Higher Monocyte Chemoattractant Protein-1 Research Articles

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Monocyte Chemoattractant Protein-1, Inflammatory Biomarkers, and Prognosis of Patients With Ischemic Stroke or Transient Ischemic Attack: Fndings From a Nationwide Registry Study.

Recent Mendelian randomization and meta-analysis highlight the relevance of MCP-1 (monocyte chemoattractant protein-1) in stroke. We aimed to investigate the associations between MCP-1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all-cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP-1 level (<337.6 pg/mL) was associated with a reduced risk of all-cause death (hazard ratio [HR], 0.65 [95% CI, 0.51-0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70-0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95-1.27]), compared with high MCP-1 level (≥337.6 pg/mL). The association between MCP-1 and all-cause death was partially mediated by highly sensitive C-reactive protein, interleukin-6, and YKL-40 (Chitinase-3-like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP-1 and inflammatory biomarkers had the highest risks of all-cause death and poor functional outcome. Low plasma MCP-1 level was associated with decreased risks of all-cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.

High Levels of Monocyte Chemoattractant Protein-1 Plasma Are A Risk Factor for Neurocognitive Disorders in Human Immunodeficiency Virus Infection with Antiretroviral Therapy

Background: HIV-associated neurocognitive disorder (HAND) is a neurocognitive dysfunction caused by HIV infection. The prevalence of neurocognitive disorders of HIV in Indonesia is about 51%. Despite receiving antiretroviral therapy, HAND is still a common complication that causes morbidity in people with HIV. One of the foundations of HAND pathogenesis is inflammation. Infection of macrophages/microglia and astrocytes leads to excessive production of viral gene products and chemokines, one of them is Monocyte chemoattractant protein 1 (MCP-1). The purpose of this study was to determine plasma MCP-1 levels that increase the risk of neurocognitive disorders in HIV infection with antiretroviral therapy. Methods: This matched case-control study involved 76 subjects with HIV, 38 subjects with neurocognitive disorders, and 38 subjects without neurocognitive disorders. Cognitive status was reviewed based on MoCA-Ina examination criteria. Plasma MCP-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Of the 76 subjects, the mean age of the case group was 42.08 ± 9.44 years and the control group was 42.16± 8.90 years. The cut point value based on the ROC curve of the plasma MCP-1 level was 82.14 pg/mL. It had an 86.8% sensitivity and 52.6% specificity for the occurrence of neurocognitive disorders in HIV. The risk of neurocognitive disorders in HIV was found in MCP-1 plasma ≥ 82.14 pg/mL (OR 7.33, p &lt; 0.001, CI 95% = 2.35-22.83). Based on multivariate analysis, MCP-1 levels were independently associated with the incidence of neurocognitive disorders in HIV (AOR 11.01, CI 95% = 2.75-44.01, p=0.001). Conclusion: This study showed that high plasma MCP-1 levels were an event risk factor for neurocognitive disorders in HIV with antiretroviral therapy.

MCP-1 expression in breast cancer and its association with distant relapse.

Distant relapse of breast cancer complicates management of the disease and accounts for 90% of breast cancer-related deaths. Monocyte chemoattractant protein-1 (MCP-1) has critical roles in breast cancer progression and is widely accepted as a pro-metastatic chemokine. This study explored MCP-1 expression in the primary tumour of 251 breast cancer patients. A simplified 'histoscore' was used to determine if each tumour had high or low expression of MCP-1. Patient breast cancers were retrospectively staged based on available patient data. p < 0.05 was used to determine significance and changes in hazard ratios between models were considered. Low MCP-1 expression in the primary tumour was associated with breast cancer-related death with distant relapse in ER- breast cancers (p < 0.01); however, this was likely a result of most low MCP-1-expressing ER- breast cancers being Stage III or Stage IV, with high MCP-1 expression in the primary tumour significantly correlated with Stage I breast cancers (p < 0.05). Expression of MCP-1 in the primary ER- tumours varied across Stage I, II, III and IV and we highlighted a switch in MCP-1 expression from high in Stage I ER- cancers to low in Stage IV ER- cancers. This study has emphasised a critical need for further investigation into MCP-1's role in breast cancer progression and improved characterisation of MCP-1 in breast cancers, particularly in light of the development of anti-MCP-1, anti-metastatic therapies.

Effects of Intravitreal Ranibizumab Injection on Peripheral Retinal Microcirculation and Cytokines in Branch Retinal Vein Occlusion with Macular Edema.

