses caused by metastasis. The article further summarizes modern pharmacological research findings on representative formulas such as Banxia Xiexintang， Weichang'an， Yangzheng Sanjie decoction， and Sijunzitang， confirming that they can inhibit the proliferation， invasion， and metastasis of gastric cancer cells， as well as epithelial-mesenchymal transition， through multiple targets and pathways， to regulate angiogenesis and lymphangiogenesis， modulate the immune microenvironment， and induce tumor cell apoptosis and ferroptosis， thereby blocking the metastasis process at multiple levels. This paper discusses the theoretical basis， pathogenetic mechanisms， therapeutic systems， and modern mechanisms of the blood harmonizing method for the diagnosis and treatment of gastric cancer metastasis. It fully embodies the TCM principles of targeting balance， reinforcing healthy Qi without aiding the pathogen， and eliminating the pathogen without harming the healthy Qi， providing a solid theoretical foundation and practical pharmacological references for the prevention and treatment of gastric cancer metastasis with integrated traditional Chinese and Western medicine in clinical practice.

ObjectiveTo investigate the synergistic promotion of malignant phenotypes in gastric cancer cells by tumor-associated bone marrow mesenchymal stem cells （TA-BMSCs） and polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） through crosstalk， and the intervention mechanism of the intestinal absorption solution containing Banxia Xiexintang （BXT）. MethodsGastric cancer MFC cells were treated with conditioned medium （co-culture-CM） prepared from a co-culture system of TA-BMSCs and PMN-MDSCs. Groups included control， co-culture-CM model， stromal cell-derived factor 1 （SDF1） inhibitor （LY2510924）， α₄β₁ inhibitor （BIO5192）， dual inhibitor combination， and different concentrations （55%， 70%， 85%） of BXT-containing intestinal absorption solutions. MFC cell proliferation， migration， invasion， and apoptosis were assessed via cell counting kit-8 （CCK-8） assay， wound-healing assay， Transwell assay， and flow cytometry. The SDF-1， α₄β₁， matrix metalloproteinase-9 （MMP-9）， and vascular endothelial growth factor A （VEGFA） levels in culture supernatants， along with the protein levels of intracellular macrophage migration inhibitory factor （MIF）， chemokine （C-X-C motif） receptor 4 （CXCR4）， CD106， MMP-9， and VEGFA in MFC cells， were measured by enzyme-linked immunosorbent assay （ELISA） and Western blot， respectively. ResultsCompared with the control group， co-culture-CM promoted the proliferation， migration， and invasion of MFC cells （P<0.01）， elevated the levels of SDF-1， α₄β₁， MMP-9， and VEGFA （P<0.01）， and upregulated the protein levels of MIF （P<0.05）， MMP-9 （P<0.01）， and VEGFA （P<0.01）. Compared with co-culture-CM， BXT-containing intestinal absorption solutions at various concentrations significantly reversed the phenotypic effects on cells， inhibited malignant phenotypes， lowered the levels of MMP-9 and SDF1， and reduced the expression of proteins in the crosstalk axis. Compared with the SDF1+α₄β₁ inhibitor group， the SDF1 inhibitor group and the α₄β₁ inhibitor group showed no differences in the inhibition of proliferation， scratch healing， and cytokine levels. The SDF1 inhibitor increased the apoptosis rate and downregulated the protein levels of MIF and CD106， while the α₄β₁ inhibitor increased the number of migrated cells and the expression of various proteins. Compared with the SDF1 inhibitor group， the α₄β₁ inhibitor group showed reduced inhibitory effect on proliferation， decreased apoptosis rate， increased number of invasive cells， decreased α₄β₁ content， and increased expression of various proteins （P<0.01）. The 55%， 70%， and 85% intestinal absorption solutions increased the inhibitory effect on proliferation， decreased the number of invasive cells， and increased the apoptosis rate （P<0.01）. The 55% BXT-containing intestinal absorption solution group showed increased wound healing rate and upregulated protein levels of VEGFA， CD106， and MMP-9 （P<0.05）. The 70% intestinal absorption solution group showed upregulated protein level of MIF （P<0.05）， and the 85% intestinal absorption solution group showed upregulated protein level of VEGFA （P<0.01） and downregulated the protein level of CXCR4 （P<0.01）. ConclusionTA-BMSCs and PMN-MDSCs synergistically activate the MIF/SDF-1/CXCR4 and MMP-9/α₄β₁/CD106 axes through crosstalk， significantly enhancing gastric cancer cell invasion and migration. BXT-containing intestinal absorption fluid effectively inhibits the malignant progression of gastric cancer cells by multi-targeted intervention in this crosstalk process.

