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OBJECTIVE: To utilize vast genetic data to reveal the interplay between 41 systemic inflammatory factors and endometriosis. DESIGN: Bidirectional Mendelian randomization study. MAINS OUTCOME MEASURES: This study obtained believable genetic instrumental variables for systemic inflammatory factors. The effect of systemic inflammatory factors on different endometriosis phenotypes, and the effect of endometriosis on the concentrations of systemic inflammatory factors were investigated. RESULTS: In this mendelian randomization study, we found 20 causal relationships involving 18 systemic inflammatory factors and it was shown that Monocyte chemotactic protein-1, Macrophage inflammatory protein-1a, Granulocyte colony-stimulating factor, Macrophage migration inhibitory factor, Interleukin-4, Interleukin-5, Interleukin-8, Interleukin-9, Interleukin-12p70, Interleukin-16, and Interleukin-17 may be the upstream causes of endometriosis (P<0.05). Additionally, if the definition of exposure in the mendelian randomization was endometriosis, it could suggestively cause an increase in Eotaxin, cutaneous T-cell attracting chemokine, and Interferon gamma-induced protein 10 levels, and a decrease in growth-regulated oncogene-alpha, Interleukin-2 receptor, alpha subunit, platelet-derived growth factor BB, and Interleukin-18 (P<0.05). Reverse causality was not observed between a single systemic inflammatory factor and endometriosis. CONCLUSIONS: Our findings indicate that several systemic inflammatory factors may act as the initiator at the onset of endometriosis. Additionally, several other inflammatory factors are far more probable to involved downstream during disease development.

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Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally leading to the phenomenon of premature aging of the body. Excessive accumulation of adipose tissue contributes to the development of chronic immune inflammation and oxidative stress, which are both precursors to various disorders, such as insulin resistance, arterial hypertension and dyslipidemia, but also trigger inflammatory processes in patients. An increasing number of studies support the importance of chronic immune inflammation in the pathogenesis of metabolic syndrome, as pro-inflammatory markers such as TNF-α, IL-1ß, IL-6, monocyte chemotactic protein-1 and growth of vascular endothelium. Among a wide range of cytokines, monocyte chemotactic protein-1 is considered one of the most important chemokines, which activates monocytes and other immune cells actively involved in inflammation. Another important point of chronic immune inflammation is its impact on the mental health of patients with metabolic syndrome. Increased levels of anxiety and depression are associated with levels of pro-inflammatory cytokines produced by adipose tissue, which ultimately has an adverse effect on the cognitive status of patients.

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BACKGROUND: To investigate the value of serum monocyte chemotactic protein 1 (MCP-1) and soluble mannose receptor (sMR) for predictive diagnosis of pediatric sepsis. METHODS: This study retrospectively analyzed the data of 82 children with acute and severe signs of inflammation. According to the diagnostic criteria of sepsis, these children were divided into a sepsis group (40 cases) and a non-sepsis group (42 cases). In addition, 50 children who received health examinations during the same time period in Cangzhou Central Hospital were selected as a control group. According to the prognosis of the children in the sepsis group, they were further divided into a survival group (33 cases) and a death group (7 cases). The levels of blood indicators, inflammatory markers, liver and kidney function indicators, MCP-1 level, and sMR were collected from the children. The efficacy of using sMR and MCP-1 levels in the predictive diagnosis of sepsis was analyzed by using the area under the ROC curve (AUC). RESULTS: Serum levels of MCP-1 and sMR were (452.32±2.79) µg/ml and (97.23±.15) µg/ml, respectively, in the sepsis group, significantly higher than those in all controls (P<0.001). In the death group, the levels of white blood cells (WBC), C-reactive protein (CRP), procalcitonin (PCT), sMR, and MCP-1 were significantly higher compared to the survival group (P<0.05). The AUC for CRP in predictive diagnosis of sepsis was 0.9075; the AUC for PCT was 0.8759; the AUC for sMR was 0.9244; and the AUC for MCP-1 was 0.9406. CONCLUSIONS: Serum sMR and MCP-1 levels can help predict the diagnosis of pediatric sepsis.

