Monocyte Chemoattractant Protein-1 Concentrations Research Articles

Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies

Rationale & ObjectiveTubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study DesignProspective cohort (ARIC) and case-cohort (MESA and REGARDS). Setting & ParticipantsAdults with eGFR ≥60 mL/min/1.73m2 and without diabetes in the ARIC, REGARDS, and MESA studies. ExposureBaseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1 (KIM-1), epidermal growth factor (EGF), and chitinase-3-like protein 1 (YKL-40). OutcomeIncident CKD or ESKD (end-stage kidney disease). Analytical ApproachMultivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all three cohorts. Results872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60±10 to 63±8 years and baseline eGFR ranged from 88±13 to 91±14 mL/min/1.73m2. In ARIC, higher concentrations of urine MCP-1, α1m, and KIM-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of EGF was each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all three cohorts, each two-fold higher α1m concentration was associated with incident CKD (HR=1.19 [1.08, 1.31]). LimitationsObservational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to three cohorts. ConclusionsIn three combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m was independently associated with incident CKD. Four biomarkers were associated with incident CKD in at least one of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

Effect of aflibercept combined with triamcinolone acetonide on aqueous humor growth factor and inflammatory mediators in diabetic macular edema.

To investigate the efficacy of aflibercept combined with sub-tenon injection of triamcinolone acetonide (TA) in treating diabetic macular edema (DME) and to examine changes in growth factors and inflammatory mediator levels in aqueous humor after injection. Totally 67 DME patients (67 eyes) and 30 cataract patients (32 eyes) were enrolled as the DME group and the control group, respectively. The DME group was divided into the aflibercept group (34 cases) and the aflibercept combined with TA group (combined group, 33 cases). The aqueous humor of both groups was collected during the study period. The aqueous levels of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β) were detected using a microsphere suspension array technology (Luminex 200TM). Aqueous cytokines, best-corrected visual acuity (BCVA), central macular thickness (CMT), and complications before and after treatment were compared between the aflibercept group and combined group. The concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly higher in the DME group than those of the control group (all P<0.01). After 1mo of surgery, the concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly lower in the combined group than those of the aflibercept group (all P<0.01). The BCVA and CMT values of the two groups were statistically different after 1 and 2mo of treatment (P<0.01). However, the difference was not statistically significant after 3mo of treatment (P>0.05). The cytokines VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor of DME patients are significantly increased. Aflibercept and aflibercept combined with TA have good efficacy in DME patients, can effectively reduce CMT, improve the patient's vision, and have high safety. Aflibercept combined with TA can quickly down-regulate the aqueous humor cytokines and help to relieve macular edema rapidly. However, the long-term efficacy is comparable to that of aflibercept alone.

Circulating Monocyte Chemoattractant Protein-1 (MCP-1) in Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that leads to the destruction of the intrahepatic bile ducts. While the inflammatory process can be mediated by monocyte chemotactic protein-1 (MCP-1), the importance of circulating MCP-1 as a biomarker is unclear. Our aim was to assess the diagnostic significance of the serum concentrations of MCP-1 in PBC patients. We compared circulating MCP-1 with biochemical, immunological and histological parameters. Serum samples were collected from 120 PBC patients, 60 pathologic controls and 30 healthy donors. MCP-1 levels were determined by using commercial enzyme-linked immunosorbent assay (ELISA). Elevated serum MCP-1 levels were detected in 66% of PBC patients with a specificity of 97%. Significantly higher levels of MCP-1 protein were found in the sera of patients with PBC than in the group of healthy individuals-410.2 pg/mL vs. 176.0 pg/mL, p < 0.01). Patients with higher concentrations of alkaline phosphatase also had higher levels of MCP-1 (r = 0.4, p < 0.01). In accordance with Ludwig's classification, a positive correlation of serum MCP-1 concentration with the degree of fibrosis was observed, OR = 6.1, p = 0.0003. We compared the MCP-1 with procollagen type III, hyaluronic acid (HA), FIB-4 index, APRI and collagen type IV when predicting the advance of liver fibrosis. Circulating MCP-1 is better correlated with liver fibrosis and is also associated with the occurrence of specific antimitochondrial autoantibodies and specific anti-nuclear autoantibodies-anti-gp210. MPC-1 can be considered to be a tool for diagnosing the degree of fibrosis in PBC, and combinations of MCP-1 and other specific biomarkers could support the diagnosis of PBC.

