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1.
Surgery ; 176(1): 154-161, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38599982

ABSTRACT

BACKGROUND: Infections are commonly seen in wounds. The overall infection rate is 1.8% to 4.2%. Improper infection management can lead to serious conditions and may progress to life-threatening sepsis. Because there is a need for assistance in predicting wound infection before obvious clinical symptoms, the measurement of cytokines in wound tissue fluids has attracted our attention for determining the overall status of wound infection. Our intent was to assess the potential biomarkers in the diagnosis of wound infection. METHODS: We collected 146 tissue fluids (acute: 59, chronic: 61, and normal: 26) for analysis of biomarkers using a human cytokine array. Serum C-reactive protein was also measured from 104 patients. The sensitivity and specificity of significant wound cytokines and serum C-reactive protein for the diagnosis of wound infection were evaluated. RESULTS: Among biomarkers examined, serum C-reactive protein and tissue C-reactive protein were highly expressed in acute infection wounds, whereas monocyte chemoattractant protein-1 was significantly expressed in chronic infection wounds. Because the expression of wound biomarkers varied in different types of wounds, relationships among them were studied. A high correlation between tissue C-reactive protein and interleukin-8 (R2 = 0.7) and a moderate correlation between systemic and local C-reactive protein (R2 = 0.47) were observed. In addition, tissue monocyte chemoattractant protein-1 had better sensitivity (74%) and specificity (65%) in the diagnosis of wound infection. Moreover, combined serum C-reactive protein with monocyte chemoattractant protein-1 examination provided a higher area under the curve in the receiver operator characteristic curve (0.75). CONCLUSION: We found that tissue monocyte chemoattractant protein-1 is a superior diagnostic marker for assistance with the diagnosis of wound infection.


Subject(s)
Biomarkers , C-Reactive Protein , Chemokine CCL2 , Sensitivity and Specificity , Humans , Chemokine CCL2/analysis , Chemokine CCL2/metabolism , Chemokine CCL2/blood , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Biomarkers/metabolism , Biomarkers/analysis , Male , Female , Middle Aged , Aged , Adult , Wound Infection/diagnosis , Wound Infection/metabolism , Aged, 80 and over , Interleukin-8/analysis , Interleukin-8/metabolism , ROC Curve , Body Fluids/chemistry , Body Fluids/metabolism
2.
Neurotoxicology ; 88: 65-78, 2022 01.
Article in English | MEDLINE | ID: mdl-34742947

ABSTRACT

Synthetic cathinones are used as stimulants of abuse. Many abused drugs, including stimulants, activate nuclear factor-κB (NF-κB) transcription leading to increases in NF-κB-regulated pro-inflammatory cytokines, and the level of inflammation appears to correlate with length of abuse. The purpose of this study was to measure the profile of IL-1α, IL-1ß, IL-6, CCL2 and TNF-α in brain and plasma to examine if drug exposure alters inflammatory markers. Male and female Sprague-Dawley rats were trained to self-administer α-pyrrolidinopentiophenone (α-PVP) (0.1 mg/kg/infusion), 4-methylmethcathinone (4MMC) (0.5 mg/kg/infusion), or saline through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Cytokine levels were examined in amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus, and plasma. Rats acquired synthetic cathinone self-administration, and there were no sex differences in drug intake. Synthetic cathinone self-administration produced sex differences in IL-1α, IL-1ß, IL-6, CCL2 and TNF-α levels. There were widespread increases in inflammatory cytokines in the brains of male rats compared to females, particularly for 4MMC, whereas females were more likely to show increased inflammatory cytokines in plasma compared to saline groups than males. Furthermore, these sex differences in cytokine levels were more common after LgA access to synthetic cathinones than ShA. These results suggest that synthetic cathinone use likely produces sex-selective patterns of neuroinflammation during the transition from use to abuse. Consequently, treatment need may differ depending on the progression of synthetic cathinone abuse and based on sex.