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BACKGROUND:Previous studies have successfully constructed erythropoietin-overexpressed umbilical cord mesenchymal stem cells.It was found that the apoptosis of ischemic and hypoxic human neuroblastoma cell line(SH-SY5Y)was significantly reduced by erythropoietin-overexpressed umbilical cord mesenchymal stem cells. OBJECTIVE:To explore the possible neuroprotective mechanisms of erythropoietin-overexpressed umbilical cord mesenchymal stem cells against ischemic-hypoxic SH-SY5Y and their associated epigenetic mechanisms. METHODS:Oxygen-glucose deprivation was applied to ischemia-hypoxia-induced SH-SY5Y cell injury,and multifactorial assays were applied to detect the expression levels of inflammatory factors in the cells before and after hypoxia and co-culture,respectively,with mesenchymal stem cells,as well as lentiviral-transfected null-loaded plasmids of the negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression levels of supernatant inflammatory factors were detected by multifactor assay after co-culture.Proteomics was used to detect the differentially expressed proteins of negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.Cleavage under targets and tagmentation sequencing was applied to detect genomic H3K4me2 modification,and joint analysis was conducted with RNA-sequencing.Lentiviral vector infection was applied to construct the stable knockdown of REST in SH-SY5Y cells.qRT-PCR and western blot assay were performed to detect the expression level of REST.The apoptosis was detected by flow cytometry after co-culture of oxygen-glucose deprivation treatment with erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression difference of H3K36me3 group proteins was detected by western blot assay,and transcriptome sequencing was performed to analyze the differentially expressed genes. RESULTS AND CONCLUSION:(1)Compared with the control group,monocyte chemotactic protein 1,interleukin-6,interleukin-18,and interleukin-1 beta,interferon α2,and interleukin-23 levels significantly increased in the cerebrospinal fluid supernatant of patients with ischemic-hypoxic encephalopathy(P<0.01).(2)After co-culturing SH-SY5Y cells with erythropoietin-overexpressed umbilical cord mesenchymal stem cells under ischemia and hypoxia,the expression levels of monocyte chemotactic protein 1 and interleukin-6 were significantly reduced.(3)Analysis of protein network interactions revealed significant downregulation of monocyte chemotactic protein 1,interleukin-6 related regulatory proteins CXCL1 and BGN.(4)Transcriptome sequencing analysis found that pro-inflammatory genes were down-regulated,and functional enrichment of histone modifications,and the expression of transcription factors REST and TET3 significantly up-regulated in the erythropoietin-overexpressed umbilical cord mesenchymal stem cell group compared with the negative control mesenchymal stem cell group.(5)Combined analysis of transcriptome sequencing and cleavage under targets and tagmentation revealed changes in epigenetic levels as well as significant activation of the promoter regions of transcription factors REST and TET3.(6)Stable knockdown REST in SH-SY5Y cells was successfully constructed;the transcript levels of REST mRNA and protein expression were both decreased.(7)After the REST knockdown SH-SY5Y cells were co-cultured with erythropoietin-overexpressed umbilical cord mesenchymal stem cells,apoptosis was significantly increased and H3K36me3 expression was significantly decreased.Transcriptome sequencing results showed that the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2 was reduced at mRNA transcription level(P<0.01).(8)It is concluded that erythropoietin-overexpressed umbilical cord mesenchymal stem cells activated the expression of REST and TET3 by altering the kurtosis of H3K4me2 and upregulated the modification level of H3K36me3,which in turn regulated the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2,and facilitated neuronal survival.