Main Colonic Metabolites from Coffee Chlorogenic Acid May Counteract Tumor Necrosis Factor-α-Induced Inflammation and Oxidative Stress in 3T3-L1 Cells.

Obesity is coupled with an altered redox state and low-level inflammation. Oxidative stress may increase pre-adipocyte proliferation, adipocyte differentiation and mature adipocyte size. Regarding inflammation, the dysregulation of cytokine production by adipose tissue takes place in obesity, which is promoted by oxidative stress. Polyphenols may exert a positive effect on obesity, not only by modulating the redox state, but also due to their anti-inflammatory activity. Coffee, which is one of the most consumed beverages, is very rich in phenolic compounds. Bioavailability studies on coffee phenols have shown that the most abundant group of metabolites in plasma and urine are dihydrocaffeic (DHCA), dihydroferulic (DHFA), and hydroxyhippuric (HHA) acids, the three acids of colonic origin. To better understand the antioxidant and anti-inflammatory properties of DHCA, DHFA, and HHA, an inflammation/oxidation model was set up in the pre-adipocyte 3T3-L1 cell line using tumor necrosis factor-α (TNF-α). After the exposure of 3T3-L1 cells to 0.5, 1, 5, and 10 µM of TNF-α at different times, the cell viability, interleukin (IL)-6 secretion, and the production of reactive oxygen species (ROS) and glutathione (GSH) were determined. Using the TNF-α prooxidant and proinflammatory conditions established (10 µM, 24 h), it was observed that the physiological concentrations (0.5, 1, 5, and 10 µM) of DHCA, DHFA, and HHA induced dose-dependent antioxidant effects according to the ROS, GSH, and antioxidant enzyme (glutathione peroxidase) results. In addition, reductions in the IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1) concentrations were observed to different extents depending on the metabolite (DHFA, HHA, or DHCA) and the concentration used. In conclusion, the main colonic metabolites from coffee chlorogenic acids may counteract TNF-α-induced inflammation and oxidative stress in the 3T3-L1 cell line, and thus, they present antiobesity potential.

Excessive aggregation of fine particles may play a crucial role in adolescent spontaneous pneumothorax pathogenesis.

The pathogenesis of primary spontaneous pneumothorax (PSP) is unclear. Fine particles aggregated in the lung can be phagocytosed by alveolar macrophages (AMs) to induce an inflammatory reaction and damage local pulmonary tissue, which could be a mechanism of PSP. This project aimed to explore the pathological association between fine particulate matter and PSP. Thirty pulmonary bullae tissues were obtained from surgery of PSP patients (B group). The adjacent normal tissues of the lungs were defined as the control S group. Another 30 normal lung tissues with nonpneumothorax disease (NPD) were applied as the control N group. Hematoxylin and eosin (H & E), Wright-Giemsa (W-G), Victoria blue, and immunohistochemical (IHC) staining experiments were performed to measure the levels of fine particulate matter, alveolar macrophages (AMs), pulmonary elastic fibers, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9) in the lung tissues. The serum levels of MCP-1 and MMP-9 were prospectively analyzed as well. Histopathological examinations revealed obvious deposition of fine particulate matter and inflammatory reactions (proliferation of AMs) in the B group, compared with those in the S group and the N group. These alterations were significantly associated with PSP. The numbers of AMs and pulmonary elastic fibers, the positive area of the H-score, as well as the concentrations of MCP-1 and MMP-9 in the lungs of the experimental group were obviously raised compared with the controls (P < 0.05). Fine particulate matter aggregation, inflammation (macrophage hyperplasia), and overexpression of MCP-1 and MMP-9 may contribute to the pathogenesis of PSP. The overaccumulation of fine particulate matter may play a crucial part in the occurrence of adolescent and young adult PSP. This project was enrolled on the Chinese Clinical Trial Registry: ChiCTR2100051460.

Clinical, Virological, and Immunological Features in Cosmopolitan Genotype DENV-2-Infected Patients during a Large Dengue Outbreak in Sri Lanka in 2017.