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.

Cytokines Associated With Onset of a Hypertensive Phase and Surgical Failure After Ahmed Glaucoma Valve Implantation

To investigate the relationship between cytokines of the aqueous humor or Tenon capsule, the onset of a hypertensive phase, and surgical failure in patients undergoing Ahmed Glaucoma Valve (AGV) implantation DESIGN: Prospective clinical cohort study. A total of 36 patients who underwent AGV implantation were included. Samples of aqueous humor and Tenon tissue were collected at the time of surgery. Multiple cytokines were evaluated in the samples using a bead-based multiplex cytokine assay. As for surgical outcomes, a hypertensive phase was defined as an intraocular pressure (IOP) of greater than 21 mm Hg within 3 months after surgery, whereas surgical failure was defined as an IOP greater than 21 mm Hg with maximum tolerable glaucoma medications during 2 consecutive visits. Patients who entered a hypertensive phase showed higher transforming growth factor-β2 (TGF-β2) levels in the aqueous humor (P=.012). A longer axial length and higher TGF-β2 concentration of the aqueous humor were associated with higher maximum IOP values during 3 months after surgery per multiple regression analysis (P=.028 and P=.034). In the multiple logistic regression analysis, higher monocyte chemoattractant protein-1 (MCP-1) concentrations in the aqueous humor and higher interleukin-4 concentrations in Tenon tissue were related to surgical failure (P=.022 and P=.040). Greater concentrations of TGF-β2 and MCP-1 were related to surgical outcome after glaucoma drainage device implantation. Further studies are needed to confirm that down-regulation of these cytokines could be helpful in improving surgical outcomes.

Usefulness of Urinary Biomarkers for Assessing Bladder Condition and Histopathology in Patients with Interstitial Cystitis/Bladder Pain Syndrome.

This study investigated the usefulness of urinary biomarkers for assessing bladder condition and histopathology in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). We retrospectively enrolled 315 patients (267 women and 48 men) diagnosed with IC/BPS and 30 controls. Data on clinical and urodynamic characteristics (visual analog scale (VAS) score and bladder capacity) and cystoscopic hydrodistention findings (Hunner’s lesion, glomerulation grade, and maximal bladder capacity (MBC)) were recorded. Urine samples were utilized to assay inflammatory, neurogenic, and oxidative stress biomarkers, including interleukin (IL)-8, C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin, IL-6, macrophage inflammatory protein 1 beta (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), 8-hydroxy-2′-deoxyguanosine (8-OHdG), and 8-isoproatane, and total antioxidant capacity. Further, specific histopathological findings were identified via bladder biopsy. The associations between urinary biomarker levels and bladder conditions and histopathological findings were evaluated. The results reveal that patients with IC/BPS had significantly higher urinary MCP-1, eotaxin, TNF-α, PGE2, 8-OHdG, and 8-isoprostane levels than controls. Patients with Hunner’s IC (HIC) had significantly higher IL-8, CXCL10, BDNF, eotaxin, IL-6, MIP-1β, and RANTES levels than those with non-Hunner’s IC (NHIC). Patients with NHIC who had an MBC of ≤760 mL had significantly high urinary CXCL10, MCP-1, eotaxin, IL-6, MIP-1β, RANTES, PGE2, and 8-isoprostane levels and total antioxidant capacity. Patients with NHIC who had a higher glomerulation grade had significantly high urinary MCP-1, IL-6, RANTES, 8-OHdG, and 8-isoprostane levels. A significant association was observed between urinary biomarkers and glomerulation grade, MBC, VAS score, and bladder sensation. However, bladder-specific histopathological findings were not well correlated with urinary biomarker levels. The urinary biomarker levels can be useful for identifying HIC and different NHIC subtypes. Higher urinary inflammatory and oxidative stress biomarker levels are associated with IC/BPS. Most urinary biomarkers are not correlated with specific bladder histopathological findings; nevertheless, they are more important in the assessment of bladder condition than bladder histopathology.