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Objective:To investigate the effects of budegforo combined with doxofylline on inflammatory indexes, monocyte chemotactic protein 1 (MCP-1) and serum amyloid A protein (SAA) levels in patients with moderate and severe chronic obstructive pulmonary disease (COPD) during exacerbation period.Methods:The method of prospective study was adopted, 80 patients with moderate and severe COPD during exacerbation period who were treated in Gongan County People′s Hospital from January 2020 to December 2021 were selected as the research objects, and they were divided into the combined group and the budegforo group by random number table method, with 40 cases in each group. The budegforo group was treated with budegforo inhalation and the conventional maintenance therapy, the combined group was treated with doxofylline on the basis treatment of the budegforo group. The patients of the two groups were treated for 12 weeks. The clinical total effective rate and pulmonary function, inflammatory indexes and MCP-1, SAA levels before and after treatment and adverse reactions of the two groups were compared.Results:The clinical total effective rate in the combined group was higher than that in the budegforo group: 95.00%(38/40) vs. 75.00%(30/40), there was statistical difference ( χ2 = 4.80, P<0.05). After 12 weeks of treatment, the forced expiratory volume in one second (FEV 1), FEV 1 and forced vital capacity (FVC) ratio (FEV 1/FVC), percentage of FEV 1 in predicted value (FEV 1% pred), maximum voluntary ventilation (MVV), percentage of predicted value of diffusing capacity of the lung for carbon monoxide (DLCO% pred) in the combined group were higher than those in the budegforo group: (2.80 ± 0.56) L vs. (2.41 ± 0.27) L, (66.35 ± 8.20)% vs. (61.84 ± 9.77)%, (72.73 ± 7.57)% vs. (65.39 ± 5.41)%, (73.56 ± 7.06) L/min vs. (68.53 ± 6.25) L/min, (71.03 ± 5.85)% vs. (66.37 ± 7.08)%; residual volume (RV) to total lung capacity (TLC) ratio (RV/TLC) level was lower than that in the budegforo group: (45.32 ± 6.64)% vs. (51.73 ± 8.45)%, there were statistical differences ( P<0.05). After 12 weeks of treatment, the levels of interleukin(IL)-17, IL-22, MCP-1, SAA in the combined group were lower than those in the budegforo group: (21.46 ± 5.86) ng/L vs. (30.55 ± 8.74) ng/L, (155.62 ± 14.39) ng/L vs. (170.81 ± 16.70) ng/L, (89.57 ± 7.41) ng/L vs. (105.25 ± 8.70) ng/L, (45.21 ± 8.86) ng/L vs. (57.67 ± 7.16) ng/L, there were statistical differences ( P<0.05). There was no statistical difference in adverse reactions between the two groups ( P>0.05). Conclusions:The application of budegforo combined with doxofylline can improve the pulmonary function and clinical efficacy of patients with moderate and severe COPD during exacerbation period, and also play a positive role in reducing MCP-1 and SAA levels.

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Objective:To observe the effect of early electroacupuncture intervention on the expression of TARDNA bind-ing protein 43(TDP-43)and HMGB1/RhoA signaling pathway in the cerebral cortex of amyotrophic lateral sclerosis(ALS)mice,and to explore the potential mechanism of early electroacupuncture intervention in im-proving motor function in ALS mice. Method:SOD1G93A gene phenotype mice were randomly divided into model group(SOD1G93A),acupuncture in-tervention group(EA),riluzole group(Riluzole),and SOD1G93A negative mice in the same litter were blank control group(Control),with 15 mice in each group.The electroacupuncture group was given acupuncture of Baihui point,bilateral Tianzhu point,bilateral Tianshu point,5 times/7 days,7 days for a course of treat-ment,a total of 4 courses of treatment.The riluzole group was treated with riluzole 30 mg/(kg·d)by gavage,once a day,five times a week for two weeks.The motor function of mice in each group was evaluated by hind limb functional neurological score and rotarod fatigue test,and the rate of TDP-43 positive cells in cere-bral cortex was observed by immunofluorescence.The relative expression of Iba-1,HMGB1 or RhoA protein in cerebral cortex was detected by Western Blot.The levels of serum TNF-α and MCP-1 were detected by Elisa.The morphological changes of cerebral cortical neurons were observed by transmission electron microscopy. Result:Compared with the control group,the rotarod latency time was decreased and the neurological score was increased in the model group(P＜0.01).The contents of serum MCP-1 and TNF-α,the expression of Iba-1,HMGB1 and RhoA protein in cerebral cortex and the rate of TDP-43 positive cells were increased in the model group(P＜0.01).Compared with the model group,the rotarod latency time of the electroacupuncture group and the riluzole group increased and the neurological score decreased(P＜0.01,P＜0.05),the serum MCP-1,TNF-α content and the cerebral cortex Iba-1,HMGB1,RhoA protein expression and TDP-43 positive cell rate decreased(P＜0.01,P＜0.05).The results of electron microscopy showed that the structure of cortical neurons in the control group was normal,and the nerve cells in the model group exhibited obvious pathologi-cal changes.The damage of nerve cells in the electroacupuncture group and the riluzole group was reduced,the structure was relatively complete,and some normal organelles were detected. Conclusion:Electroacupuncture intervention can improve the motor function of ALS model mice.The mecha-nism may be related to the inhibition of HMGBl/RhoA signaling pathway and the reduction of microglia-in-duced neuroinflammation,and it is speculated that it has a positive effect on the reduction of ALS pathologi-cal substrate TDP-43 deposition.