Subject(s)
Alkaloids/pharmacology , Central Nervous System Stimulants/pharmacology , Cytokines/analysis , Alkaloids/administration & dosage , Animals , Brain Chemistry/drug effects , Central Nervous System Stimulants/administration & dosage , Chemokine CCL2/analysis , Chemokine CCL2/blood , Cytokines/blood , Female , Interleukin-1alpha/analysis , Interleukin-1alpha/blood , Interleukin-1beta/analysis , Interleukin-1beta/blood , Interleukin-6/analysis , Interleukin-6/blood , Male , Neuroinflammatory Diseases/chemically induced , Neuroinflammatory Diseases/metabolism , Rats , Rats, Sprague-Dawley , Self Administration , Sex Factors , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/blood
3.
Bull Exp Biol Med ; 172(2): 250-253, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34855084

ABSTRACT

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/prevention & control , Cytokines/analysis , Graft vs Host Disease/prevention & control , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , COVID-19/immunology , Cells, Cultured , Chemokine CCL2/analysis , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-6/analysis , Interleukin-8/analysis , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/immunology , Transplantation, Homologous/adverse effects
4.
Front Immunol ; 12: 784975, 2021.
Article in English | MEDLINE | ID: mdl-34925365

ABSTRACT

Hashimoto's thyroiditis (HT) is an autoimmune disease, and its incidence continues to rise. Although scientists have studied this disease for many years and discovered the potential effects of various proteins in it, the specific pathogenesis is still not fully comprehended. To understand HT and translate this knowledge to clinical applications, we took the mass spectrometric analysis on thyroid tissue fine-needle puncture from HT patients and healthy people in an attempt to make a further understanding of the pathogenesis of HT. A total of 44 proteins with differential expression were identified in HT patients, and these proteins play vital roles in cell adhesion, cell metabolism, and thyroxine synthesis. Combining patient clinical trial sample information, we further compared the transient changes of gene expression regulation in HT and papillary thyroid carcinoma (PTC) samples. More importantly, we developed patient-derived HT and PTC organoids as a promising new preclinical model to verify these potential markers. Our data revealed a marked characteristic of HT organoid in upregulating chemokines that include C-C motif chemokine ligand (CCL) 2 and CCL3, which play a key role in the pathogenesis of HT. Overall, our research has enriched everyone's understanding of the pathogenesis of HT and provides a certain reference for the treatment of the disease.


Subject(s)
Chemokine CCL2/metabolism , Chemokine CCL3/metabolism , Hashimoto Disease/immunology , Thyroid Cancer, Papillary/immunology , Thyroid Neoplasms/immunology , Adult , Biomarkers/analysis , Biomarkers/metabolism , Chemokine CCL2/analysis , Chemokine CCL3/analysis , Female , Hashimoto Disease/pathology , Humans , Male , Middle Aged , Organoids , Primary Cell Culture/methods , Proteomics , Thyroid Cancer, Papillary/pathology , Thyroid Gland/immunology , Thyroid Gland/pathology , Thyroid Neoplasms/pathology
5.
Stroke ; 52(11): 3670-3679, 2021 11.
Article in English | MEDLINE | ID: mdl-34587791

ABSTRACT

Background and Purpose: Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. Methods: An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system­specific ischemic injury. Results: In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. Conclusions: These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.


Subject(s)
Biomarkers/analysis , Chemokine CCL2/analysis , Ischemic Stroke , Animals , Disease Models, Animal , Humans , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Translational Research, Biomedical
6.
Crit Care ; 25(1): 39, 2021 01 28.
Article in English | MEDLINE | ID: mdl-33509215

ABSTRACT

BACKGROUND: The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. METHODS: This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1ß, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. RESULTS: Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1ß, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. CONCLUSION: EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. TRIAL REGISTRATION: NCT03231748, registered on 27th July 2017.


Subject(s)
Acute Kidney Injury/etiology , Cytokines/metabolism , Metabolic Clearance Rate/physiology , Sepsis/complications , Acute Kidney Injury/physiopathology , Aged , Chemokine CCL2/analysis , Chemokine CCL2/blood , Epidermal Growth Factor/analysis , Epidermal Growth Factor/blood , Female , Humans , Interferon-gamma/analysis , Interferon-gamma/blood , Interleukin-10/analysis , Interleukin-10/blood , Interleukin-1alpha/analysis , Interleukin-1alpha/blood , Interleukin-1beta/analysis , Interleukin-1beta/blood , Interleukin-2/analysis , Interleukin-2/blood , Interleukin-4/analysis , Interleukin-4/blood , Interleukin-6/analysis , Interleukin-6/blood , Male , Middle Aged , Peptide Fragments/analysis , Peptide Fragments/blood , Prospective Studies , Renal Replacement Therapy/methods , Sepsis/physiopathology , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/blood , Vascular Endothelial Growth Factors/analysis , Vascular Endothelial Growth Factors/blood
7.
Curr Drug Discov Technol ; 18(1): 65-74, 2021.
Article in English | MEDLINE | ID: mdl-31657689

ABSTRACT

BACKGROUND: Based on the encouraging results of phase III clinical trial of ß-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. METHODS: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 µg/mL) of M2000 and optimum dose (1 µg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. RESULTS: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac. CONCLUSION: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.


