This study aims to explore the mechanism of Jiaotai Pills in treating depression based on metabolomics and network pharmacology. The chemical constituents of Jiaotai Pills were identified by UHPLC-Orbitrap Exploris 480, and the targets of Jiaotai Pills and depression were retrieved from online databases. STRING and Cytoscape 3.7.2 were used to construct the protein-protein interaction network of core targets of Jiaotai Pills in treating depression and the "compound-target-pathway" network. DAVID was used for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses of the core targets. The mouse model of depression was established with chronic unpredictable mild stress(CUMS) and treated with different doses of Jiaotai Pills. The behavioral changes and pathological changes in the hippocampus were observed. UHPLC-Orbitrap Exploris 120 was used for metabolic profiling of the serum, from which the differential metabolites and related metabolic pathways were screened. A "metabolite-reaction-enzyme-gene" network was constructed for the integrated analysis of metabolomics and network pharmacology. A total of 34 chemical components of Jiaotai Pills were identified, and 143 core targets of Jiaotai Pills in treating depression were predicted, which were mainly involved in the arginine and proline, sphingolipid, and neurotrophin metabolism signaling pathways. The results of animal experiments showed that Jiaotai Pills alleviated the depression behaviors and pathological changes in the hippocampus of the mouse model of CUMS-induced depression. In addition, Jiaotai Pills reversed the levels of 32 metabolites involved in various pathways such as arginine and proline metabolism, sphingolipid metabolism, and porphyrin metabolism in the serum of model mice. The integrated analysis showed that arginine and proline metabolism, cysteine and methionine metabolism, and porphyrin metabolism might be the key pathways in the treatment of depression with Jiaotai Pills. In conclusion, metabolomics combined with network pharmacology clarifies the antidepressant mechanism of Jiaotai Pills, which may provide a basis for the clinical application of Jiaotai Pills in treating depression.
Animals ; Drugs, Chinese Herbal/chemistry* ; Depression/genetics* ; Mice ; Network Pharmacology ; Metabolomics ; Male ; Disease Models, Animal ; Humans ; Protein Interaction Maps/drug effects* ; Antidepressive Agents

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

OBJECTIVE: To investigate changes of myeloid differentiation factor 2 (MD2) in inflammation-induced pain and acupuncture-mediated analgesia. METHODS: Mice were randomly divided into three groups by a random number table method: saline group (n=16), complete Freund's adjuvant (CFA) group (n=24) and CFA+electroacupuncture (EA) group (n=26). Inflammation-induced pain was modelled by injecting CFA to the plantar surface of the hind paw of mice and EA was applied to bilateral Zusanli (ST 36) to alleviate pain. Only mice in the CFA+EA group received EA treatment (30 min/d for 2 weeks) 24 h after modelling. Mice in the saline and CFA groups received sham EA. von-Frey test and Hargreaves test were used to assess the pain threshold. Brain and spinal tissues were collected for immunofluorescence staining or Western blotting to quantify changes of MD2 expression. RESULTS: CFA successfully induced plantar pain and EA significantly alleviated pain 3 days after modelling (P<0.01). Compared with the CFA group, the number of MD2⁺/c-fos⁺ neurons was significantly increased in the dorsal horn of the spinal cord 7 and 14 days after EA, especially in laminae I - II_o (P<0.01). The proportion of double positive cells to the number of c-fos positive cells and the mean fluorescence intensity of MD2 neurons were also significantly increased in laminae I - II_o (P<0.01). Western blotting showed that the level of MD2 was significantly decreased by EA only in the hippocampus on day 7 and 14 (both P<0.01) and no significant changes were observed in the cortex, thalamus, cerebellum, or the brainstem (P<0.05). Fluorescence staining showed significant decrease in the level of MD2 in periagueductal gray (PAG) and locus coeruleus (LC) after CFA injection on day 7 (P<0.01 for PAG, P<0.05 for LC) and EA significantly reversed this decrease (P<0.01 for PAG, P<0.05 for LC). CONCLUSION The unique changes of MD2 suggest that EA may exert the analgesic effect through modulating neuronal activities of the superficial laminae of the spinal cord and certain regions of the brain.
Animals ; Acupuncture Analgesia/methods* ; Male ; Central Nervous System/pathology* ; Freund's Adjuvant ; Mice ; Pain ; Proto-Oncogene Proteins c-fos/metabolism* ; Spinal Cord/metabolism* ; Mice, Inbred C57BL ; Electroacupuncture/methods* ; Inflammation/pathology*