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Lipopolysaccharide­induced (LPS) neuroinflammation serves an important role in the development of depression. Monocyte chemotactic protein­1­induced protein 1 (MCPIP1, also known as ZC3H12A and Regnase­1) possesses endoribonuclease and deubiquitinase activities. In the present study, the effects of MCPIP1 on LPS­induced depression were assessed. A mouse model of hippocampal neuroinflammation was established by intraperitoneal injection of LPS. Microglia were treated with LPS, MCPIP1 overexpression vector, MCPIP1 knockdown vector or TLR4 inhibitor. MCPIP1 alleviated LPS­induced depressive­like behaviors. MCPIP1 facilitated M2 polarization of microglia. MCPIP1 attenuated the inflammatory response in microglia via inhibition of the TLR4/TNF receptor associated factor 6 (TRAF6)/NF­κB signaling pathway. The results indicated that MCPIP1 accelerated M2­polarization of microglia and alleviated depressive­like behaviors of mice via the inhibition of the TLR4/TRAF6/NF­κB signaling pathway.

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Background: To explore the effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract complicated with non-proliferative diabetic retinopathy (NPDR) and its effects on fundus microcirculation, intercellular adhesion molecule 1 (ICAM-1), mono - cyte chemoattractant protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). Methods: From March 2019 to January 2021, a total of 114 patients with cataract and NPDR were included, and the patients were assigned into the control and the observation groups by random number table method, with 57 cases/group. The control was given hypoglycemic drugs, and the observation was given calcium dobesilate combined therapy. The therapeutic efficacy, blood glucose and blood lipid levels, fluorescein fundus angiography results, fundus microcirculation indexes, retinal neovascularizationrelated factors, and ICAM-1, MCP-1, and MIF levels before and after treatment were compared between the two groups. Results: The total effective rate of treatment in the observation was higher vs. the control (P < 0.05); Fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) in the observation after treatment were reduced vs. the control (P < 0.05); The number of micro-hemangiomas in the observation after treatment was less vs. the control, and the area of hemorrhage, the area of exudation and the thickness of the yellow plate were smaller vs. the control (P < 0.05); The resistance index (RI) value of the observation after treatment was lower than the control, and the end-diastolic blood flow velocity (EDV) and the peak systolic blood flow velocity (PSV) of the observation were higher vs. the control (P < 0.05). ICAM-1, MCP-1, MIF, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1) in the observation after treatment were reduced vs. the control, but pigment epithelium-derived factor (PEDF) were higher vs. the control (P < 0.05); one case of gastrointestinal reaction took place in the observation, but no adverse reaction occurred in the control, and no clear difference exhibited in the incidence of adverse reactions between the two groups (P > 0.05). Conclusions: Calcium dobesilate combined with hypoglycemic drugs has good clinical efficacy in the treatment of cataract complicated with NPDR, which can effectively reduce the level of blood glucose and blood lipids, reduce inflammation, and mitigate the microcirculation of branch retinal vein occlusion lesions.