In 2017, Sri Lanka experienced its largest dengue epidemic and reported severe and unusual presentations of dengue with high morbidity. This outbreak was associated with the reemergence of dengue virus-2 (DENV-2), with the responsible strain identified as a variant of the previously circulating DENV-2 cosmopolitan genotype. In this study, we characterized the DENV-2 cosmopolitan genotype from patients during this epidemic. Also, we identified host factors that contributed to the severity of dengue infection in patients infected with this particular virus. Ninety-one acute serum samples from patients at the National Hospital in Kandy were randomly selected. Of these, 40.2% and 48.9% were positive for dengue IgM and IgG, respectively. NS1 antigen levels were significantly higher in primary infections. The severe dengue (SD) and dengue with warning signs (DWWS) groups exhibited significantly higher viral genome and infectivity titers than the dengue without warning signs (DWoWS) group. The highest viremia level was observed in SD patients. As for host cytokine response, interferon α (IFN-α) levels were significantly higher in the DWoWS group than in the DWWS and SD groups, whereas interleukin (IL)-12p40 and tumor necrosis factor α (TNF-α) levels in SD patients were significantly higher than in the other two groups. The TNF-α, IL-4, and monocyte chemoattractant protein-1 concentrations were positively correlated with NS1 antigen levels. From whole-genome analysis, NS4 had the highest frequency of amino acid variants, followed by the E gene. Our study suggests that viremia levels and immune responses contributed to SD outcomes, and these findings may help in identifying an effective therapeutic strategy against SD infection.

Electroacupuncture activates angiogenesis by regulating the PI3K/Pten/Thbs1 signaling pathway to promote the browning of adipose tissue in HFD-induced obese mice

This study investigated the effect of electroacupuncture (EA) on the browning of white adipose tissue (WAT) via angiogenesis and its potential mechanism in obese mice. Four-week-old male C56BL/6 mice were randomly divided into a high-fat diet (HFD) and a normal chow diet (ND) group. After 12 weeks, HFD mice were randomly divided into two groups to receive or not receive EA for 3 weeks. After EA treatment, body weight, adipocyte size, serum glucose (GLU), triacylglycerol (TG), cholesterol (CHO), leptin (Lep), monocyte chemoattractant protein-1 (MCP-1), WAT browning-related genes, angiogenesis-related genes, and the PI3K/Pten/Thbs1 signaling pathway were evaluated. The results indicated that EA significantly reduced body weight, adipocyte size, and serum concentrations of GLU, TG, CHO, Lep and MCP-1 and promoted WAT browning. Angiogenesis and the PI3K/Pten/Thbs1 signaling pathway were all activated by EA intervention. The expression levels were consistent with the results of RNA-seq and confirmed via qRTPCR and WB. Our study showed that EA may activate angiogenesis via the PI3K/Pten/Thbs1 signaling pathway in WAT, thereby promoting the browning and thermogenesis of adipose tissue.

Prenatal exposure to perfluoroalkyl substances and inflammatory biomarker concentrations.

We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models. Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations. PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy.

Poster 151: Femoral Cartilage T2* Relaxation Times Correlate With Inflammatory Biomarker MCP-1 Levels In Serum, But Not Synovial Fluid, After ACL Injury In A Skeletally Immature Porcine Model