This study aimed to investigate the effect of Jiaotai Pills on protein expression in the hippocampus of the rat model of chronic unpredictable mild stress(CUMS)-induced depression by quantitative proteomics and explore the anti-depression mechanism of Jiaotai Pills. The SD rats were randomized into control, model, Jiaotai Pills, and fluoxetine groups(n=8). Other groups except the control group were subjected to CUMS modeling for 4 weeks. After 4 weeks of continuous administration, the changes of behavior and pathological morphology of the hippocampal tissue were observed. Proteins were extracted from the hippocampal tissue, and bioinformatics analysis was performed for the differentially expressed proteins(DEPs) identified by quantitative proteomics. Western blot was employed to verify the key DEPs. The results showed that Jiaotai Pills significantly alleviated the depression behaviors and hippocampal histopathological changes in the rat model of CUMS-induced depression. A total of 5 412 proteins were identified in the hippocampus of rats, including 65 DEPs between the control group and the model group and 35 DEPs between the Jiaotai Pills group and the model group. There were 16 DEPs with the same trend in the Jiaotai Pills group and the control group, which were mainly involved in sphingolipid, AMPK, and dopaminergic synapse signaling pathways. The Western blot results of Ppp2r2b, Cers1, and Ndufv3 in the hippocampus were consistent with the results of proteomics. In conclusion, Jiaotai Pills may play an anti-depression role by modulating the levels of Ppp2r2b, Cers1, Ndufv3 and other proteins and regulating sphingolipid, AMPK, and dopaminergic synapse signaling pathways.
Rats ; Animals ; Rats, Sprague-Dawley ; Depression/drug therapy* ; AMP-Activated Protein Kinases/metabolism* ; Proteomics ; Hippocampus ; Stress, Psychological/metabolism* ; Sphingolipids/metabolism* ; Disease Models, Animal ; Drugs, Chinese Herbal

Although anti-thrombotic therapy has been successful for prevention of deaths from acute myocardial infarction (MI), by far, there are few preventive and therapeutic options for ischemic heart failure (IHF) after MI. Qi-Tai-Suan (QTS) is an oleanolic acid (OA) derivative which once underwent a clinical trial for treating hepatitis. In this study, we investigated the potential cardioprotective effect of QTS on IHF. IHF mouse model was constructed by coronary artery ligation in male C57BL/6J mice, and the protective effects of QTS on IHF were examined by echocardiography measurement, histological and TUNEL analysis, etc. We found that QTS exhibited promising cardioprotective effect on IHF. QTS treatment significantly improved cardiac function of IHF mice and the symptoms of heart failure. Notably, QTS had much better oral bioavailability (F = 41.91%) in mice than its parent drug OA, and took effects mainly as its original form. Mechanistically, QTS ameliorated ischemic heart failure likely through suppression of cardiac apoptosis, inflammation and fibrosis. Taken together, QTS holds great promise as a preventive and therapeutic agent for ischemic heart failure and related diseases.
Animals ; Apoptosis ; Fibrosis ; Heart Failure/drug therapy* ; Inflammation/drug therapy* ; Male ; Mice ; Mice, Inbred C57BL ; Myocardial Ischemia/pathology* ; Oleanolic Acid/pharmacology*

Objective To investigate the influence of long sea voyage working environment on the symbiotic microorganisms and their relationship with their hosts .Methods The periumbilical microbial sam-ples from the operating workers of long sea voyage before and after operation were collected .Then 16S rRNA V4 section amplification ,sequencing and whole metagenome shotgun high-throughput sequencing were per-formed .Moreover the bacterial community structure ,kinds and microorganism metabolic function change were analyzed .The peripheral blood was collected from the workers of long sea voyage operation and shore-based operation for conducting the blood routine analysis .Results After 105 d ocean sailing ,the diversity of perium-bilical microbial community in the workers with long sea voyage operation decreased and the relative abun-dance of Firmicutes increased ,w hile w hich of Proteobacteria decreased ;w hich of Staphylococcus increased , while which of Corynebacteria decreased ,the differences were statistically significant (P<0 .05) ,the relative a-bundance of pathogenic bacteria or conditional pathogenic bacteria ,especially Staphylococcus epidermidis and Staphylococcusaureus aureus ,increased significantly .T he functional gene analysis indicated that the expres-sion of periumbilical microbial infection related genes increased after the long sea voyage operation .Compared with shore-based operation workers ,the proportion of workers with peripheral blood lymphocytes abnormal elevation in the long sea voyage group increased significantly ,the difference was statistically significant (P<0 .05) .Conclusion The periumbilical skin symbiotic microorganisms may reflect the health conditions in the workers with long sea voyage operation .