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Background and Objectives: To investigate peripheral blood flow in retinal vessels and vessel diameters after intravitreal ranibizumab injection (IRI) and the relationship between these parameters and cytokines in branch retinal vein occlusion (BRVO) with macular edema. Materials and Methods: We assessed relative flow volume (RFV) and the width of the main and branch retinal arteries and veins in the occluded and non-occluded regions before and after IRI in 37 patients with BRVO and macular edema. Measurements were made using laser speckle flowgraphy (LSFG). When performing IRI, we obtained samples of aqueous humor and analyzed them using the suspension array method to evaluate vascular endothelial growth factor (VEGF), placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, and interferon-inducible 10-kDa protein (IP-10). Results: In both retinal regions, before and after IRI, the RFV in the main artery and vein showed a significant correlation with the summed RFV in the respective branch vessels 1 and 2. In the occluded region, the RFV in the main vein was significantly negatively correlated with MCP-1, PDGF-AA, IL-6, and IL-8; the RFV in branch vein 1 was significantly negatively correlated with PlGF, MCP-1, IL-6, and IL-8; PDGF-AA was significantly negatively correlated with the width of the main and branch veins; and the RFVs of the main artery and vein decreased significantly from before to 1 month after IRI. Conclusions: Contrary to expectations, the study found that anti-VEGF therapy does not affect RFV in arteries and veins in patients with BRVO and macular edema. Furthermore, retinal blood flow is poor in patients with high MCP-1, IL-6, and IL-8. Finally, high PDGF-AA may result in smaller venous diameters and reduced retinal blood flow.

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Remifentanil is a potent ultra-short acting µ-opioid analgesic drug, frequently used in anaesthesia due to its favorable pharmacodynamic and pharmacokinetic profile. It may be associated with the occurrence of hyperalgesia. Preclinical studies suggest a potential role of microglia, although the molecular mechanisms have not been fully elucidated. Considering the role of microglia in brain inflammation and the relevant differences among species, the effects of remifentanil were studied on the human microglial C20 cells. The drug was tested at clinically relevant concentrations under basal and inflammatory conditions. In the C20 cells, the expression and secretion of interleukin 6, interleukin 8 and the monocyte chemotactic protein 1 were rapidly induced by a mixture of pro-inflammatory cytokines. This stimulatory effect was sustained up to 24 h. Remifentanil did not exert any toxic effect nor modify the production of these inflammatory mediators, thus suggesting the lack of direct immune modulatory actions on human microglia.

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PURPOSE: We evaluated the renal arterial resistive index (RRI), urine monocyte chemotactic protein 1 (uMCP-1), and urine neutrophil gelatinase-associated lipocalin (uNGAL) to predict acute kidney injury (AKI) in critically ill cancer patients. METHODS: In this prospective study, we included patients without AKI. We compared the area under the curve (AUC) of RRI, uMCP-1, and uNGAL to predict any stage of AKI and stage-3 AKI with the DeLong method, and we established cutoff points with the Youden index. RESULTS: We included 64 patients, and 43 (67.2%) developed AKI. The AUC to predict AKI were: 0.714 (95% CI 0.587-0.820) for the RRI, 0.656 (95% CI 0.526-0.770) for uMCP-1, and 0.677 (95% CI 0.549-0.789) for uNGAL. The AUC to predict stage-3 AKI were: 0.740 (95% CI 0.615-0.842) for the RRI, 0.757 (95% CI 0.633-0.855) for uMCP-1, and 0.817 (95% CI 0.701-0.903) for uNGAL, without statistical differences among them. For stage 3 AKI prediction, the sensitivity and specificity were: 56.3% and 87.5% for a RRI > 0.705; 70% and 79.2% for an uMCP-1 > 2169 ng/mL; and 87.5% and 70.8% for a uNGAL > 200 ng/mL. The RRI was significantly correlated to age (r = 0.280), estimated glomerular filtration rate (r = - 0.259), mean arterial pressure (r = - 0.357), and serum lactate (r = 0.276). CONCLUSION: The RRI, uMCP-1, and uNGAL have a similar ability to predict AKI. The RRI is more specific, while urine biomarkers are more sensitive to predict stage 3 AKI. The RRI correlates with hemodynamic variables. The novel uMCP-1 could be a useful biomarker that needs to be extensively studied.