Objectives: Pediatric anterior cruciate ligament (ACL) injuries are on the rise and result in high rates of post-traumatic osteoarthritis (PTOA). The pro-inflammatory biomarker monocyte chemoattractant protein-1 (MCP-1) is elevated in serum and synovial fluid (SF) in skeletally mature ACL injured patients as well as patients with OA, making it a potential target for treatments to prevent PTOA. Understanding the time course of MCP-1 after ACL injury and how it relates to cartilage health in skeletally immature subjects is important for identifying OA risk and developing novel treatment targets for OA prevention. Therefore, the objective of this study was to evaluate the time course of MCP-1 levels in serum and synovial fluid (SF) after ACL injury in a skeletally immature porcine model and assess how MCP-1 levels relate to T2* magnetic resonance imaging (MRI) measurements, indicative of cartilage matrix organization. We hypothesized that higher levels of MCP-1 in serum and synovial fluid post-injury would correspond to higher cartilage T2* values 12 weeks after ACL injury. Methods: All experimental protocols were approved by the NC State IACUC. Juvenile (3 month old) female Yorkshire cross-breed pigs (n=7) underwent unilateral arthroscopic ACL transection (ACLT) and a sham operation in the contralateral joint (Fig. 1A). Prior to surgery and at 2, 4, and 12 weeks post- operatively, injured stifle SF and serum samples were collected (pre-op synovial fluid only obtained from 4 animals). MRI scans were performed prior to surgery and at 12 weeks post-operatively. MCP-1 levels in serum and SF samples were evaluated longitudinally using a commercial enzyme-linked immunosorbent assay. Cartilage matrix organization was evaluated longitudinally using T2* MRI. Specifically, both knee joints were imaged using a 3T Siemens MAGNETOM Skyra MRI system (T2 SWI sequence, FA=15°, TR=50ms, TE: 3.4, 7, 13.47, 21, 29, 37.07ms, voxel size: 0.5x0.5x0.8mm). T2* relaxation maps were created in MATLAB by fitting mono-exponential curves on a voxel-by-voxel basis. Weight-bearing cartilage was segmented from the medial and lateral compartments of the femur, and the median T2* value of each compartment was calculated. Paired MCP-1 levels in the serum and injured stifle SF across all time points were compared using linear regression. Multiple paired t-tests with Holm-Sidak correction were performed to compare cartilage T2* values between ACLT and sham- operated joints at each time point. The interlimb percent difference in femoral cartilage T2* at 12 weeks was calculated and compared to MCP-1 levels in serum and SF using linear regressions and several methods to assess MCP-1 levels (Fig. 2). Statistical significance was set at α=0.05 overall for each analysis. Results: Generally, MCP-1 levels in serum and ACLT stifle SF were elevated after ACLT (Fig. 1). The serum MCP-1 response over time differed between animals. Specifically, serum MCP-1 levels peaked at 2 weeks in 2 animals, peaked at 4 weeks in 3 animals, and decreased after ACLT in 2 animals (Fig 1A). Contrastingly, ACLT stifle SF MCP-1 responses were more consistent between animals; six peaked at 2 week and returned near baseline levels by 12 weeks (Fig 1B). The linear regression between paired measurements of MCP-1 concentrations in the serum and ACLT stifle SF were associated (p=0.053), yet had high variability (r2=0.15, Fig. 1C). Interlimb differences in cartilage matrix organization were largest and most consistent at 12 weeks in the medial femoral cartilage compartment, where median T2* times were 8% longer in the medial femoral cartilage compartment of the ACLT limb compared to sham limb, yet this was not statistically significant due to variability between animals (p&gt;0.05, Fig. 2). In the lateral femoral cartilage, the median T2* times were 3-4% longer at 12 weeks (p&gt;0.05) and were more variable between subjects compared to the medial femoral cartilage. Associations between the interlimb percent difference in medial femoral cartilage T2* and serum MCP-1 fit well (r2=0.25-0.69), with Methods 2, 3, and 5 achieving statistical significance (p=0.02, p=0.03, p=0.03), but resulted in poor fits for associations with SF MCP-1 (r2=0.07-0.45) using a variety of MCP-1 measurement methods (Fig 2C). Similar associations between lateral femoral cartilage T2* and serum MCP- resulted in poor fits (r2=0.01-0.24), and associations with SF MCP-1 resulted in negative slopes (Methods 2-5, r2=0.00-0.58). Conclusions: This preliminary study showed that inflammatory biomarker MCP-1 levels in serum displayed a subject-dependent response, which correlated with later femoral cartilage compositional changes after ACLT in the skeletally immature porcine model. This partially supported our hypothesis. The poor correlation between serum and SF MCP-1 indicate different local and systemic responses to ACLT. The stronger correlations between serum MCP-1 and cartilage T2* values could point to the importance of the systemic inflammatory response to OA progression. The increases in cartilage T2* values and serum MCP-1 levels after ACL injury in this study are consistent with those reported in adult humans. This study includes several limitations, including the use of an animal model to study human disease, the small sample size, and the relatively short time-course. However, the results demonstrate feasibility of using a large animal porcine model to longitudinally study the link between early MCP-1 serum levels and long-term cartilage health after ACL injury. Establishing the pig as a preclinical model to study longitudinal inflammation and OA progression after ACL injury will enable development of effective treatments before translating to humans.

