Plasma Monocyte Chemoattractant Protein-1 Research Articles

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 < 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.

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

BackgroundMatrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.MethodsWe investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16–20 weeks.ResultsDKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs.ConclusionWe conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

Association Between Plasma Levels of Monocyte Chemoattractant Protein-1 (MCP-1) and 28-Day Mortality in Elderly Patients with Sepsis: A Retrospective Single-Center Study.

BACKGROUND Previous studies have identified an association between plasma levels of the inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1), and outcomes for patients with sepsis. This retrospective single-center study assessed the association between plasma levels of MCP-1 and 28-day mortality in 136 patients ≥65 years diagnosed with sepsis between October 2020 and October 2021. MATERIAL AND METHODS The objective was to compare and analyze the parameters in the survival group (n=35) and the 28-day mortality group (n=101), including Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), plasma MCP-1, and laboratory test results. Plasma MCP-1 was quantified by cytokine test kit (LKTM014B, R&D). Statistical analysis was carried out in SPSS 26.0 and MedCalc 92.1.0 software. RESULTS The 28-day mortality group exhibited higher levels of SOFA, APACHEII, and plasma MCP-1 (all P<0.001), as well as lower levels of albumin, compared to the survival group (P<0.05). The logistic regression analysis findings indicated that SOFA, APACHEII, plasma MCP-1, and SBP are all independent risk factors for 28-day mortality. The area under the curve for SOFA, APACHEII, MCP-1, MCP-1+ SOFA, and MCP-1+APACHEII were 0.845, 0.744, 0.712, 0.879, and 0.822, respectively. MCP-1+SOFA exhibited higher sensitivity than SOFA alone. Furthermore, the assessment values of plasma MCP-1 combined with SOFA were superior to those of APACHE II or plasma MCP-1 (Z₁=2.661, Z₂=3.272, both P<0.01). CONCLUSIONS The findings from this study from a single center support those of previous studies that increased plasma levels of MCP-1 are significantly associated with 28-day mortality in patients with sepsis.

Development of a novel humanized mouse model to study bronchopulmonary dysplasia.

The role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia. Cord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay. Across the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P < 0.05). Monocyte injection was associated with increased microvessel density at P14 as compared with placebo (26.7 ± 0.73 vs. 18.8 ± 1.7 vessels per lung field; P < 0.001). Pooled analysis of patients revealed that injection of monocytes from births complicated by lower GA and preeclampsia was associated with changes in alveolarization and vascularization under normoxic conditions. These differences were modified by hyperoxia. CD45+ cell count was positively correlated with plasma monocyte chemoattractant protein-1 (P < 0.001) and macrophage inflammatory protein-1β (P < 0.01). Immunohistochemical staining for human CD206 and mouse F4/80 confirmed absence of macrophages in MISTRG lungs at P14. Despite the inherent absence of macrophages in early stages of lung development, immunodeficient MISTRG mice revealed changes in alveolar and microvascular development induced by human monocytes. MISTRG mice exposed to neonatal hyperoxia may serve as a novel model to study isolated effects of human monocytes on alveolar and pulmonary vascular development.

Characterising the Cytokine and Circulating Immune Cell Response After a Single Bout of Eccentric Stepping Exercise in Healthy Untrained Males