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Severe bone trauma can lead to poor or delayed bone healing and nonunion. Bone regeneration is based on the interaction between osteogenesis and angiogenesis. Angiogenesis serves a unique role in the repair and remodeling of bone defects. Monocyte chemoattractant protein-1, also known as CC motif ligand 2 (CCL2), is a member of the CC motif chemokine family and was the first human chemokine to be revealed to be an effective chemokine of monocytes. However, its underlying mechanism in angiogenesis of bone defect repair remains to be elucidated. Therefore, the present study investigated the detailed mechanism by which CCL2 promoted angiogenesis in bone defects based on cell and animal model experiments. In the present study, CCL2 promoted proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. Western blot analysis revealed that treatment of HUVECs with CCL2 upregulated the protein expression levels of rho-associated coiled-coil-containing protein kinase (Rock)1, Rock2, N-cadherin, c-Myc and VEGFR2. Furthermore, CCL2 promoted the expression of MAPK/ERK1/2/MMP9, PI3K/AKT and Wnt/ß-catenin signaling pathway-related proteins, which also demonstrated that CCL2 promoted these functions in HUVECs. Immunohistochemical staining of Sprague Dawley rat femurs following bone defects revealed that VEGF expression was positive in the newly formed bone area in each group, while the expression area of VEGF in the CCL2 addition group was markedly increased. Therefore, CCL2 is a potential therapeutic approach for bone defect repair and reconstruction through the mechanism of angiogenesis-osteogenesis coupling.

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Objective:To investigate the placenta tissue expression levels of monocyte chemotactic protein-1 (MCP-1), nuclear factor-κBp65 (NF-κBp65) and proliferating cell nuclear antigen (PCNA) in pregnant women with gestational diabetes mellitus (GDM), and to analyze their correlation with pregnancy outcomes.Methods:The clinical data of 124 pregnant women with GDM from May 2020 to December 2021 in PLA Northern Theater General Hospital were retrospectively analyzed. Among them, 62 pregnant women were willing to receive treatment (treatment group), while 62 pregnant women were unwilling to receive treatment (untreated group). In addition, 80 healthy pregnant women in the same period were selected as the healthy control group. The natural birth rate, neonatal Apgar score and the incidences of macrosomia, neonatal hypoglycemia, neonatal hyperbilirubinemia were record. The placenta tissue expression levels of MCP-1, NF-κBp65 and PCNA were detected by immunohistochemical.Results:The natural birth rate in untreated group was significantly lower than that in treatment group and healthy control group: 24.19% (15/62) vs. 75.81% (47/62) and 88.75% (71/80), the natural birth rate in treatment group was significantly lower than that in healthy control group, and there was statistical difference ( P<0.05). The Apgar score in untreated group was significantly lower than that in treatment group and healthy control group: (8.45 ± 2.02) scores vs. (9.46 ± 2.59) and (9.71 ± 3.21) scores, the incidences of macrosomia, neonatal hypoglycemia and neonatal hyperbilirubinemia were significantly higher than those in treatment group and healthy control group: 35.48% (22/62) vs. 11.29% (7/62) and 3.75% (3/80), 29.03% (18/62) vs. 8.06% (5/62) and 2.50% (2/80), 24.19% (15/62) vs. 9.68% (6/62) and 2.50% (2/80), and there were statistical differences ( P<0.05); there were no statistical difference in the indexes treatment group and healthy control group ( P>0.05). The positive expression rates of MCP-1, NF-κBp65 and PCNA in untreated group were significantly higher than those in treatment group and healthy control group: 72.58% (45/62) vs. 25.81% (16/62) and 12.50% (10/80), 69.35% (43/62) vs. 27.43% (17/62) and 13.75% (11/80), 69.35% (43/62) vs. 24.19% (15/62) and 11.25% (9/80), the indexes in treatment group were significantly higher than those in healthy control group, and there were statistical differences ( P<0.05). Conclusions:The placenta tissue expression levels of MCP-1, NF-κBp65 and PCNA in pregnant women with GDM are associated with adverse pregnancy outcomes. After active treatment, the positive rates of the three indexes in pregnant women with GDM significantly decrease, and the prognosis got improved.