Pre-existing serum indoxyl sulfate and COVID-19 outcomes in patients undergoing hemodialysis: A retrospective cohort study

Patients undergoing hemodialysis (HD) are at increased risk of severe complications from COVID-19 due to compromised immune function and comorbidities. This retrospective study aimed to investigate the association between pre-existing serum indoxyl sulfate (IS) concentrations and COVID-19 outcomes in HD patients.&#x0D; Methods. Data on pre-existing IS and proinflammatory cytokines, such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) were extracted from an existing patient database. The patients were followed up for 1.5 years and compared according to median serum IS concentration: low-IS (&lt; 22.2 μg/mL) and high-IS (≥22.2 μg/mL) groups. The primary outcomes focused on assessing the risk and severity of COVID-19 infection.&#x0D; Results. A total of 56 patients aged 62 (56-67) years with a dialysis vintage of 37.5 (30-168) months were included in the analysis. Serum levels of IS were significantly correlated with Kt/V values (p = 0.043), arterial hypertension (p = 0.001), IL-6 (p = 0.023), MCP-1 (p = 0.023), and TNF-α (p = 0.033) concentrations. Elevated serum IS levels were significantly associated with an increased risk of COVID-19 infection (p &lt; 0.0001) and a higher likelihood of hospitalization (p = 0.03). Patients with higher IS levels exhibited more severe lung involvement (p &lt; 0.0001) and a greater need for respiratory support (p = 0.004). A serum IS concentration of 21.5 μg/mL was the optimal threshold for predicting COVID-19 infection in HD patients (sensitivity of 83.4% and specificity of 92.3%, p &lt; 0.0001).&#x0D; Conclusion: Our study highlights the detrimental impact of serum IS on COVID-19 infection and its clinical outcomes in patients undergoing HD. Further research is warranted to elucidate the underlying mechanisms and explore potential therapeutic strategies targeting IS in this population.

Cerebrospinal fluid cytokines and chemokines exhibit distinct profiles in bacterial meningitis and viral meningitis.

Differential diagnosis of bacterial meningitis (BM) and viral meningitis (VM) is a critical clinical challenge, as the early and accurate identification of the causative agent determines the appropriate treatment regimen and markedly improves patient outcomes. Clinical and experimental studies have demonstrated that the pathogen and the host immune response contribute to mortality and neurological sequelae. As BM is associated with the activation of an inflammatory cascade, the patterns of pro- and anti-inflammatory cytokines/chemokines (CTs/CKs) present in the cerebrospinal fluid (CSF) in response to the immune assault may be useful as sensitive markers for differentiating BM from VM. In the present study, the ability of CTs/CKs in the CSF to differentiate between BM and VM was investigated. For this, biochemical markers and CT/CK profiles were analysed in 145 CSF samples, divided into three groups: BM (n=61), VM (n=58) and the control group (C; n=26) comprising patients with meningism. The CSF concentrations of monocyte chemoattractant protein-1, interleukin (IL)-8, IL-1β, IL-6, macrophage inflammatory protein-1α (MIP-1α), epithelial-neutrophil activating peptide, IL-10, tumour necrosis factor-α (TNF-α), proteins and white blood cells were significantly higher and the CSF glucose level was significantly lower in the BM group compared with the VM and C groups (P<0.01). Correlation analysis identified 28 significant correlations between various CTs/CKs in the BM group (P<0.01), with the strongest positive correlations being for TNF-α/IL-6 (r=0.75), TNF-α/MIP-1α (r=0.69), TNF-α/IL-1β (r=0.64) and IL-1β/MIP-1α (r=0.64). To identify the optimum CT/CK patterns for predicting and classifying BM and VM, a dataset of 119 BM and VM samples was divided into training (n=90) and testing (n=29) subsets for use as input for a Random Forest (RF) machine learning algorithm. For the 29 test samples (15 BM and 14 VM), the RF algorithm correctly classified 28 samples, with 92% sensitivity and 93% specificity. The results show that the patterns of CT/CK levels in the CSF can be used to aid discrimination of BM and VM.

Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1year and 58.9% at 2years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Effects of Ethanolic and Aqueous Extracts of Garcinia gardneriana Leaves in an In Vivo Experimental Model Induced by a Hyperlipidic Diet

The study of medicinal plants, such as the genus Garcinia (Clusiaceae), in the treatment of non-communicable chronic diseases has aroused the interest of researchers. However, there are no studies in the literature that have investigated the effects of Garcinia gardneriana in experimental models of obesity for possible metabolic alterations. Swiss mice receiving a high-fat diet were supplemented with aqueous or ethanolic extract of G. gardneriana at doses of 200 or 400 mg/kg/day. It was found that there was a reduction in food consumption in experimental groups compared with the control groups, and the group supplemented with aqueous extract at a dose of 200 mg/kg/daydisplayed a reduction in weight. The results showed an increase in the values of high density lipoprotein (HDL-c), total cholesterol, triglycerides and fasting blood glucose. G. gardneriana did not protect against insulin resistance, and caused in an increase in monocyte chemoattractant protein-1 (MCP-1) concentrations and a reduction in interleukin 10 (IL-10). In addition, hepatic steatosis and microvesicular steatosis were indicated. It was revealed that, under the experimental conditions in the study, G. gardneriana did not prevent weight gain or comorbidities; that is, a different behavior was obtained from that described in the literature with regard to the medicinal potential of the Garcinia species, which is probably related to the phytochemical properties.

The salivary and nasopharyngeal microbiomes are associated with SARS-CoV-2 infection and disease severity.

Emerging evidence suggests the oral and upper respiratory microbiota may play important roles in modulating host immune responses to viral infection. As the host microbiome may be involved in the pathophysiology of coronavirusdisease 2019 (COVID-19), we investigated associations between the oral and nasopharyngeal microbiome and COVID-19 severity.We collected saliva (n = 78) and nasopharyngeal swab (n = 66) samples from a COVID-19 cohort and characterized the microbiomes using 16S ribosomal RNA gene sequencing. We also examined associations between the salivary and nasopharyngeal microbiome and age, COVID-19 symptoms, and blood cytokines.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status, but not COVID-19 severity, was associated with community-level differences in the oral and nasopharyngeal microbiomes. Salivary and nasopharyngeal microbiome alpha diversity negatively correlated with age and were associated with fever and diarrhea. Oral Bifidobacterium, Lactobacillus, and Solobacterium were depleted in patients with severe COVID-19. Nasopharyngeal Paracoccus was depleted while nasopharyngeal Proteus, Cupravidus, and Lactobacillus were increased in patients with severe COVID-19. Further analysis revealed that the abundance of oral Bifidobacterium was negatively associated with plasma concentrations of known COVID-19 biomarkers interleukin 17Fand monocyte chemoattractant protein-1.Our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.

NLRX1 increases human retinal pigment epithelial autophagy and reduces H2O2-induced oxidative stress and inflammation by suppressing FUNDC1 phosphorylation and NLRP3 activation.

Age-related macular degeneration (AMD) is a leading cause of impaired vision as well as some earlier effects, such as reading and face recognition. Oxidative damage and inflammation of retinal pigment epithelial (RPE) cells are major causes of AMD. Additionally, autophagy in RPE cells can lead to cellular homeostasis under oxidative stress. Nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) is a mysterious modulator of the immune system function which inhibits inflammatory response, attenuates reactive oxygen species (ROS) production, and regulates autophagy. This study attempted to explore the role of NLRX1 in oxidative stress, inflammation, and autophagy in AMD. An in vitro model of AMD was built in human retinal pigment epithelial cell line 19 (ARPE-19) treated with H2O2. The cell viability, NLRX1 expressions, levels of superoxide dismutase (SOD), glutathione (GHS), and ROS, concentrations of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, and monocyte chemoattractant protein-1 (MCP-1), expressions of NLRX1, p62, LC3-II/LC3-I, FUNDC1, and NOD-like receptor protein 3 (NLRP3) inflammasome were expounded by cell counting kit-8, colorimetric, enzyme-linked immunosorbent serologic assay (ELISA), and Western blot assay. H2O2 treatment notably reduced the relative protein expression of NLRX1. Meanwhile, H2O2 incubation decreased cell viability, diminished SOD and GSH concentrations, accompanied with the increased level of ROS, enhanced IL-1β, TNF-α, IL-6, and MCP-1 concentrations, and aggrandized the relative protein expression of p62 with reduced LC3-II/LC3-I ratio. Moreover, these results were further promoted with knockdown of NLRX1 and reversed with overexpression. Mechanically, silencing of NLRX1 further observably enhanced the relative levels of -phosphorylated FUNDC1/FUNDC1, and NLRP3 inflammasome-related proteins, while overexpression of NLRX1 exhibited inverse results in the H2O2-induced ARPE-19 cells. NLRX1 suppressed H2O2-induced oxidative stress and inflammation, and facilitated autophagy by suppressing FUNDC1 phosphorylation and NLRP3 activation in ARPE-19 cells.