1,25-dihydroxyvitamin D3 ameliorates high glucose-mediated proliferation, migration, and MCP-1 secretion of vascular smooth muscle cells by inhibiting MAPK phosphorylation

ObjectivesTo explore the impacts of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the proliferation, migration, and monocyte chemoattractant protein-1 (MCP-1) secretion of vascular smooth muscle cells (VSMCs) in a high glucose environment and its possible mechanism.MethodsWe extracted VSMCs from the thoracic aorta of a male Sprague–Dawley rats before culturing them in a 25-mM glucose-containing medium in the presence or absence of 1,25(OH)2D3 (10−9 –10−7 M). Cell proliferation was determined by bromodeoxyuridine incorporation assays. Subsequently, cell migratory capacity was examined by performing a transwell assay. An enzyme-linked immunosorbent assay was conducted to assess MCP-1 levels. Protein levels of matrix metalloproteinase-9 (MMP-9), mitogen-activated protein kinases (MAPKs), cyclin D1, and phosphorylated MAPKs were determined by immunoblotting.Results1,25(OH)2D3 significantly suppressed the proliferation, migration, and MCP-1 secretion of VSMCs mediated by high glucose in a dose-dependent manner, diminished the enhanced protein expression of MMP-9 and cyclin D1, and attenuated MAPK phosphorylation. The p38 inhibitor SB203580 and ERK1/2 inhibitor PD98059 suppressed high glucose-mediated upregulation of MMP-9 and cyclin D1 protein expression and MCP-1 secretion, respectively.Conclusions1,25(OH)2D3 ameliorates high glucose-mediated proliferation, migration, and MCP-1 secretion of VSMCs by inhibiting MAPK phosphorylation, implying a potential therapeutic approach using 1,25(OH)2D3 for diabetic macrovascular complications.

Biomarkers of Endothelial Damage in Distinct Phases of Multisystem Inflammatory Syndrome in Children

Endothelial hyperinflammation and vasculitis are known hallmarks of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). They are due to the direct effect of the virus on endothelial cells enhanced by pro-inflammatory modulators and may cause venous/arterial thrombosis. Therefore, it is essential to identify patients with endothelial damage early in order to establish specific therapies. We studied the monocyte chemoattractant protein 1 (MCP-1), the perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), and the vascular endothelial growth factor A (VEGF-A) in serum from 45 MIS-C patients at hospital admission and 24 healthy controls (HC). For 13/45 MIS-C patients, we measured the three serum biomarkers also after one week from hospitalization. At admission, MIS-C patients had significantly higher levels of MCP-1 and VEGF-A than the HC, but no significant differences were observed for pANCA. While after one week, MCP-1 was significantly lower, pANCA was higher and VEGF-A levels were not significantly different from the admission values. These findings suggest an involvement of epithelium in MIS-C with an acute phase, showing high MCP-1 and VEGF-A, followed by an increase in pANCA that suggests a vasculitis development. The serum biomarker levels may help to drive personalized therapies in these phases with anticoagulant prophylaxis, immunomodulators, and/or anti-angiogenic drugs.

Interleukin-6 Is an Early Plasma Marker of Severe Postoperative Complications in Thoracic Surgery: Exploratory Results From a Substudy of a Randomized Controlled Multicenter Trial.

Postoperative complications in surgery are a significant burden, not only for the patients but also economically. While several predicting factors have already been identified, it is still not well known if increased levels of inflammatory markers in the immediate perioperative phase correlate with a higher incidence of postoperative complications. This study aimed to evaluate which patient characteristics and intraoperative parameters correlate with increased plasma values of monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) of thoracic surgery patients. A second goal was to explore whether MCP-1 and IL-6 are associated with the incidence of postoperative complications. We hypothesized that there is a positive association between inflammatory markers and the occurrence of complications within 6 months after surgery. This is a substudy of a recent randomized controlled trial, which defined the effect of desflurane versus propofol anesthesia on morbidity and mortality in patients undergoing thoracic surgery. MCP-1 and IL-6 were determined in plasma obtained before and 30 minutes after 1-lung ventilation, 6 hours after surgery, and on postoperative days 1 and 2. Complications were recorded for 6 months. Mixed linear models were used to examine factors associated with MCP-1 and IL-6 levels. Logistic regression models and receiver operating characteristic curves were used to determine the association between MCP-1 and IL-6 and postoperative complications. In the original study, 460 patients were included, MCP-1 and IL-6 levels were determined in 428 patients. MCP-1 was positively associated with the duration of surgery (P = .016), whereas IL-6 levels increased with both the length (P < .001) and invasiveness of lung surgery (thoracoscopic wedge resection or lobectomy versus open lobectomy, P = .005; thoracoscopic wedge resection or lobectomy versus pneumonectomy, P = .021). In an exploratory approach, elevated IL-6 plasma peaks were associated with the occurrence of severe complications defined as Clavien-Dindo score grade ≥IVa during the postoperative phase up to 6 months after thoracic surgery (P = .006). In summary, this substudy reveals factors, which correlate with high MCP-1 and IL-6 values. Moreover, higher IL-6 seems to be associated with postoperative severe complications. Perioperative IL-6 monitoring might be helpful for risk estimation in the perioperative setting of patients after lung surgery.