Abstract Purpose The mechanisms that underpin exercise-induced muscle damage and recovery are believed to be mediated, in part, by immune cells recruited to the site of injury. The aim of this study was to characterise the effects of muscle damage from bench-stepping on circulating cytokine and immune cell populations post-exercise and during recovery. Methods Ten untrained, healthy male volunteers completed 30 min of bench-stepping exercise to induce muscle damage to the eccentrically exercised leg. Muscle function, muscle pain and soreness were measured before, immediately after and 24, 48 and 72 h after exercise. Plasma creatine kinase, cartilage oligomeric matrix protein, cytokines and circulating immune cell phenotyping were also measured at these timepoints. Results Significant decreases occurred in eccentric, isometric and concentric (P = 0.018, 0.047 and 0.003, respectively) muscle function in eccentrically, but not concentrically, exercised quadriceps post-exercise. Plasma monocyte chemoattractant protein (MCP)-1 concentrations significantly increased immediately after exercise (69.0 ± 5.8 to 89.5 ± 10.0 pg/mL), then declined to below pre-exercise concentrations (58.8 ± 6.3 pg/mL) 72 h after exercise. These changes corresponded with the significant decrease of circulating CD45+ CD16− CD14+ monocytes (5.8% ± 1.5% to 1.9% ± 0.5%; Pre-exercise vs. 48 h) and increase of CD45+ CD3+ CD56− T-cells (60.5% ± 2.2% to 66.1% ± 2.1%; Pre-exercise vs. 72 h) during recovery. Conclusion Bench-stepping induced muscle damage to the quadriceps, which mediated systemic changes in MCP-1, monocytes and T-cells immediately post-exercise and during recovery. Further research is needed to clarify how modulations in immune subpopulations facilitate muscle recovery and adaptation following muscle damage.

Association of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis

Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10years; 48% were men; mean eGFR was 96±16ml/min/1.73m2; mean LVmvr was 0.93±0.18g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria.

The Roles of Aerobic Exercise and Folate Supplementation in Hyperhomocysteinemia-Accelerated Atherosclerosis.

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Effective interventions to reduce HHcy-accelerated atherosclerosis are required. This study aimed to investigate the effects of aerobic exercise (AE) and folate (FA) supplementation on plasma homocysteine (Hcy) level and atherosclerosis development in a mouse model. Six-week-old female apoE-/- mice were grouped into five groups (N = 6-8): HHcy (1.8 g/L DL-homocysteine (DL-Hcy) in drinking water), HHcy + AE (1.8 g/L DL-Hcy and aerobic exercise training on a treadmill), HHcy + FA (1.8 g/L DL-Hcy and 0.006% folate in diet), HHcy + AE + FA (1.8 g/L DL-Hcy, 0.006% folate, and aerobic exercise training on a treadmill), and a control group (regular water and diet). All treatment was sustained for 8 weeks. Triglyceride, cholesterol, lipoprotein, and Hcy levels were determined enzymatically. Plaque and monocyte chemoattractant protein-1 (MCP-1) expression levels in mouse aortic roots were evaluated by immunohistochemistry. Compared to the HHcy group (18.88 ± 6.13 μmol/L), plasma Hcy concentration was significantly reduced in the HHcy + AE (14.79 ± 3.05 μmol/L, p = 0.04), HHcy + FA (9.4 ± 3.85 μmol/L, p < 0.001), and HHcy + AE + FA (9.33 ± 2.21 μmol/L, p < 0.001) groups. Significantly decreased aortic root plaque area and plaque burden were found in the HHcy + AE and HHcy + AE + FA groups compared to those in the HHcy group (both p < 0.05). Plasma MCP-1 level and MCP-1 expression in atherosclerotic lesions were significantly decreased in the HHcy + AE and HHcy + AE + FA groups compared to the HHcy group (all p < 0.05). AE reduced atherosclerosis development in HHcy apoE-/- mice independently of reducing Hcy levels. FA supplementation decreased plasma Hcy levels without attenuating HHcy-accelerated atherosclerosis. AE and FA supplementation have distinct mechanisms in benefiting atherosclerosis.