Sex-stratified RNA-seq analysis reveals traumatic brain injury-induced transcriptional changes in the female hippocampus conducive to dementia.

Traumatic brain injury (TBI), resulting from a violent force that causes functional changes in the brain, is the foremost environmental risk factor for developing dementia. While previous studies have identified specific candidate genes that may instigate worse outcomes following TBI when mutated, TBI-induced changes in gene expression conducive to dementia are critically understudied. Additionally, biological sex seemingly influences TBI outcomes, but the discrepancies in post-TBI gene expression leading to progressive neurodegeneration between the sexes have yet to be investigated. We conducted a whole-genome RNA sequencing analysis of post-mortem brain tissue from the parietal neocortex, temporal neocortex, frontal white matter, and hippocampus of 107 donors characterized by the Aging, Dementia, and Traumatic Brain Injury Project. Our analysis was sex-stratified and compared gene expression patterns between TBI donors and controls, a subset of which presented with dementia. We report three candidate gene modules from the female hippocampus whose expression correlated with dementia in female TBI donors. Enrichment analyses revealed that the candidate modules were notably enriched in cardiac processes and the immune-inflammatory response, among other biological processes. In addition, multiple candidate module genes showed a significant positive correlation with hippocampal concentrations of monocyte chemoattractant protein-1 in females with post-TBI dementia, which has been previously described as a potential biomarker for TBI and susceptibility to post-injury dementia. We concurrently examined the expression profiles of these candidate modules in the hippocampus of males with TBI and found no apparent indicator that the identified candidate modules contribute to post-TBI dementia in males. Herein, we present the first sex-stratified RNA sequencing analysis of TBI-induced changes within the transcriptome that may be conducive to dementia. This work contributes to our current understanding of the pathophysiological link between TBI and dementia and emphasizes the growing interest in sex as a biological variable affecting TBI outcomes.

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.

Monocyte chemoattractant protein 1 plasma concentration in blood from varicose veins decreases under venoactive drug treatment.

Vein-specific inflammation leads to vascular smooth muscle cells proliferation and extracellular matrix degradation of vein wall. This process is known as remodeling and is promoted by "trapped" leukocytes. Monocyte chemoattractant protein 1 (MCP-1) is a chemokine responsible for trafficking of leukocytes from blood to vein wall. The aim of this study was to measure the MCP-1 concentration in varicose veins blood before and after venoactive drug therapy and to compare it with a concentration of blood from varicose veins of subjects who did not receive drug treatment. Non-randomized comparative study was conducted on 30 patients with primary varicose veins. 20 patients of the study group received diosmin 900 mg/hesperidin 100 mg once daily. 10 controls received no treatment. MCP-1 level was measured (pg/mL) in the blood from varicose veins twice, at the day of inclusion and after 60 days. Legs discomfort related to chronic venous disease (CVD) symptoms was measured with 10-cm Visual Analogue Scale (VAS) at inclusion and at completion of the study. Median (interquartile range, IQR) MCP-1 concentrations in treatment and control groups at inclusion were 171.9 (124.4-216.0) and 157.0 (120.1-163.1), resp., P=0.285. After 60 days of treatment MCP-1 level decreased, but non-significantly to 152.3 (124.1-178.3). In patients who did not receive treatment chemokine level slightly increased to 163.0 (134.0-172.9). Median changes over time were -6.6 (-30.9-7.4) and 10.6 (-3.7-19.2) in the study and control groups, resp. (P=0.048). After 60 days in 12 of 19 and 2 of 9 patients of treatments and control groups MCP-1 decreased (P=0.103). Odds ratio for MCP-1 decreasing was 9.5 (95% CI 1.1-81.5, P=0.043) for those who received venoactive drug. Mean (± standard deviation [SD]) legs discomfort significantly dropped in the study group from 5.7 (±2.5) to 1.9 (±2.2) (P=0.0003), while in controls no changes were registered: 3.4 (±1.3) and 3.5 (± 1.4), resp., P=0.28). Mean difference of VAS at baseline and at follow-up was -3.5 (±2.6) and 0.9 (±2.1), resp. (P<0.0001). Plasma concentration of MCP-1 in varicose veins blood demonstrates a tendency to decrease under two months treatment with a venoactive drug. Future studies are needed to reveal a possible role of MCP-1 as a target considering its role in varicose veins pathogenesis.