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OBJECTIVE To investigate the impacts of isorhynchophylline （IRN） on airway inflammation in asthmatic mice by regulating the monocyte chemotactic protein-1 （MCP-1）/CC chemokine receptor 2 （CCR2） signaling pathway. METHODS The asthmatic mice model was established by injecting and inhaling ovalbumin. The successfully modeled mice were randomly grouped into asthma group， IRN low-dose group （IRN-L， intragastric administration of 10 mg/kg IRN）， IRN high-dose group （IRN-H， intragastric administration of 20 mg/kg IRN）， IRN-H+CCL2 group [intragastric administration of 20 mg/kg IRN+intraperitoneal injection of 7.5 ng CC chemokine ligand 2 （CCL2）] and positive control group （intraperitoneal injection of 2 mg/kg dexamethasone）. The mice injected and inhaled with sterile phosphate-buffered solution were included in the blank control group， with 10 mice in each group. The mice in administration groups were given relevant medicine once a day， for consecutive 2 weeks. The levels of airway hyperreactivity indexes such as enhanced （Penh） value， tumor necrosis factor-α （TNF-α），interleukin-13 （IL-13） and IL-4 in serum， the number of eosinophil （EOS）， lymphocyte （LYM） and neutrophils （NEU） in alveolar lavage fluid and the protein expressions of MCP-1 and CCR2 in lung tissue were observed in each group； the pulmonary histopathological changes were observed， and inflammatory cell infiltration score was evaluated. RESULTS Compared with the blank control group， the infiltration of inflammatory cells in the lung tissue of mice was more significant in the asthma group， and there was swelling and shedding of cells； inflammatory infiltration score， Penh value， the levels of IL-4， IL-13 and TNF-α， the number of EOS， NEU and LYM， the protein expressions of MCP-1 and CCR2 were increased significantly （P＜0.05）. Compared with the asthma group， the pathological injuries of the IRN-L group， IRN-H group and positive control group were improved， and the above quantitative indexes were decreased significantly （P＜0.05）. Compared with the IRN-L group， the above quantitative indexes of the IRN-H group and positive control group were decreased significantly （P＜0.05）. There was no statistical significance in the above quantitative indexes between the IRN-H group and the positive control group （P＞0.05）. Compared with the IRN-H group， the above quantitative indexes of the IRN-H+CCL2 group were increased significantly （P＜0.05）. CCL2 reversed the protective effect of high-dose IRN on asthmatic mice. CONCLUSIONS IRN may reduce the release of airway inflammatory factors in asthmatic mice by inhibiting the activation of the MCP-1/CCR2 signaling pathway， so as to achieve the purpose of improving asthma.

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BACKGROUND: Temporomandibular joint osteoarthritis (TMJ-OA) causes cartilage degeneration, bone cavitation, and fibrosis of the TMJ. However, the mechanisms underlying the fibroblast-like synoviocyte (FLS)-mediated inflammatory activity in TMJ-OA remain unclear. METHODS AND RESULTS: Reverse transcription-quantitative polymerase chain reaction analysis revealed that the P2Y1, P2Y12, and P2Y13 purinergic receptor agonist adenosine 5'-diphosphate (ADP) significantly induces monocyte chemotactic protein 1 (MCP-1)/ C-C motif chemokine ligand 2 (CCL2) expression in the FLS1 synovial cell line. In contrast, the uracil nucleotide UTP, which is a P2Y2 and P2Y4 agonist, has no significant effect on MCP-1/CCL2 production in FLS1 cells. In addition, the P2Y13 antagonist MRS 2211 considerably decreases the expression of ADP-induced MCP-1/CCL2, whereas ADP stimulation enhances extracellular signal-regulated kinase (ERK) phosphorylation. Moreover, it was found that the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor U0126 reduces ADP-induced MCP-1/CCL2 expression. CONCLUSION: ADP enhances MCP-1/CCL2 expression in TMJ FLSs via P2Y13 receptors in an MEK/ERK-dependent manner, thus resulting in inflammatory cell infiltration in the TMJ. Collectively, the findings of this study contribute to a partial clarification of the signaling pathway underlying the development of inflammation in TMJ-OA and can help identify potential therapeutic targets for suppressing ADP-mediated purinergic signaling in this disease.