Sensitivity to Iron‐Mediated Pro‐Inflammatory Signaling in NZBWF1 Mice, a Model of Systemic Lupus Erythematosus

IntroductionThe autoimmune disease systemic lupus erythematosus predominantly affects women and can lead to lupus nephritis (LN) as a common and severe complication in approximately 50% of patients. The F1 hybrid of New Zealand Black (NZB) X New Zealand White (NZW) mice (NZBWF1) is a well‐established mouse model to study LN. Our previous data indicated that the onset of albuminuria in female 34‐week NZBWF1 mice was associated with renal iron accumulation, and iron may contribute to renal injury. This study tests the hypothesis that 34‐week NZBWF1 lupus mice are sensitized to iron's injurious and pro‐inflammatory effects compared to 8‐week normal NZBWF1 mice. As a means to differentiate effects of age as opposed to development of lupus, parallel experiments were performed in 8 and 34‐week‐old NZW mice as healthy controls.Methods and ResultsFemale 8‐week (pre‐autoimmune) and 34‐week NZBWF1 (autoimmune, pre‐albuminuric) mice together with age‐matched healthy control NZW mice underwent 24 h urine collection to confirm non‐albuminuric status. Mice were then were injected i.v. with a single dose of iron‐sucrose (2 mg elemental iron) or vehicle (saline) and sacrificed 24 h later. Plasma blood urea nitrogen (BUN) was measured to determine renal health, SRY‐Box Transcription Factor 9 (SOX‐9)‐ positive cells were quantified in kidney sections as an early tubular injury marker, and plasma monocyte chemoattractant protein‐1 (MCP‐1) was measured by ELISA as an inflammatory marker. Lupus (NZBWF1) and control mice (NZW) were compared within strains by age (8‐week vs. 34‐week) and treatment (Vehicle vs. Treatment). All statistical analyses were done by 2‐way ANOVA (n=7‐12/group), and post‐hoc testing was done using Bonferroni. Iron‐sucrose treatment significantly increased plasma MCP‐1 concentrations in the NZBWF1 and the control NZW mice (PTreatment &lt; 0.01). There was no significant effect of age on this effect for NZW mice (PTreatment*Age = 0.2); however, in NZBWF1 mice, the iron‐sucrose induced increase in MCP‐1 was significantly greater in 34‐week compared to 8‐week mice (PTreatment*Age &lt; 0.05; P&lt;0.05 by posthoc test). BUN was significantly increased with age in both strains (PAge&lt;0.05), but there was no significant effect of iron‐sucrose (PTreatment&gt;0.05). The numbers of SOX‐9+ tubular cells increased in the 34‐week NZBWF1 mice compared to 8‐week mice (Page&lt;0.05), consistent with early stages of renal injury, but iron sucrose treatment did not show any significant effect (PTreatment= 0.9).ConclusionOur data suggest that at the autoimmune but pre‐albuminuric stage, 34‐week NZBWF1 mice show increased pro‐inflammatory responsiveness to iron‐mediated stress. Further studies to determine whether the enhanced pro‐inflammatory effects of iron contribute to pathology in lupus nephritis are ongoing.

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults.

We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aβ] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73-80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4years. In the models utilizing plasma Aβ alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aβ levels. Models incorporating Aβ plus multiple plasma biomarkers performed similarly to models included Aβ alone in predicting dementia and CDR progression. However, improving Aβ model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aβ, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted β [95% CI], - 0.21 [- 0.35 to - 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aβ models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aβ pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance.

Diagnostic accuracy of muscle ultrasound and plasma monocyte chemoattractant protein-1 for ICU-acquired weakness in patients with sepsis