Subject(s)
Arthritis, Rheumatoid , Hexuronic Acids/pharmacology , Leukocytes, Mononuclear/immunology , Anti-Inflammatory Agents/pharmacology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Cells, Cultured , Chemokine CCL2/analysis , Diclofenac/pharmacology , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Receptors, CXCR4/analysis , Receptors, Chemokine/analysis , Synovial Membrane/immunology
8.
Article in English | MEDLINE | ID: mdl-32872648

ABSTRACT

The study aimed to determine if oral hygiene influences not only oral health but also potentially metabolic disorders such as overweight or obesity. Participants were 94 patients: 40 with increased body mass and 54 with normal body mass. The methods included dental examination, a questionnaire concerning hygienic habits and an assessment of selected salivary inflammatory markers. The new parameter named "cleaning index" (describing the interaction between average time of tooth brushing in minutes and its frequency per day) significantly correlated with Body Mass Index (RSpearman = 0.300). The multivariate regression model incorporating cleaning index, approximal plaque index, receptor 1 for tumor necrosis factor-alpha (TNFα-R1) and interleukin-15 (IL-15) had a high power to predict overweight or obesity (AUC = 0.894). Patients with poor oral hygiene (approximal plaque index >40%) were more than eight times more likely to suffer from obesity than patients with good oral hygiene. Cleaning index higher than 4 decreased the odds by about 85%. Oral hygiene habits, adjusted by salivary concentrations of selected inflammatory markers may allow predicting effectively overweight or obesity risk. Early proper dental prophylaxis and treatment could lead to the better prevention of metabolic disorders.


Subject(s)
Oral Hygiene , Overweight , Saliva , Adult , Body Mass Index , Chemokine CCL2/analysis , Cytokines/analysis , Dental Plaque Index , Female , Humans , Interleukin-15/analysis , Male , Middle Aged , Obesity/epidemiology , Obesity/immunology , Oral Health , Oral Hygiene Index , Overweight/epidemiology , Overweight/immunology , Periodontal Diseases/diagnosis , Periodontal Diseases/epidemiology , Periodontal Diseases/immunology , Predictive Value of Tests , Saliva/chemistry , Young Adult
9.
Life Sci ; 260: 118307, 2020 Nov 01.
Article in English | MEDLINE | ID: mdl-32841665

ABSTRACT

AIM: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied. MATERIALS AND METHODS: Two doses of febuxostat (10 and 20 mg/kg, orally) were administered either 1 h before or 30 min after the administration of Con A. Febuxostat at a low dose (10 mg/kg) before and after Con A modulated the elevation of serum ALT, liver uric acid, liver myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) induced by Con A. The same dose of febuxostat before Con A also decreased serum total bilirubin and neutrophil infiltration, as evidenced by flow cytometry and histopathological analysis. KEY FINDINGS: Febuxostat at a high dose (20 mg/kg) significantly improved serum ALT, AST, albumin, total bilirubin, liver uric acid, MPO, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-1ß, and neutrophil infiltration induced by Con A administration. The results of histopathological examination of liver cells paralleled the observed biochemical improvements. Hepatocyte apoptosis as evidenced by immunohistochemical examination of cleaved caspase-3 was markedly decreased in the febuxostat protection and treatment groups, in a dose-dependent manner SIGNIFICANCE: These results indicate that febuxostat, especially at the higher dose, may be an effective inhibitor of immune reactions evoked by Con A administration.