ObjectiveTo explore whether the intestinal absorption solution containing Banxia Xiexintang （BXT） can inhibit the invasion and migration of gastric cancer cells by interfering with the stromal cell-derived factor 1 （SDF1）-CXC chemokine receptor 4 （CXCR4） axis in tumor-associated bone marrow mesenchymal stem cells （TA-BMSCs）. MethodsThe intestinal absorption solution containing BXT was prepared， and the optimal intervention concentration and duration for MFC cells were determined through the cell counting kit-8 （CCK-8） assay. A co-culture system was established comprising TA-BMSCs conditioned medium （TA-BMSCs-CM） and gastric cancer MFC cells. The experiment was conducted with a blank control group， a TA-BMSCs-CM group， an SDF1 inhibitor （LY2510924） group， and intervention groups with varying concentrations （55%， 70%， 85%） of the intestinal absorption solution containing BXT. Cell proliferation was assessed by the CCK-8 assay. Horizontal and vertical cell migration were evaluated via scratch and Transwell assays， respectively. Cell invasion was examined by a Transwell assay with Matrigel. Cell apoptosis was detected by flow cytometry. The levels of factors such as SDF1， matrix metalloproteinase-9 （MMP-9）， and vascular endothelial growth factor A （VEGFA）， as well as the protein levels of macrophage migration inhibitory factor （MIF）， CXCR4， VEGFA， and MMP-9， were quantified by ELISA and Western blot， respectively. ResultsThe CCK-8 assay results indicated that compared with the 24 h intervention， the 48 h interventions with all concentrations of the intestinal absorption solution containing BXT increased the inhibition rate on MFC cells （P<0.01）. The half-maximal inhibitory concentration （IC₅₀） of the intestinal absorption solution containing BXT at the time point of 48 h was 68.51%， and subsequent intervention concentrations were selected as 55%， 70%， and 85%. Compared with the TA-BMSCs-CM group， the intestinal absorption solution containing BXT （particularly at concentrations of 70% 85%） suppressed the proliferation， migration， and invasion of MFC cells， promoted the cell apoptosis （P<0.05， P<0.01）， decreased the levels of SDF1， MMP-9， and VEGFA， and downregulated the protein levels of MIF， CXCR4， VEGFA， and MMP-9 （P<0.05， P<0.01）. The inhibitory effects of the intestinal absorption solution containing BXT were comparable to or superior to those of the SDF1 inhibitor （P<0.01）. ConclusionThe intestinal absorption solution containing BXT can inhibit the invasion and migration of gastric cancer cells by interfering with the SDF1-CXCR4 axis in TA-BMSCs. The underlying mechanism may involve the regulation of the MIF/SDF1/CXCR4 signaling pathway and its downstream effector molecules.

OBJECTIVE: To study incident and clinical characteristics of the coronary microcirculation dysfunction (CMD) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) by myocardial contrast echocardiography (MCE) and to explore the predictive value of CMD for in-hospital acute heart failure event. METHODS: One hundred and forty five patients with AMI who had received PCI and completed MCE during hospitalization in Peking University People' s Hospital from November 2015 to July 2021 were enrolled in our study. The patients were divided into CMD group and normal group according to the coronary microcirculation status detected by MCE. Clinical data and MCE data of the two groups were collected and analyzed. The acute heart failure event during hospitalization was described. A multivariate Logistic regression model was built to analyze the risk of acute heart failure in patients with CMD. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of CMD in predicting acute heart failure event. RESULTS: CMD detected by MCE occurred in 87 patients (60%). Compared with normal group, patients with CMD had higher troponin I (TnI) peak level [52.8 (8.1, 84.0) μg/L vs. 18.9 (5.7, 56.1) μg/L, P=0.005], poorer Killip grade on admission (P=0.030), different culprit vessel (P < 0.001) and more patients had thrombolysis in myocardial infarction (TIMI) flow pre-PCI less than grade 3 in culprit vessel (65.1% vs. 43.1%, P=0.025). Meanwhile, patients with CMD had poorer left ventricular ejection fraction (LVEF) [52% (43%, 58%) vs. 61% (54%, 66%)], poorer global longitudinal strain (GLS) [-11.2% (-8.7%, -14.0%) vs.-13.9% (-10.8%, -17.0%)] and worse wall motion score index (WMSI) (1.58±0.36 vs. 1.25± 0.24) (P all < 0.001). Acute left heart failure happened in 13.8% of the CMD patients, which were significant higher than that in the patients with normal coronary microcirculation perfusion (1.7%, P=0.013). After correcting for the culprit vessel, the TIMI flow pre-PCI in the culprit vessel and the peak TnI value, the risk of acute left heart failure in the patients with CMD was still high (OR=9.120, 95%CI: 1.152-72.192, P=0.036). The area under ROC curve (AUC) was 0.677 (95%CI: 0.551-0.804, P=0.035). CONCLUSION The incidence of CMD detected by MCE in patients with AMI post-PCI was 60%. Patients with CMD have a higher risk of acute left heart failure during hospitalization.
Humans ; Heart Failure/physiopathology* ; Microcirculation ; Percutaneous Coronary Intervention/adverse effects* ; Myocardial Infarction/complications* ; Male ; Female ; Hospitalization ; Middle Aged ; Aged ; Echocardiography ; Coronary Circulation ; Predictive Value of Tests ; Troponin I/blood*

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the"therapeutic module"of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.