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Objective: The objective of the study was to reveal the presence of cellular interplay through extracellular vesicle (EV) microRNAs (miRs), to dampen the vicious cycle to degenerate human corneal endothelium (HCE) tissues. Design: Prospective, comparative, observational study. Methods: The miR levels in neonate-derived corneal tissues, in the aqueous humor (AqH) of bullous keratoplasty and cataract patients, as well as in the culture supernatant (CS) and EV of cultured human corneal endothelial cells (hCECs), were determined using 3D-Gene human miR chips and then validated using the real-time polymerase chain reaction. The extracellularly released miRs were profiled after the forced downregulation of cellular miR-34a, either by an miR-34a inhibitor or exposure to H2O2. The senescence-associated secretory phenotypes and mitochondrial membrane potential (MMP) were assessed to determine the functional features of the released miRs. Main Outcome Measures: Identification of functional miRs attenuating HCE degeneration. Results: The miRs in AqH were classified into 2 groups: expression in 1 group was significantly reduced in neonate-derived tissues, whereas that in the other group remained almost constant, independent of aging. The miR-34a and -29 families were typical in the former group, whereas miR-184 and -24-3p were typical in the latter. Additionally, a larger amount of the latter miRs was detected in AqH compared with those of the former miRs. There was also a greater abundance of miR-184 and -24-3p in hCECs, EV, and CS in fully mature CD44-/dull hCEC, leading to sufficient clinical tissue regenerative capacity in cell injection therapy. The repression of cellular miR-34a, either due to miR-34a inhibitors or exposure to oxidative stress, unexpectedly resulted in the elevated release of miR-184 and -24-3p. Secretions of VEGF, interleukin 6, monocyte chemotactic protein-1, and MMP were all repressed in both mature CD44-/dull and degenerated CD44+++ hCEC, transfected with an miR-184 mimic. Conclusions: The elevated release of miR-184 into AqH may constitute cellular interplay that prevents the aggravation of HCE degeneration induced by oxidative stress, thereby sustaining tissue homeostasis in HCE.

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Background: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. Results: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. Conclusions: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

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Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). The CerK/C1P pathway regulates many cellular functions, but its roles in immune/inflammation-related (IIR) diseases in vivo are not well known. Sepsis is an acute systemic inflammatory disease accompanied by damage/dysfunction in multiple organs. In the present study, we investigated the effects of CerK knockout on the onset/progression of sepsis-related events in lipopolysaccharide (LPS)-treated sepsis-model mice. In CerK-null mice, the lethality at 48 h after i.v. injection of LPS was significantly increased compared with that in wild-type (WT) mice. The increased lethality by CerK knockout was reproduced in mice treated with i.p. injections of LPS. Changes in serum levels of 23 IIR molecules, including cytokines and chemokines, were measured. In WT mice, levels of these molecules increased 4 and/or 20 h after i.v. injection of LPS. Although the basal levels of IIR molecules were not affected, LPS-induced increases in interleukin-17 (IL-17), C-C motif chemokine ligands (CCL-2 and CCL-11), and tumor necrosis factor-α were significantly up-regulated, whereas IL-2 levels were slightly down-regulated by CerK knockout. Putative mechanisms for the CerK/C1P pathway-mediated regulation of IIR molecules and increased lethality in LPS-treated mice are discussed.

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Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.

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In vitro osteoclast methods require constant treatment with macrophage colony stimulating factor (M-CSF) to support precursor survival and addition of the differentiation agent receptor activator of NF-κB ligand (RANKL). Constant exposure to granulocyte macrophage colony stimulating factor (GM-CSF) suppresses human osteoclast formation in vitro. Addition of the chemokine monocyte chemotactic protein-1 (MCP1) to such cultures dramatically increases osteoclast formation and overcomes GM-CSF mediated suppression. We investigated the effect of M-CSF, GM-CSF and the combination of M-CSF and GM-CSF treatment on the expression of chemokines in human CD14+ cells in culture. Of assayed chemokines, MCP1 was the most abundant in terms of mRNA transcript and protein in M-CSF treated cultures and was suppressed by GM-CSF. MCP1 protein accumulated up to 50 ng/mL in culture medium, greatly exceeding other assayed chemokines. C-C chemokine receptor-2 (CCR2) is the receptor for MCP1: the formation of osteoclast-like cells was inhibited by constant exposure to the CCR2 antagonist RS102895, in part by decreasing expression of RANK, the receptor for RANKL.