Subject(s)
Chemokine CCL2/analysis , Concanavalin A/pharmacokinetics , Febuxostat/administration & dosage , Hepatitis/prevention & control , Interleukin-1beta/analysis , Tumor Necrosis Factor-alpha/analysis , Animals , Apoptosis/drug effects , Caspase 3/analysis , Febuxostat/pharmacology , Hepatitis/immunology , Hepatitis/physiopathology , Liver/chemistry , Liver/pathology , Liver/physiopathology , Male , Mice , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Neutrophils/pathology , Peroxidase/analysis , Uric Acid/analysis
10.
Med Princ Pract ; 29(5): 492-498, 2020.
Article in English | MEDLINE | ID: mdl-32241014

ABSTRACT

OBJECTIVE: A widely used chemical-mechanical method of gingival retraction can cause gingival tissue damage. The aim of this study was to test the influence of the chemical-mechanical gingival retraction procedures on the gingival bleeding index (GBI) and the salivary concentration of monocyte chemoattractant protein 1 (MCP-1) as an indicator of inflammatory changes in the gingiva. MATERIALS AND METHODS: The effects of 2 different retraction agents (aluminum chloride and ferric sulfate) were compared, particularly their tissue damaging effect during tooth preparation. Therefore, GBI values and the salivary concentration of MCP-1 were assessed during the chemical-mechanical method of gingival retraction in a homogenous group of respondents. The subjects (n = 60) were divided into 2 experimental groups (G1 and G2) regarding the need for tooth preparing and making artificial crowns. Each group was further divided into 2 subgroups (R1 and R2) according to the type of the gingival retraction agent used (aluminum chloride and ferric sulfate). RESULTS: Compared to the values at the study start, a statistically significant increase in GBI and salivary MCP-1 (p < 0.001) 1 day after gingival retraction agent application was observed in both experimental groups. After 72 h, the values were lower than in the second observation period but still statistically significantly higher compared to the study start (p < 0.001), which indicated the reversibility of the tissue changes. CONCLUSION: Higher values of the investigated parameters were observed in the group of subjects with prepared teeth, and clinical changes were more pronounced after the use of ferric sulfate.


Subject(s)
Chemokine CCL2/analysis , Gingival Retraction Techniques/adverse effects , Gingivitis/chemically induced , Saliva/immunology , Adult , Aluminum Chloride/adverse effects , Female , Ferric Compounds/adverse effects , Humans , Inflammation/immunology , Male , Periodontal Index , Young Adult
11.
Front Immunol ; 11: 354, 2020.
Article in English | MEDLINE | ID: mdl-32218781

ABSTRACT

Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear. Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension. Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039). Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.


Subject(s)
Chemical and Drug Induced Liver Injury/immunology , Chemokine CCL2/blood , Liver Cirrhosis, Experimental/complications , Liver/immunology , Macrophage Activation , Acute-On-Chronic Liver Failure/complications , Acute-On-Chronic Liver Failure/immunology , Animals , Chemokine CCL2/analysis , Chemokine CCL2/genetics , Chemokine CCL2/physiology , Kupffer Cells/physiology , Liver Cirrhosis, Experimental/immunology , Male , Mice , Mice, Inbred C57BL
12.
Dis Model Mech ; 13(1)2020 01 24.
Article in English | MEDLINE | ID: mdl-31953345

ABSTRACT

Receptor-interacting protein kinase 3 (RIPK3) was recently implicated in promoting atherosclerosis progression through a proposed role in macrophage necroptosis. However, RIPK3 has been connected to numerous other cellular pathways, which raises questions about its actual role in atherosclerosis. Furthermore, RIPK3 is expressed in a multitude of cell types, suggesting that it may be physiologically relevant to more than just macrophages in atherosclerosis. In this study, Ripk3 was deleted in macrophages, endothelial cells, vascular smooth muscle cells or globally on the Apoe-/- background using Cre-lox technology. To induce atherosclerosis progression, male and female mice were fed a Western diet for three months before tissue collection and analysis. Surprisingly, necroptosis markers were nearly undetectable in atherosclerotic aortas. Furthermore, en face lesion area was increased in macrophage- and endothelial-specific deletions of Ripk3 in the descending and abdominal regions of the aorta. Analysis of bone-marrow-derived macrophages and cultured endothelial cells revealed that Ripk3 deletion promotes expression of monocyte chemoattractant protein 1 (MCP-1) and E-selectin in these cell types, respectively. Western blot analysis showed upregulation of MCP-1 in aortas with Ripk3-deficient macrophages. Altogether, these data suggest that RIPK3 in macrophages and endothelial cells protects against atherosclerosis through a mechanism that likely does not involve necroptosis. This protection may be due to RIPK3-mediated suppression of pro-inflammatory MCP-1 expression in macrophages and E-selectin expression in endothelial cells. These findings suggest a novel and unexpected cell-type specific and athero-protective function for RIPK3.This article has an associated First Person interview with the first author of the paper.