Preintervention MCP-1 serum levels as an early predictive marker of tumor response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BackgroundTransarterial chemoembolization (TACE) is a widely accepted treatment for unresectable or intermediate-stage hepatocellular carcinoma (HCC). However, response rates to TACE are heterogeneous and it is not fully understood which patients benefit most from TACE therapy in terms of tumor response. To identify the possible predictive roles of the perioperative monocyte chemoattractant protein-1 (MCP-1) levels in patients of HCC treated with TACE.MethodsForty patients of HCC receiving TACE were enrolled in a single center prospective observational study. MCP-1 and miR-210 levels were measured in 40 HCC patients at baseline before TACE and compared with 17 healthy controls by immunoassay and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Tumor response assessments were taken after TACE treatment 4–6 weeks. Univariate and multivariate analysis were conducted to analyze factors correlated with tumor response in a Logistic regression model. The predictive roles of the involved variables on tumor response in patients with HCC suffering TACE were examined by receiver operating characteristic (ROC) curve analysis.ResultsThe serum MCP-1 and miR-210 levels were significantly elevated in HCC patients compared to healthy subjects. Patients with the low preintervention MCP-1 and miR-210 levels attained a higher probability of achieving an objective response (OR) (88.5% vs.42.9%, P=0.007; 76.9% vs. 35.7%, P=0.010, respectively). Pre-TACE MCP-1 level (<816.63 pg/mL) was an independent risk factor associated with OR after TACE by univariate and multivariate analysis while Pre-TACE miR-210 level (<4.43 relative expression) was just positive by univariate analysis. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the involved variables (area under the curve =0.823, 95% CI: 0.681–0.965). Additionally, high pre-TACE serum MCP-1 level was correlated with cirrhosis, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage. Elevated pre-TACE serum miR-210 level was associated with and BCLC stage.ConclusionsThe study demonstrates that the pre-TACE serum MCP-1 level serves as an effective predictor for tumor response. These findings probably help discriminate HCC patients pre-TACE who specially benefit from TACE regarding OR.

Inflammatory cytokines levels in aqueous humour and surgical outcomes of trabeculectomy in patients with prior acute primary angle closure.

To quantify the levels of three inflammatory cytokines in the aqueous humour of patients with prior acute primary angle closure (APAC) and investigate their correlation with surgical outcomes of trabeculectomy. In this prospective cohort study, aqueous humour samples were collected from 44 prior APAC eyes. Analyte concentrations of monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) were measured using multiplexed immunoassay kits. Intraocular pressure was measured using Goldmann application tonometry. Forty-four prior APAC eyes were followed up for 24months after trabeculectomy and divided into success and failure groups according to surgical outcomes. Monocyte chemoattractant protein-1 (MCP-1) levels in the aqueous humour were significantly higher in the failure group (p=0.0118). Univariate and multivariate analyses showed that MCP-1 level was a significant risk factor for trabeculectomy outcomes (univariate analysis: p=0.016, odds ratio=14.538; multivariate analysis: p=0.023, odds ratio=13.718). When prior APAC eyes were divided according to MCP-1 levels, the overall success rate was significantly higher in eyes with low MCP-1 levels than eyes with high MCP-1 levels (p=0.0249). In prior APAC patients, the MCP-1 level in the aqueous humour predicts trabeculectomy results. Therefore, modulation of MCP-1 expression may have potential clinical applications after filtration surgery.

Salivary and serum concentrations of monocyte chemoattractant protein-1, macrophage inhibitory factor, and fractalkine in relation to rheumatoid arthritis and periodontitis.

Monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), and fractalkine are chemokines that are expressed by a variety of cell types to regulate macrophage inflammatory response. The aim of the study was to examine the effects of periodontitis and rheumatoid arthritis (RA) on their serum and salivary concentrations. Adults with either periodontitis (P, n=21), or with rheumatoid arthritis (RA, n=23), or with both diseases (RA+P, n=23) were included in the study. Systemically and periodontally healthy individuals (n=22) served as controls. Saliva and serum samples were collected from all participants before the medical and periodontal examinations. Salivary and serum MCP-1, MIF, and fractalkine concentrations were measured by the Luminex technique. Total salivary protein levels were determined by the Bradford assay. Salivary MCP-1, MIF, and fractalkine concentrations were elevated in both RA groups (RA+P and RA) in comparison with systemically healthy controls. As related to total salivary protein levels, higher MCP-1 (P=0.003) and fractalkine (P=0.045) concentrations were found in controls compared with the P group. In serum, MCP-1 concentrations in the RA+P group were higher (P=0.003) than those of group P. Elevated serum fractalkine concentrations were observed in both periodontitis groups (RA+P, P=0.014; and P, P=0.013) compared with controls. In RA, MCP-1, MIF, and fractalkine concentrations are elevated in saliva. These chemokines may disrupt oral macrophage responses and potentially take part in the interaction between periodontitis and RA.

Monocyte Chemoattractant Protein-1 promotes cancer cell migration via c-Raf/MAPK/AP-1 pathway and MMP-9 production in osteosarcoma

BackgroundOsteosarcoma is generally reported among younger individuals and has a very poor prognosis, particularly for the development of metastasis. However, more effective metastatic biomarkers and therapeutic methods are absent. Monocyte chemoattractant protein-1 (MCP-1) is involved in cancer progression and inflammatory recruitment. Although previous studies have reported higher serum MCP-1 levels in patients with osteosarcoma, the role of MCP-1 in osteosarcoma progression remains to be addressed.MethodsThe osteosarcoma cell migratory ability was assessed by transwell migration assay. The MCP-1 and MMP-9 expression levels were analyzed by Western blot and qPCR. The signal activation was conducted by Western blot. The in vivo mouse experiment and tumor tissue array were performed to confirm our findings in vitro.ResultsThe present study demonstrates that MCP-1 regulates cell mobility through matrix metalloproteinase (MMP)-9 expression in osteosarcoma cells. Moreover, MCP-1 promotes MMP-9 expression, cell migration, and cell invasion by mediating CCR2, c-Raf, MAPK, and AP-1 signal transduction. Using MCP-1 knockdown stable cell lines, we found that MCP-1 knockdown reduces MMP-9 expression and cell mobility. Finally, we found high MCP-1 expression levels in osteosarcoma specimens.ConclusionsOur results provide prognostic value of MCP-1 in osteosarcoma by promoting MMP-9 expression.

Galectin-3 predicts cardiovascular events in patients with type-2 diabetes

Abstract Introduction Type-2 diabetes mellitus (T2DM) is associated with early and severe atherosclerosis. However, few biomarkers can predict cardiovascular events in this population. Methods We followed 964 patients with coronary artery disease (CAD), assessing at baseline galectin-3, monocyte chemoattractant protein-1 (MCP-1) and N-terminal fragment of brain natriuretic peptide (NT-proBNP) plasma levels. Secondary outcomes were acute ischemia and heart failure or death. Primary outcome was the combination of the secondary outcomes. Results Male patients were 75.0% in T2DM and 76.6% in the non-T2DM subgroup (p=0.609). Age was 61.0 (54–72) and 60.0 (51–71) years, respectively (p=0.092). 232 patients had T2DM. Patients with T2DM showed higher MCP-1 [144 (113–195) vs. 133 (105–173) pg/ml, p=0.006] and galectin-3 [8.3 (6.5–10.5) vs. 7.8 (5.9–9.8) ng/ml, p=0.049] levels. Median follow-up was 5.39 years (2.81- 6.92). Galectin-3 levels were associated with increased risk of the primary outcome in T2DM patients [HR 1.57 (1.07–2.30); p=0.022], along with a history of cerebrovascular events. Treatment with clopidogrel was associated with lower risk. In contrast, NT-proBNP and MCP-1, but not galectin-3, were related to increased risk of the event in non-diabetic patients [HR 1.21 (1.04–1.42); p=0.017 and HR 1.23 (1.05–1.44); p=0.012, respectively], along with male sex and age. Galectin-3 was also the only biomarker that predicted the development of acute ischemic events and heart failure or death in T2DM patients, while in non-diabetics MCP-1 and NT-proBNP, respectively, predicted these events. Conclusion In CAD patients, cardiovascular events are predicted by galectin-3 plasma levels in patients with T2DM, and by MCP-1 and NT-proBNP in those without T2DM. Effect of Gal-3 on the primary endpoint Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Insituto de Salud Carlos III