To explore the diagnostic accuracy of muscle ultrasound and plasma monocyte chemoattractant protein-1 (MCP-1) for ICU-acquired weakness (ICU-AW) in patients with sepsis. A prospective observational study was conducted. Patients with sepsis admitted to the intensive care unit (ICU) of Henan Provincial People's Hospital from April 2021 to October 2021 were enrolled. The demographic data were collected. The enrolled patients were evaluated with Medical Research Council (MRC) score every day until discharged from ICU. During this period, patients with total MRC score < 48 (for two consecutive times and a time interval of 24 hours) were divided into ICU-AW group, those with total MRC score ≥ 48 were served as non-ICU-AW group. On the 1st, 4th and 7th day following admission into ICU, ultrasound was used to measure the muscle linear thickness of the rectus femoris (RF-MLT), the cross sectional area of the rectus femoris (RF-CSA) and the muscle linear thickness of the vastus intermedius muscle (VI-MLT). And meanwhile, the plasmas samples of patients were collected to measure MCP-1 concentration by enzyme-linked immunosorbent assay (ELISA). The difference of each index was compared between the ICU-AW group and the non-ICU-AW group. The risk factors of ICU-AW in patients with sepsis were analyzed by binary Logistic regression. Besides, receiver operator characteristic curve (ROC curve) was plotted, the diagnostic value of ultrasound parameters and plasma MCP-1 level for ICU-AW in patients with sepsis was analyzed. A total of 99 septic patients were enrolled, with 68 patients in the ICU-AW group and 31 patients in the non-ICU-AW group. Compared with the patients in the ICU-AW group, the patients in the non-ICU-AW group tended to be older, and had higher sequential organ failure assessment (SOFA) score, higher acute physiology and chronic health evaluation II (APACHE II) score, higher rates of septic shock, higher blood lactic acid and lower Glasgow coma score (GCS). Binary Logistic regression analysis showed that APACHE II score and septic shock were the risk factors of ICU-AW for septic patients [odds ratio (OR) and 95% confidence interval (95%CI) were 1.310 (1.138-1.509) and 0.232 (0.072-0.746), respectively, both P < 0.05]. The RF-MLT, RF-CSA and VI-MLT on the 1st, 4th and 7th ICU day was falling over time. Compared with the patients in the ICU-AW group, the patients in the non-ICU-AW group had smaller RF-MLT on the 7th day [cm: 0.32 (0.22, 0.47) vs. 0.45 (0.34, 0.63), P < 0.05] and higher 7-day RF-CSA atrophy rate [25.85% (10.37%, 34.28%) vs. 11.65% (2.28%, 22.41%), P < 0.05]. According to ROC curve analysis, 7-day RF-MLT had diagnostic value for ICU-AW of septic patients. Area under ROC curve (AUC) was 0.688 (95%CI was 0.526-0.849); when the cut-off value was 0.41 cm, the sensitivity and the specificity were 66.7% and 68.4%. The levels of plasma MCP-1 in the ICU-AW group were significantly higher than those in the non-ICU-AW group on the 1st, 4th and 7th day. ROC curve analysis showed that the plasma MCP-1 levels on the 1st, 4th and 7th day played a significant role to diagnose ICU-AW for septic patients, the AUC and 95%CI were 0.732 (0.629-0.836), 0.865 (0.777-0.953), 0.891 (0.795-0.986), respectively. When the cut-off values were 206.3, 410.9, 239.5 ng/L, the sensitivity was 87.1%, 64.0%, 82.4%, and the specificity was 54.4%, 96.1%, 86.2%, respectively. The muscle mass parameters on the 7th day of bedside ultrasound and plasma MCP-1 levels had certain diagnostic values for ICU-AW in patients with sepsis.

MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology.

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

Protective effects of rosmarinic acid against azoxymethane-induced colorectal cancer in rats.

Colorectal cancer (CRC) incidence is increasing gradually and has been become one of the most common cancers worldwide. Hence, it is important to discover cheap, naturally occurring compounds to be effective in suppressing the devastating effect of colon-related tumors. Rosmarinic acid (RA), one of the compounds of plant origin, possesses attractive features for use as an agent for cancer prevention and treatment. This study investigated the ability of RA to prevent azoxymethane (AOM)-induced rat colon carcinogenesis by evaluating the effect of RA on tumor formation and circulatory oxidant-antioxidant status. Moreover, plasma levels of adiponectin (APN) monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) were detected by enzyme linked immunosorbent assay. The animals were divided into three groups: Control, AOM, and AOM + RA. Rats were fed a modified pellet diet (15.8% peanut oil was added to the standard diet) during the experimental period. Colon cancer was formed by applying 15 mg/kg AOM intraperitoneal once a week for 4 weeks in both the CRC group and AOM + RA group. Besides AOM, AOM + RA group received 5 mg/kg body weight RA orally every day during the study. The results showed that adenocarcinoma rates formed87.5% ofthe AOM group. With treatment of RA, a reduction in the incidence of adenocarcinoma was observed in the AOM + RA group. The plasma MCP-1, IL-6, and TO levels were significantly higher, APN and TAS levels were significantly lower in the AOM group with respect tocontrols. In addition, there was a significant increase in TAS levels in the RA treatment group compared to the AOM group. These findings suggested that RA may be beneficial in preventing AOM-induced colon carcinogenesis formation.