Subject(s)
Atherosclerosis/prevention & control , Receptor-Interacting Protein Serine-Threonine Kinases/physiology , Animals , Atherosclerosis/etiology , Chemokine CCL2/analysis , Chemokine CCL2/physiology , Disease Models, Animal , E-Selectin/analysis , Endothelial Cells/physiology , Interleukin-1beta/blood , Interleukin-1beta/physiology , Macrophages/physiology , Mice , Mice, Inbred C57BL , Necroptosis
13.
Biosci Biotechnol Biochem ; 84(1): 208-215, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31532348

ABSTRACT

Dihomo-γ-linolenic acid (DGLA, C20: 3n-6) is known to have an anti-inflammatory activity, but its range of effects was not well studied because of its limited natural sources. We addressed these issues by constructing an yeast Saccharomyces cerevisiae strain having a complete metabolic pathway for DGLA synthesis by introducing two desaturase and one elongase genes to convert endogenous oleic acid to DGLA. Taking advantage of well-known safety of S. cerevisiae, we previously investigated the efficacy of heat-killed whole DGLA-producing yeast cells on irritant contact dermatitis, and showed that oral intake of this yeast significantly suppressed inflammatory reactions, whereas no such suppression was observed by the intake of 25 times the amount of purified DGLA. Since this method is considered to be a simple and efficient way to suppress inflammation, we examined its effectiveness against allergic contact dermatitis (ACD) in this study and showed that this method was also effective against ACD.


Subject(s)
8,11,14-Eicosatrienoic Acid/pharmacology , Cell- and Tissue-Based Therapy/methods , Dermatitis, Allergic Contact/therapy , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/metabolism , 8,11,14-Eicosatrienoic Acid/administration & dosage , 8,11,14-Eicosatrienoic Acid/metabolism , Acetone/chemistry , Administration, Oral , Animals , Chemokine CCL2/analysis , Chemokines/analysis , Dermatitis, Allergic Contact/etiology , Dinitrofluorobenzene/adverse effects , Dinitrofluorobenzene/immunology , Ear, External/pathology , Female , Immunization , Inflammation/therapy , Interferon-gamma/analysis , Mice , Oleic Acid/metabolism , Olive Oil/chemistry
14.
BMJ Open Respir Res ; 6(1): e000440, 2019.
Article in English | MEDLINE | ID: mdl-31673364

ABSTRACT

Background: Pleural infection (PI) is a major global disease with an increasing incidence, and pleural fluid (PF) drainage is essential for the successful treatment. The MIST2 study demonstrated that intrapleural administration of tissue plasminogen activator (t-PA) and DNase, or t-PA alone increased the volume of drained PF. Mouse model studies have suggested that the volume increase is due to the interaction of the pleura with the t-PA via the monocyte chemoattractant protein 1 (MCP-1) pathway. We designed a study to determine the time frame of drained PF volume induction on intrapleural delivery of t-PA±DNase in humans, and to test the hypothesis that the induction is mediated by the MCP-1 pathway. Methods: Data and samples from the MIST2 study were used (210 PI patients randomised to receive for 3 days either: t-PA and DNase, t-PA and placebo, DNase and placebo or double placebo). PF MCP-1 levels were measured by ELISA. One-way and two-way analysis of variance (ANOVA) with Tukey's post hoc tests were used to estimate statistical significance. Pearson's correlation coefficient was used to assess linear correlation. Results: Intrapleural administration of t-PA±DNase stimulated a statistically significant rise in the volume of drained PF during the treatment period (days 1-3). No significant difference was detected between any groups during the post-treatment period (days 5-7). Intrapleural administration of t-PA increased MCP-1 PF levels during treatment; however, no statistically significant difference was detected between patients who received t-PA and those who did not. PF MCP-1 expression was not correlated to the drug given nor the volume of drained PF. Conclusions: We conclude that the PF volume drainage increment seen with the administration of t-PA does not appear to act solely via activation of the MCP-1 pathway.