Plasma Cytokine Profiles in Patients With Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration.

The concentrations of cytokines in plasma may be different between neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). We studied plasma levels of cytokines in patients with nAMD and PCV and compared them with control individuals. This was a prospective, clinic-based, case-control study of treatment-naive participants (n=49) with PCV (n=24), nAMD (n=11), and cataract controls (n=14). We sampled fresh venous blood and isolated plasma for analysis. Plasma concentrations of 34 angiogenic and inflammatory cytokines were determined by Luminex bead-based multiplex array. After adjusting for gender and age using multivariate logistic analysis, we found that the plasma concentrations of monocyte chemoattractant protein-1, vascular endothelial growth factor (VEGF)-A, and VEGF-D significantly higher in both nAMD and PCV patients than those in controls (all P<0.05, times in nAMD: 3.5, 4.3, and 13.8, respectively, times in PCV: 4.1, 4.0, and 11.5, respectively). In contrast, the plasma concentration of platelet-derived growth factor-BB was significantly lower in nAMD and PCV patients than those in controls (all P<0.05, times in nAMD: 1.6, times in PCV: 1.7). The plasma levels of leukemia inhibitory factor in nAMD group were significantly higher compared with PCV group (P<0.0167). Multiple cytokines involved in systemic inflammation and angiogenesis including monocyte chemoattractant protein-1, platelet-derived growth factor-BB, VEGF-A, and VEGF-D may contribute to the pathogenesis of nAMD and PCV. Measurement of leukemia inhibitory factor in the plasma may help differentiate nAMD from PCV. This finding suggests that the 2 disorders may have different molecular mechanisms, and additional longitudinal studies will be needed to determine whether these findings have clinical relevance to influence treatment algorithms or provide novel targets for medical therapy.

Assessment of Monocyte Chemo-Attractant Protein-1 (MCP-1) and Other Biochemical Parameters in Iraqi Pregnant Women

      The monocyte chemo-attractant protein-1 (MCP-1) is one of the pro-inflammatory cytokines. It controls the passage and infiltration of monocytes, macrophages, natural killers, and T cells into the sites of inflammation. The aim of this study is to inspect the role of MCP-1 in maternal metabolic, physiological changes and pregnancy complications like gestational diabetes mellitus, dyslipidemia, and hypertension to develop pharmaceutical strategies for these complications. This study included ninety Iraqi women divided into three groups: thirty pregnant women in their first trimester as the P1 group; thirty pregnant women in their third trimester as the P2 group; and thirty healthy non-pregnant women as the control or C group. Serum concentrations of MCP-1 were analyzed by the ELISA technique (sandwich principle). Fasting plasma glucose (FPG), C-reactive protein (CRP), fasting serum insulin (FSI), glycosylated hemoglobin (HbA1c), lipid profile, systolic, diastolic blood pressure, liver function enzymes ALT, AST and anthropometric parameters were measured. Our results revealed that serum MCP-1 significantly declined in the first trimester (P1) compared to the C group (p&lt;0.05) and non-significantly declined in the third trimester (P2) compared to that in the C group, while there was a significant difference in serum MCP-1 between the P1 and P2 groups (p&lt;0.05 ). Serum CRP showed a highly significant increase in the P1 and P2 groups compared to the C group at (p&lt;0.01). There is a highly significant difference between the P1 and P2 groups (p&lt;0.01). Serum MCP-1 had a significant positive correlation with body mass index (BMI), body fat percentage (BF %), systolic blood pressure (SBP) and C-reactive protein (CRP) in the P2 group (p&lt;0.05). No significant differences in FPG or HbA1C were found between all the studied groups. Lipid parameters: TC, TG, LDL, and VLDL showed a highly significant increase in the P2 group compared to the C and P1 groups (p&lt;0.01). HDL showed a highly significant decrease in the P2 group compared to the C group (p&lt;0.01), while it was only significantly decreased in the P2 group compared to the P1 group (p&lt;0.05). Depending on these results, we found that serum MCP-1 declines in pregnancy, the BMI, BF%, and the contractile arterial blood pressure (SBP) have a positive correlation with MCP-1 in late pregnancy, and the inflammation marker (CRP) has an independent association with MCP-1 in early gestation.