INVESTIGATION OF CCL2/MCP-1 LEVEL IN BLOOD SERUM OF SURGICAL PAEDIATRIC PATIENTS AS MARKER OF ADEQUACY OF PERIOPERATIVE PAIN MANAGEMENT

BACKGROUND. Surgical treatment leads to the development of postoperative pain in 80% of cases. Therefore, prompt and effective pain management is among the key priorities for healthcare professionals. The aim of the study is to determine the CCL2 / MCP-1 level in the blood serum of patients in the postoperative period under different analgesic methods and to assess the relationship between the inflammatory response and the pain response using the Visual Analog Scale (VAS). Materials and methods. We studied 30 pediatric patients with acute surgical abdominal pathologies, aged 8 to 15 years for urgent surgical procedures requiring general anesthesia. The patients were divided into 3 groups according to selected methods of intraoperative anesthesia: the 1 group included 12 patients, who received standard general anesthesia, the 2 group involved 10 patients, who received general anesthesia and infiltration anesthesia of the wound with 0.5% bupivacaine, a local anesthetic, and the 3 group included 8 children, who received general anesthesia and wound infiltration with 0.5% bupivacaine plus adjuvant (dexamethasone – 4 mg). One hour before surgery and in the postoperative period (3 and 12 hours after surgery), the patients were asked to fill in a pain diary assessing the intensity of pain syndrome and its dynamic characteristics using a visual analogue scale (VAS). Investigation to the rate of inflammatory response was assessed by monocytechemoattractant protein-1 (MCP-1). RESULTS. We found out that the plasma CCL2 / MCP-1 level in the patients prior surgery averaged 17.25 ± 7.8 pg / ml; (p &lt;0.05), the baseline plasma CCL2 / MCP-1 levels in the patients of all groups were nearly the same. In patients of the 1st group there was an increase in the level of CCL2 / MCP-1 in the blood plasma (2.3 times) 3 hours after surgery, p &lt;0.05, and 12 hours after surgery, the level of the studied chemokine increased by 6.7 times compared with the results obtained before surgery (p &lt;0,05). Patients in the second group had no increase in inflammatory markers after 3 hours, but after 12 hours after surgery, plasma CCL2 / MCP-1 level significantly increased in 2.2 times compared with the values of the chemokine before surgery (p &lt;0,05). In patients of group 3, the level of CCL2 / MCP-1 in blood plasma did not change statistically at 3 hours and 12 hours after surgery, although on average it decreased quantitatively. In the preoperative period the pain intensity ranked by the VAS scale averaged 7.8 scores and almost did not differ in the all study groups, but in the postoperative period, the degree of pain intensity was quantitatively the lowest in group 3 compared with 1 and 2 study groups. CONCLUSION. The dynamics of plasma CCL2 / MCP-1 levels in the patients reflects the development of the general adaptation syndrome in response to trauma. The CCL2 / MCP-1 level is significantly influenced by the type of anesthesia. The multimodal approach to the pain management is considered as the most effective and optimal method in perioperative care of patients

Association Between Plasma Monocyte Trafficking-Related Molecules and Future Risk of Depression in Older Adults.