Subject(s)
Deoxyribonucleases/administration & dosage , Drainage , Empyema, Pleural/therapy , Pleural Effusion/therapy , Tissue Plasminogen Activator/administration & dosage , Chemokine CCL2/analysis , Humans , Pleura
15.
Int J Mol Sci ; 20(23)2019 Nov 24.
Article in English | MEDLINE | ID: mdl-31771293

ABSTRACT

The aim of the study was to clarify the distinctive features of stem cells for effective cell-based therapy strategies in regenerative medicine. The expression levels of cytokines secreted from stem cells from exfoliated deciduous teeth (SHED), dental pulp stem cells (DPSCs), and bone marrow derived mesenchymal stem cells (BMMSCs) were examined to identify the details of their characteristics. A total of 174 cytokines were analyzed using cytokine antibody array, and their expression levels were confirmed by an enzyme-linked immunosorbent assay. These results indicated that 11 cytokines that were related to tissue regeneration, including growth factors, chemokines, and inflammatory cytokines, were identical in SHED, DPSCs, and BMMSCs. The comparative analyses between SHED and BMMSCs revealed that hepatocyte growth factor (HGF), matrix metalloproteinase-3, and stromal cell derived factor 1 (SDF-1) were expressed 6.7-, 2.5-, and 2.1-fold higher, respectively, in SHEDs. HGF was also expressed 3.4-fold higher in DPSCs than BMMSCs. Monocyte chemoattractant protein-1, and-3 were expressed more strongly in BMMSCs. SHED contained significantly higher SDF-1 levels than DPSCs. The distinct cytokine secretion indicated that they had different character besides basic MSC features. This knowledge of diagnostic cytokines analysis secreted from SHED, DPSCs, and BMMSCs extends our understanding, and can provide a novel therapeutic paradigm shift for functional cell-based therapy.


Subject(s)
Bone Marrow Cells/cytology , Cytokines/metabolism , Dental Pulp/cytology , Mesenchymal Stem Cells/metabolism , Tooth, Deciduous/cytology , Cell- and Tissue-Based Therapy , Cells, Cultured , Chemokine CCL2/analysis , Chemokine CCL2/metabolism , Chemokine CCL7/analysis , Chemokine CCL7/metabolism , Chemokine CXCL12/analysis , Chemokine CXCL12/metabolism , Enzyme-Linked Immunosorbent Assay , Hepatocyte Growth Factor/metabolism , Humans , Matrix Metalloproteinase 3/metabolism , Mesenchymal Stem Cells/cytology
16.
J Nutr Biochem ; 73: 108222, 2019 11.
Article in English | MEDLINE | ID: mdl-31665675

ABSTRACT

Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing the risk of cardiovascular diseases. However, the dosages of phytochemicals in the cellular and animal studies are too high to reach in humans by relevant foods or dietary supplement intake. The aims of this study were to investigate whether and how combined curcumin and luteolin synergistically inhibit tumor necrosis factor-alpha (TNF-α)-induced monocytes adhesion endothelium, a crucial step of the development of endothelial dysfunction, both in human vascular cells and mouse aortic endothelium. Our results show that combined curcumin (1 µM) and luteolin (0.5 µM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocytes adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. We also found that TNF-α-enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and nuclear factor (NF)-κB translocation were synergistically reduced by the combined curcumin and luteolin in EA.hy 926 cells while the individual chemical did not have this inhibitory effect. Consistently, 2 weeks dietary intake of combined curcumin (500 mg/kg) and luteolin (500 mg/kg) in C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium ex vivo as well as the TNF-α-increased aortic protein expression of MCP-1 and VCAM-1. Therefore, combined curcumin and luteolin at physiological concentrations synergistically inhibits TNF-α-induced monocytes adhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into the nucleus.