Objective To analyze the risk factors related to in-hospital bleeding for patients with acute coronary syndrome (ACS).Methods Clinical and therapeutic data of 3807 patients who were registered with acute coronary syndrome in SINO-GRACE in China from March 2001 to December 2007 were reviewed.A total of 57 patients were grouped to bleeding group and 234 out of the remaining 3750 patients without bleeding were randomly chosen and served as non-bleeding group.Hemorrhage-related factors were screened and compared between the two groups.Unitary logistic regression analysis was performed to detect the possible factors related to hemorrhage.Factors with P ＜ 0.1 were further analyzed by stepwise regression method and multivariate conditional logistic regression analyses.Results (1) Age,history of coronary artery bypass graft (CABG),previous hemorrhage,renal failure and heart failure as well incidence of acute coronary syndrome were significantly higher in bleeding group than in non-bleeding group (all P ≤0.05).Patients were more often treated with clopidogrel and glycoprotein (GP) Ⅱ b/Ⅲ a receptor antagonist in bleeding group than in non-bleeding group.(2) Single factor logistic regression analysis showed that age ＞70 years,history of previous bleeding,renal failure,heart failure,clopidogrel and GP Ⅱ b/Ⅲ a receptor antagonists use,non-ST-segment elevation myocardial infarction,inferior wall,lateral myocardial infarction,CABG were risk factors for bleeding (all P ＜ 0.05).(3) Multivariate logistic regression analysis showed that history of renal failure (OR =19.77,95％ CI 4.38-89.18,P ＜ 0.01) and clopidogrel (OR =19.77,95％ CI 4.38-89.18,P ＜ 0.01) and GP Ⅱ b/Ⅲ a receptor antagonist (OR =343.57,95％ CI 40.39-999.99,P ＜ 0.01) use were the independent risk factors for bleeding.Conclusion Our results show that renal failure history and clopidogrel and GP Ⅱ b/Ⅲ a receptor antagonist use are independent risk factors for in-hospital bleeding in patients with acute coronary syndrome.

Objective To assess the relationship between pregnancy associated plasma protein-A (PAPP-A)and culprit coronary plaque morphology in patients with unstable angina(UA).Methods Sixtyeight UA patients undergoing diagnostic coronary angiography and intravascular ultrasound were included in this study.A sandwich enzyme-linked immunosorbent assay technique was used to assay the circulating PAPP-A.Plaque characteristics of culprit lesion were analyzed for UA patients with various PAPP-A levels.Results PAPP-A level was significantly higher in high-risk UA than in non-high-risk UA[(19.9±20.1)mIU/L vs.(6.9 ±5.7)mIU/L,P=0.002].Optimal threshold of PAPP-A to prediet high-risk UA was determined as 11.0 mIU/L with a sensitivity of 78.6%and a specificity of 77.5%.Patients with higher PAPP-A level(≥11.0 mIU/L)was associated with larger external elastic membrane cross-sectional area,plaque area and more plaque burden compared with patients with lower PAPP-A Ievel(all P<0.01).Positive remodeling,attenuated plaque and plaque rupture were significantly more often in patients with higher PAPP-A than in patients with lower PAPP-A level(all P<0.01).PAPP-A≥11.0 mIU/L(OR=5.921,P=0.014)and attenuated plaque(OR=7.541,P=0.038)were independent risk predictors for high-risk UA.Conclusions PAPP-A was associated with instability of culprit plaque in UA patients.PAPP-A≥11.0 mIU/L and attenuated plaque were independent predictors for high-risk UA.

BACKGROUNDThere are numerous articles on the endothelial progenitor cells (EPCs) in different disease conditions. However, the functional properties of EPCs in acute coronary syndrome (ACS) are still uncertain. Here we aimed to study the number and functions of EPCs in ACS patients.