The association of PAI-1 with 24 h blood pressure in young healthy adults is influenced by smoking and alcohol use: The African-PREDICT study

Background and aimsThe association between plasminogen activator inhibitor-1 (PAI-1) and blood pressure is well established, but it is debatable whether raised PAI-1 levels precede or result from raised blood pressure. Furthermore, it is unclear whether this association already exists in the absence of overt hypertension and to what degree it is influenced by health behaviours. Our aim was to investigate the association of 24 h blood pressure with PAI-1 activity (PAI-1act) in a young, healthy cohort, and to assess the influence of alcohol consumption and smoking on these associations. Methods and resultsHealthy black and white men and women (aged 20–30 years, n = 1156) were cross-sectionally analysed. Statistical analysis was performed first split by ethnicity and sex and then by alcohol consumption and smoking. Regression analyses adjusted for age revealed positive associations of 24 h blood pressure with PAI-1act in most groups (p < 0.05). In multivariate-adjusted analyses, significance was lost in all groups except black men, who also had higher monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor antigen (vWFag) compared to white men (both p < 0.001). Analyses in black men, split by self-reported alcohol use and smoking, revealed 24 h blood pressure-PAI-1act associations only in alcohol users (24 h SBP [B = 4.22, p < 0.001], DBP [B = 2.04, p = 0.015] and PP [B = 2.18, p = 0.013]) and smokers (24 h SBP [B = 6.10, p < 0.001] and PP [B = 4.33, p = 0.001]). ConclusionOur findings support a positive association between 24 h blood pressure and PAI-1, particularly in individuals with higher MCP-1 and vWFag levels. Furthermore, smoking and alcohol consumption play an important role in modifying the association between blood pressure and PAI-1.

Matrix Metalloproteinase-9 and Monocyte Chemoattractant Protein-1 Are Associated With Collateral Status in Acute Ischemic Stroke With Large Vessel Occlusion.

In ischemic stroke, inflammatory status may condition the development of collateral circulation. Here we assessed the relationship between systemic inflammatory biomarkers and collateral status in large vessel occlusion before mechanical thrombectomy. HIBISCUS-STROKE is a cohort study including acute ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. MMP-9 (matrix metalloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) were measured on blood sampling collected at admission. Collateral status was assessed on pretreatment Digital subtraction angiography and categorized into poor (Higashida score, 0-2) and good (Higashida score, 3-4). A multiple logistic regression model was performed to detect independent markers of good collateral status. One hundred and twenty-two patients were included, of them 71 patients (58.2%) had a good collateral status. In univariate analysis, low MMP-9 levels (P=0.01), high MCP-1 levels (P<0.01), a low National Institute of Health Stroke Score (P=0.046), a high diastolic blood pressure (P=0.049), the absence of tandem occlusion (P=0.046), a high Alberta Stroke Program Early CT Score (P<0.01) and a low volume on the diffusion-weighted imaging (P<0.01) were associated with good collateral status. Following multivariate analysis, low MMP-9 levels (P=0.02) and high MCP-1 levels (P<0.01) remained associated with good collateral status. Low MMP-9 and high MCP-1 levels were associated with good pretreatment collateral status in patients with acute ischemic stroke with large vessel occlusion. These results might suggest a relationship between collateral status and inflammation.

Aqueous humour proteins and treatment outcomes of anti-VEGF therapy in neovascular age-related macular degeneration.