Subject(s)
Curcumin/administration & dosage , Luteolin/administration & dosage , Tumor Necrosis Factor-alpha/administration & dosage , Vasculitis/prevention & control , Animals , Cell Adhesion/drug effects , Cell Line , Chemokine CCL2/analysis , Drug Synergism , Endothelium, Vascular/chemistry , Endothelium, Vascular/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Monocytes/physiology , NF-kappa B/metabolism , Signal Transduction/drug effects , Vascular Cell Adhesion Molecule-1/analysis , Vasculitis/chemically induced
17.
JCI Insight ; 4(20)2019 10 17.
Article in English | MEDLINE | ID: mdl-31550243

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 in Saudi Arabia and has caused over 2400 cases and more than 800 deaths. Epidemiological studies identified diabetes as the primary comorbidity associated with severe or lethal MERS-CoV infection. Understanding how diabetes affects MERS is important because of the global burden of diabetes and pandemic potential of MERS-CoV. We used a model in which mice were made susceptible to MERS-CoV by expressing human DPP4, and type 2 diabetes was induced by administering a high-fat diet. Upon infection with MERS-CoV, diabetic mice had a prolonged phase of severe disease and delayed recovery that was independent of virus titers. Histological analysis revealed that diabetic mice had delayed inflammation, which was then prolonged through 21 days after infection. Diabetic mice had fewer inflammatory monocyte/macrophages and CD4+ T cells, which correlated with lower levels of Ccl2 and Cxcl10 expression. Diabetic mice also had lower levels of Tnfa, Il6, Il12b, and Arg1 expression and higher levels of Il17a expression. These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response, which results in more severe and prolonged lung pathology.


Subject(s)
Coronavirus Infections/immunology , Diabetes Mellitus, Type 2/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Chemokine CCL2/analysis , Chemokine CCL2/metabolism , Chemokine CXCL10/analysis , Chemokine CXCL10/metabolism , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Diet, High-Fat/adverse effects , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Disease Models, Animal , Female , Humans , Lung/immunology , Lung/pathology , Macrophages/immunology , Macrophages/metabolism , Male , Mice , Mice, Transgenic , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Monocytes/immunology , Monocytes/metabolism , Risk Factors , Severity of Illness Index
18.
Bull Hosp Jt Dis (2013) ; 77(3): 189-193, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31487484

ABSTRACT

BACKGROUND: Synovial fluid biomarkers can highlight the molecular milieu associated with knee pathology and have been shown to be significantly different in patients with anterior cruciate ligament (ACL) injuries compared to uninjured controls. The purpose of the current study was to establish how synovial fluid biomarker concentrations change in patients undergoing ACL reconstruction between the immediate preoperative period to the acute postoperative period. METHODS: Patients were prospectively enrolled at the time of surgery from September 2016 to March 2017. Patients who had an operative knee synovial fluid sample obtained at the time of ACL reconstruction and provided a synovial fluid sample at their first postoperative appointment were included. The concentrations of 10 biomarkers were determined using a multiplex magnetic bead immunoassay. Biomarker concentrations before and after surgery were compared using a paired sample t-test. RESULTS: Eight patients with mean age of 33.4 years who underwent isolated ACL reconstruction using a bonepatellar tendon-bone autograft were included. The mean time between surgery and postoperative office visit was 10.4 days. There was a statistically significant increase in the concentrations of interleukin-6 (IL-6, p = 0.014), monocyte chemoattractant protein-1 (MCP-1, p = 0.024), human matrix metalloproteinase 3 (MMP-3, p = 0.00002), macrophage inflammatory protein-1 beta (MIP-1ß, p = 0.006), human interleukin-1 receptor antagonist (IL-1Ra, p = 0.017), and vascular endothelial growth factor (VEGF, p = 0.023) between the time of surgery and the first postoperative visit and a decrease in the concentration of tissue inhibitor of metalloproteinase-2 (p = 0.050). CONCLUSION: The molecular profile of the synovial fluid changes in the early postoperative period following arthroscopic ACL reconstruction. The concentration of proinflammatory markers (such as IL-6, MCP-1, MMP-3, and MIP-1ß) and growth factors including VEGF increases. The concentration of the anti-inflammatory marker tissue inhibitor of metalloproteinase-2 (TIMP-2) appears to decrease postoperatively.