The recruitment of monocytes to the brain plays an important role in the development of depression. However, the association between plasma biomarkers of monocyte trafficking and depression is unclear. This study is aimed to examine the effects of plasma monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) on the risk of depression. Data were acquired from an ongoing prospective cohort study involving randomly sampled, community-dwelling Korean older adults, which has been followed every 2 years. We included 1539 euthymic older adults (age = 68.2 [5.6] years; 51.7% were women) without a history of major psychiatric disorders and dementia and neurological diseases. Geriatric psychiatrists diagnosed incident depression through a structured interview using the Korean version of the Mini-International Neuropsychiatric Interview. Depression had developed in 134 (8.7%) participants during the follow-up period of 5.7 (0.8) years. The high-plasma MCP-1 tertile group showed twofold higher risk of depression than the low-plasma MCP-1 tertile group (hazards ratio = 2.00, 95% confidence interval = 1.27-3.13, p = .003). The association between high levels of plasma MCP-1 and future risk of depression was significant in the middle-plasma ICAM-1 and VCAM-1 tertile groups; the high-plasma MCP-1 tertile group showed about fourfold higher risk of depression than the low-plasma MCP-1 tertile group. Molecules involved in monocyte trafficking may be good candidates as diagnostic biomarkers and/or therapeutic targets for late-life depression.

Relationships Between Age, Frailty, Length of Care Home Residence and Biomarkers of Immunity and Inflammation in Older Care Home Residents in the United Kingdom.

Aging is associated with changes to the immune system, collectively termed immunosenescence and inflammageing. However, the relationships among age, frailty, and immune parameters in older people resident in care homes are not well described. We assessed immune and inflammatory parameters in 184 United Kingdom care home residents aged over 65 years and how they relate to age, frailty index, and length of care home residence. Linear regression was used to identify the independent contribution of age, frailty, and length of care home residence to the various immune parameters as dependent variables. Participants had a mean age (±SD) of 85.3 ± 7.5 years, had been residing in the care home for a mean (±SD) of 1.9 ± 2.2 years at the time of study commencement, and 40.7% were severely frail. Length of care home residence and frailty index were correlated but age and frailty index and age and length of care home residence were not significantly correlated. All components of the full blood count, apart from total lymphocytes, were within the reference range; 31% of participants had blood lymphocyte numbers below the lower value of the reference range. Among the components of the full blood count, platelet numbers were positively associated with frailty index. Amongst plasma inflammatory markers, C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1ra), soluble E-selectin and interferon gamma-induced protein 10 (IP-10) were positively associated with frailty. Plasma soluble vascular cell adhesion molecule 1 (sVCAM-1), IP-10 and tumor necrosis factor receptor II (TNFRII) were positively associated with age. Plasma monocyte chemoattractant protein 1 was positively associated with length of care home residence. Frailty was an independent predictor of platelet numbers, plasma CRP, IL-1ra, IP-10, and sE-selectin. Age was an independent predictor of activated monocytes and plasma IP-10, TNFRII and sVCAM-1. Length of care home residence was an independent predictor of plasma MCP-1. This study concludes that there are independent links between increased frailty and inflammation and between increased age and inflammation amongst older people resident in care homes in the United Kingdom. Since, inflammation is known to contribute to morbidity and mortality in older people, the causes and consequences of inflammation in this population should be further explored.

Long Term High Protein Diet Feeding Alters the Microbiome and Increases Intestinal Permeability, Systemic Inflammation and Kidney Injury in Mice.