METHODSPatients were enrolled with admitted ACS (n = 25) and another 25 gender-, age-, atherosclerotic risk factors-matched stable coronary artery disease (CAD) controls. EPCs were defined as CD34(+)/CD133(+)/VEGFR-2(+) and quantified by flow cytometry. Moreover, functional properties of EPCs including colony-forming unit (CFU), proliferation, migration as well as apoptosis were evaluated and compared between the two groups. Plasma matrix metalloproteinase-9 (MMP-9) was detected in all patients as well.

RESULTSThe two groups had similar medication and clinical characteristics on admission. The EPCs in ACS patients were more than 2.6 times that in stable CAD subjects (15.6 ± 2.7 vs. 6.0 ± 0.8/100 000 events, P < 0.01). CFU was not statistically different between the two groups (10.8 ± 2.9 vs. 8.2 ± 1.8, number/well, P > 0.05). Furthermore, EPCs isolated from ACS patients were significantly impaired in their proliferation (0.498 ± 0.035 vs. 0.895 ± 0.067, OD value, P < 0.01) and migration capacity (20.5 ± 3.4 vs. 30.7 ± 4.3, number/well, P < 0.01) compared with controls. Moreover, the apoptosis cell in cultured EPCs was drastically increased in ACS group ((18.3 ± 2.1)% vs. (7.8 ± 0.4)%, P < 0.01).

CONCLUSIONSPatients with ACS exhibited apparently increased circulating EPCs as well as cultured apoptosis percentage together with a remarkable impairment of proliferation and migration activities compared with stable CAD subjects.

Acute Coronary Syndrome ; metabolism ; pathology ; Apoptosis ; physiology ; Cell Movement ; physiology ; Cell Proliferation ; Cells, Cultured ; Endothelial Cells ; cytology ; metabolism ; Female ; Flow Cytometry ; Humans ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Middle Aged ; Stem Cells ; cytology ; metabolism

Objective Novel stents loaded with antibody against CD105 were analyzed for their potential to limit coronary neointima formation and to accelerate endothelialization by attracting activated endothelial cell. Methods Thirty Stents coated with antibody against CD105, thirty unloaded polymer, and thirty bare metal stents were deployed in 90 coronary arteries of 30 minipigs. Oral aspirin (300 mg before operation and 100 mg post operation) and clopidogrel (300 mg before operation and 75 mg post operation) were orally administrated. Coronary artery quantitative analysis was completed by coronary arteriography,the vascular endothelium changes were observed under scanning electron microscope and the vascular morphological changes were observed under light microscope 7 and 14 days after operation. Results Complete procedural and angiographic success was achieved in all 30 minipigs. There were no major adverse cardiac and cerebrovascular events. At 7 days, there was no difference for mean neointimal area and percent rea stenosis among various groups. At 14 days, endothelialization scores were significantly higher in the CD10S antibody-loaded stents and bare metal stents group than in sirolimus-eluting stents group (1.78 ± 0.49, 1. 50±0. 67 vs. 1. 08±0. 29, all P < 0. 05 ), mean percent area stenosis in the CD105 antibody-loaded stents, sirolimus-eluting stents group were less than that in bare metal stents group [ (23. 8± 4) % , (24. 2±2)% vs. (38.0 ±3)% , all P <0.05] ,mean angiographic late luminal loss in the CD105 antibody-loaded stents, sirolimus-eluting stents group were less than that in bare metal stents group [ (0. 29±0. 28) mm, (0. 28±0. 02) mm vs. (0.41±0. 01) mm, all P < 0. 05 ]. There was no difference for mean percent area stenosis in the CD105 antibody-loaded stents and sirolimus-eluting stents group. The mean neointimal area in the CD105 antibody-loaded stents,and sirolimus-elutingstents group were less than that in bare metal stents group [(0.88±0.08) mm2, (0. 89 ±0. 12mm)2 vs. ( 1. 00 ±0. 14) mm2 , all P<0.05] and there was no difference for the mean neointimal area in the CD105 antibody-loaded stents and sirolimus-eluting stents group. At 7 and 14 days, there was no difference for the injury score and the inflammation score among various groups, scanning electron microscopy evidenced enhanced endothelial coverage on CD105 antibody-loaded stents compared to sirolimus-eluting stents group. Conclusion Stent coated with antibody against CD105 could effectively reduce in-stent restenosis and accelerate endothelialization in th eminipigs.