We aimed to construct a better model for predicting treatment outcomes of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration (nAMD) using the concentrations of aqueous humour proteins at baseline and during treatment. From the data of 48 treatment-naïve nAMD eyes that received intravitreal ranibizumab pro re nata for up to 12 months, we used the aqueous humour concentrations of C-X-C motif chemokine ligand 1 (CXCL1), CXCL12, CXCL13, interferon-γ-induced protein 10, monocyte chemoattractant protein 1 (MCP-1), C-C motif chemokine ligand 11, interleukin 6 (IL-6), IL-10, and matrix metalloproteinase 9 (MMP-9). After stepwise regression, multivariate analysis was performed to identify which predictors were significantly associated with best-corrected visual acuity (BCVA) changes and the number of injections. The results demonstrated that besides male sex (β coefficient = -0.088, P = 0.040) and central retinal thickness (β coefficient = 0.00051 per μm, P = 0.027), MCP-1 (β coefficient = 0.44, P < 0.001) and IL-10 (β coefficient = -0.16, P = 0.033) were significantly correlated with baseline BCVA. Additionally, high MCP-1 at baseline (β coefficient = -0.20, P = 0.015) and low CXCL13 at baseline (β coefficient = 0.10, P = 0.0054) were independently associated with better BCVA change at 12 months. High MMP-9 at the first injection (β coefficient = 0.56, P = 0.01), CXCL12 at the third injection (β coefficient = 0.10, P = 0.0002), and IL-10 at the third injection (β coefficient = 1.3, P = 0.001) were predictor variables associated with the increased number of injections. In conclusion, aqueous humour protein concentrations may have predictive abilities of BCVA change over 12 months and the number of injections in pro re nata treatment of exudative nAMD.

Interactions among thyroid hormone (FT4), chemokine (MCP-1) and neurotrophin (NGF-β) levels studied in Hungarian postmenopausal and obese women

Thyroid dysfunction is more frequent in postmenopause and metabolic syndrome characterized by increased proinflammatory cytokines (IL-1, IL-6, TNFα), insulin resistance and overweight.Serum levels of monocyte chemoattractant protein-1 (MCP-1) chemokine and nerve growth factor-β (NGF-β) and their effects were studied on thyroid hormone levels in 133 Hungarian women (postmenopausal 66, obese 32, control 35). MCP-1 and NGF-β levels were measured with enzyme-linked, and thyroid hormones with chemiluminescence immunoassays.Subclinical hypothyroidism in postmenopause (7/66 vs 1/32 cases) and the presence of low FT4 levels in obese women were more frequent (6/32 vs 2/66 cases, p < 0.0447). Obese women showed reduced serum FT4 and higher MCP-1 or NGF-β levels compared to those in postmenopausal women [geometric mean (95%CI): 13.6 (10.9–21.69) vs 15.37 (9.06–20.42) pmol/l, p < 0.003 for FT4, and 19.36 (14.27–26.26) vs 17.29 (12.65–23.63) ng/ml, p < 0.0013 for MCP-1 or 18.64 (6.8–51.11) vs 14.01 (8.59–22.83) ng/ml, p < 0.0003 for NGF-β]. Serum FT4 levels inversely associated with MCP-1 (p < 0.0023, r = −0.1971) or estradiol levels (p < 0.0286, r = −0.1913), and positively associated with age (p < 0.0175, r = 0.2058). As opposed to estradiol and NGF-β levels, BMI had no effects on serum FT4 levels in postmenopausal and obese women forming 3 subgroups displaying only MCP-1, both MCP-1 and NGF-β positivities or no positivities at all.In summary, not only proinflammatory cytokines, but also MCP-1 chemokine and NGF-β levels can play a role in reduced serum FT4 levels in postmenopausal and obese women. Particularly, the decreased FT4 levels were connected to both increased MCP-1 and NGF-β levels in obese women.

Inflammatory profile dysregulation in nuclear workers occupationally exposed to low-dose gamma radiation.

ABSTRACTChronic inflammation is a common denominator linking a wide range of health conditions, including tissue response to radiation exposure. This pilot study investigates whether inflammatory cytokines—interleukins IL-6, −8, −10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNFα)—can be used as early biomarkers of radiation-induced adverse health effects in occupationally exposed individuals. The study included 33 workers externally exposed to gamma radiation from the nuclear industry with cumulated doses from 0.11 to 190 mSv and 42 non-exposed controls of comparable age and socio-economic status. IL-6, IL-8, MCP-1, TNFα and IL-10 were analyzed by enzyme-linked assay (ELISA) in blood plasma samples. Total antioxidant status (TAS) of blood plasma was determined by a colorimetric assay. The radiation-exposed and control groups measured significantly different levels of MCP-1, TNFα and IL-10. Seventy-five percent of radiation workers had either high MCP-1 levels or low IL-10 levels and 30% had all three cytokines dysregulated. Approximately 50% of workers showed upregulated antioxidant status, which appeared to compensate the pro-inflammatory cytokine shift in these individuals. In contrast, only 2% of the control subjects were found to have three dysregulated cytokines, and all of them measured within the normal TAS range. The present study may represent an important step towards the establishment of a reliable set of biomarkers for health-risk estimation in population cohorts exposed to low radiation doses.