This study evaluates the effects of a chronic high protein diet (HPD) on kidney injury, intestinal permeability and gut microbiota perturbations in a mouse model. Mice are fed a diet containing either 20% or 52% energy from protein for 24 weeks; protein displaced an equivalent amount of wheat starch. The HPD does not alter glycemic control or body weight. The HPD induces kidney injury as evidenced by increase in albuminuria, urinary kidney injury molecule-1, blood urea nitrogen, urinary isoprostanes and renal cortical NF-κB p65 gene expression. HPD decreases intestinal occludin gene expression, increases plasma endotoxin and plasma monocyte chemoattractant protein-1, indicating intestinal leakiness and systemic inflammation. Cecal microbial analysis reveals that HPD feeding does not alter alpha diversity; however, it does alter beta diversity, indicating an altered microbial community structure with HPD feeding. Predicted metagenome pathway analysis demonstrates a reduction in branched-chain amino acid synthesis and an increase of the urea cycle with consumption of a HPD. These results demonstrate that long term HPD consumption in mice causes albuminuria, systemic inflammation, increase in gastrointestinal permeability and is associated with gut microbiome remodeling with an increase in the urea cycle pathway, which may contribute to renal injury.

Plasma PTX3, MCP1 and Ang2 are early biomarkers to evaluate the severity of sepsis and septic shock.

Sepsis is associated with significant mortality. Early diagnosis and prognosis of patients with sepsis is still a difficult clinical challenge. In this study, the ability of plasma PTX3 (pentraxin 3), MCP1 (monocyte chemoattractant protein 1) and Ang (angiopoietin)1/2 was investigated to evaluate the severity of sepsis. Blood samples were obtained from 43 patients with sepsis. A total of 33 post‐surgery patients with infections and 25 healthy individuals served as controls. The results showed that plasma PTX3, MCP1 and Ang2 significantly increased in patients on the first day of septic shock onset, while sepsis patients had significantly higher Ang2 level, compared with controls. Furthermore, PTX3, MCP1 and Ang2 had high AUROC values in patients with septic shock on the first day of sepsis onset. The findings suggest that PTX3, MCP1 and Ang2 maybe early predictors to evaluate the severity of sepsis and septic shock with the latest Sepsis 3.0 definitions.

Antiobesogenic Potential of Seaweed Dulse (Palmaria palmata) in High-fat Fed C57BL/6 J Mice (P21-014-19)

Abstract Objectives The growing obesity challenge around the world continues to warrant interventions that could mitigate disease onset and progression. This study aimed to evaluate the potential of seaweed supplementation using dulse (Palmaria palmata) and wakame (Undaria pinnatifida), in improving caloric management and insulin resistance, and mitigating inflammation and gut microbiome shifts in diet-induced obesity in C57BL/6 J mice. Methods Twenty-four individually-caged C57BL/6 J mice were fed ad libitum with a high-fat diet (HFD) with and without seaweed inclusion, and another 8 mice for low-fat control (n = 8). Freeze-dried dulse and wakame were incorporated in the test diets at 5% inclusion level. Glucose tolerance test was performed during week 4 to assess insulin resistance state of test animals. After 9 weeks, fresh fecal samples were collected from all 32 mice prior to necropsy. These were used for the gut microbiome analysis using MiSeq. Fecal triglyceride levels were determined using Infinity Triglycerides Kit while plasma Monocyte Chemoattractant Protein-1 (MCP-1) was quantified using ELISA. Results Despite higher feed intake, dulse-fed mice had lower feed efficiency, indicating less weight gain from same amount of diet. This group also showed improved early-phase insulin response compared to HFD and wakame-fed groups. Plasma inflammatory marker MCP-1 levels were also significantly reduced in dulse-fed mice. While liver triglyceride levels were not affected with the dietary inclusion, fecal samples showed that there was higher lipid being excreted in dulse-fed group. This suggests that caloric excess and inflammatory progression may have been mitigated by increased lipid excretion in the feces. Gut microbiome analysis showed that dulse-fed mice retained microflora composition that is comparable to those fed with low-fat diet. Conclusions Our work reveals that dulse supplementation improved obesity and associated metabolic parameters by increasing lipid excretion, improving early-phase insulin response, and mitigating both inflammation and gut microbiome shifts associated with HFD, more effectively than wakame. These provide initial evidences that dietary inclusion of dulse holds therapeutic promise in mitigating diet-induced obesity. Funding Sources Oregon State University Agricultural Research Foundation. Supporting Tables, Images and/or Graphs

Monocyte Chemoattractant Protein-1, a Possible Biomarker of Multiorgan Failure and Mortality in Ventilator-Associated Pneumonia.