Subject(s)
Anterior Cruciate Ligament Injuries/surgery , Biomarkers/analysis , Synovial Fluid , Adult , Anterior Cruciate Ligament Reconstruction/adverse effects , Anterior Cruciate Ligament Reconstruction/methods , Arthroscopy/methods , Chemokine CCL2/analysis , Chemokine CCL4/analysis , Female , Humans , Interleukin 1 Receptor Antagonist Protein/analysis , Interleukin-6/analysis , Knee Joint/immunology , Knee Joint/metabolism , Knee Joint/surgery , Male , Matrix Metalloproteinase 3/analysis , Perioperative Period , Synovial Fluid/immunology , Synovial Fluid/metabolism , Vascular Endothelial Growth Factor A/analysis
19.
Biomark Med ; 13(17): 1447-1457, 2019 12.
Article in English | MEDLINE | ID: mdl-31552762

ABSTRACT

Aim: Due to active engagement of sensory and afferent nerve fibers in reflex tearing which could be affected in Parkinson's disease (PD), we tested reflex tears as a source of potential PD biomarkers. Patients & methods: Reflex tears collected from 84 PD and 84 age- and sex-equivalent healthy controls (HC) were used to measure levels of oligomeric α-Syn (α-SynOligo), total α-Syn (α-SynTotal), CCL2, DJ-1, lactoferrin and MMP9. Results: α-synOligo (p < 0.0001), CCL2 (p = 0.003) and lactoferrin (p = 0.002) were significantly elevated in PD patient tears relative to HC tears. Tear flow was significantly lower in PD relative to HC (p = 0.001). Conclusion: Reflex tears are a potential source for detection of characteristic changes in PD patients.


Subject(s)
Biomarkers/analysis , Parkinson Disease/diagnosis , Tears/chemistry , alpha-Synuclein/chemistry , Aged , Biomarkers/metabolism , Case-Control Studies , Chemokine CCL2/analysis , Chemokine CCL2/metabolism , Female , Humans , Lactoferrin/analysis , Lactoferrin/metabolism , Male , Middle Aged , Parkinson Disease/metabolism , Tears/metabolism
20.
Balkan Med J ; 36(6): 331-336, 2019 10 28.
Article in English | MEDLINE | ID: mdl-31486327

ABSTRACT

Background: Elevated levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 have been identified in fibromyalgia patients. Aims: To examine the potential association among serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 with disease severity of fibromyalgia. Study Design: Cross-sectional study. Methods: Seventy-nine female patients with fibromyalgia and 75 healthy normal controls were included in our study. Serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 were detected by enzyme-linked immune sorbent assays. The existence of tender points was evaluated based on the standardized manual tender point examination. Pressure pain thresholds at the knees, and bilateral trapezius muscles were measured with an algometer. A visual analog scale and the Revised Fibromyalgia Impact Questionnaire were utilized to assess the degree of pain and functional abilities. Results: Serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 were significantly greater in patients with fibromyalgia compared with healthy controls (151.6±31.9 pg/mL vs 103.3±25.2 pg/mL, p<0.001). Patients with severe fibromyalgia had significantly higher serum levels of chemokine C-C motif ligand 2 than patients with mild and moderate fibromyalgia (173.1±21.9 pg/mL vs 151.0.0±35.1 pg/mL, p=0.01). Patients with moderate fibromyalgia revealed markedly augmented serum levels of chemokine C-C motif ligand 2 compared with patients with mild fibromyalgia (151.0±35.1 pg/mL vs 133.3±23.9 pg/mL, p=0.03). Serum levels of chemokine C-C motif ligand 2 were positively associated with tender point scores (r=0.455, p<0.001). In addition, serum levels of chemokine C-C motif ligand 2 were positively associated with pressure pain thresholds in both knees and bilateral trapezius muscles (knees: r=-0.349, p=0.002; trapezius muscles: r=-0.318, p=0.004). Finally, we found elevated serum levels of chemokine C-C motif ligand were also positively associated with the visual analog scale (r=0.368, p=0.001), and the Fibromyalgia Impact Questionnaire score (r=0.401, p<0.001). Conclusion: Elevated serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 are linked to disease severity of fibromyalgia. Therapeutic interventions inhibiting monocyte chemotactic protein-1/chemokine C-C motif ligand 2 in fibromyalgia deserve additional studies.


Subject(s)
Chemokine CCL2/analysis , Fibromyalgia/blood , Adult , Aged , Analysis of Variance , Biomarkers/analysis , Biomarkers/blood , Chemokine CCL2/blood , Cross-Sectional Studies , Female , Humans , Middle Aged , Severity of Illness Index
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