Ventilator-associated pneumonia (VAP) leads to increased patients’ mortality and medical expenditure. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the pathogenesis of lung inflammation and infection. Therefore, the plasma concentration of MCP-1 was assessed and correlated with the clinical course in VAP patients. This retrospective observational study recruited 45 healthy volunteers, 12 non-VAP subjects, and 30 VAP patients. The diagnostic criteria for VAP were based on the American Thoracic Society guidelines, and the level of plasma MCP-1 was determined by ELISA. Plasma MCP-1 concentration was significantly elevated in the acute stage in VAP patients when compared with the control (p < 0.0001) and non-VAP patient groups (p = 0.0006). Subsequently, it was remarkably decreased following antibiotic treatment. Moreover, plasma MCP-1 concentration was positively correlated with indices of pulmonary dysfunction, including the lung injury score (p = 0.02) and the oxygenation index (p = 0.02). When patients with VAP developed adult respiratory distress syndrome (ARDS), their plasma MCP-1 concentrations were significantly higher than those of patients who did not develop ARDS (p = 0.04). Moreover, plasma MCP-1 concentration was highly correlated with organ failure scores, including simplified acute physiology score II (SAPS II, p < 0.0001), sequential organ failure assessment score (SOFA, p < 0.0001), organ dysfunctions and/or infection (ODIN, p < 0.0001), predisposition, insult response and organ dysfunction (PIRO, p = 0.005), and immunodeficiency, blood pressure, multilobular infiltrates on chest radiograph, platelets and hospitalization 10 days before onset of VAP (IBMP-10, p = 0.004). Our results demonstrate that plasma MCP-1 is an excellent marker for recognizing VAP when the cut-off level is set to 347.18 ng/mL (area under the curve (AUC) = 0.936, 95% CI = 0.863–0.977). In conclusion, MCP-1 not only could be a biological marker related to pulmonary dysfunction, organ failure, and mortality in patients with VAP, but also could be used for early recognition of VAP.

Cardioprotective Effects of Eritoran During Polymicrobial Sepsis Through Decreases of p38MAPK/NF-κB Signaling Pathway

Background: Sepsis is a systemic inflammatory response usually correlates with multiorgan dysfunction. Myocardial dysfunction is one of adverse outcomes in septic patients resulted in high mortality rate. Aim: To study the impact of eritoran in attenuation of cardiac depression during polymicrobial sepsis via decreased of phospho-p38MAPK/NF-κB signaling pathway. Methods and materials: Polymicrobial sepsis induced via cecal ligation and puncture model (CLP), in 8-12 weeks' age albino mice, 1hr prior to CLP mice were treated with IP eritoran (5mg/kg). Twenty-four hours post CLP hemodynamic parameters including: heart rate, ejection fraction, LVEDP, LVSP and cardiac output, were carried out using micro-tipped transducer catheter. Plasma levels of proinflammatory cytokines, including TNF-α, IL-1β and IL-6, chemokine MCP-1 and cTn-I were measured via ELISA analysis. Phosphorylation degree of P38 MAPK and NF-κB carried out through western blot technique. Results: Mice were treated with eritoran displayed improvement of LV function (Ejection fraction: 42.4 ± 1.1% versus 27.8 ± 3% in CLP mice). The attenuation of cardiac depression in eritoran treated mice was associated with lower levels of monocyte chemoattractant protein-1 (MCP-1) in plasma, and reduction in the levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). Furthermore, eritoran treated mice displayed less expression levels of phosphorylation p38-MAPK and NF-κB. Conclusion: eritoran can attenuate the cardiac dysfunction during polymicrobial sepsis possibly via a reduction of proinflammatory cytokines through decreased of both p38MAPK and NF-κB activation.