Circulating inflammatory cytokines and gestational diabetes mellitus: Unraveling the role of macrophage migration inhibitory factor (MIF) through a bidirectional mendelian randomization study.

BACKGROUND: Several studies have identified associations between some of circulating inflammatory cytokines and gestational diabetes mellitus (GDM). However, the causal role of these associations remains unclear and unsystematic. We aimed to provide evidence for the causal relationships between circulating inflammatory cytokines and gestational diabetes mellitus. METHODS: We performed bidirectional two-sample Mendelian randomization (2SMR) to investigate the causal connection between circulating inflammatory cytokines and gestational diabetes mellitus. Publicly accessible data for circulating inflammatory cytokines (8,293 individuals) and gestational diabetes mellitus (123,579 individuals) were obtained from genome-wide association study (GWAS). RESULTS: Only one causal association was identified between circulating inflammatory cytokines and GDM. The inverse variance weighting (IVW) method showed that macrophage migration inhibitory factor (MIF) increased the risk of GDM (OR 1.162, 95%CI 1.044,1.293). Moreover, two causal associations were detected between GDM and circulating inflammatory cytokines. GDM was negatively correlated with interferon gamma-induced protein 10 (IP10) (Beta -0.129, 95%CI -0.236,-0.231) and interleukin-18 (IL18) (Beta -0.133, 95%CI -0.241,-0.026). CONCLUSION: Mendelian randomization study revealed MIF as a risk factor for gestational diabetes mellitus. This finding offers a new and valuable insight into the pathophysiological mechanisms underlying GDM.

Macrophage Migration Inhibitory Factor Promotes Thromboinflammation and Predicts Fast Progression of Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.

The clinical signature of genetic variants and serum levels of macrophage migration inhibitory factor in Egyptian breast cancer patients.

PURPOSE: Macrophage migration inhibitory factor (MIF) is an integral cytokine for the modulation of both innate and adaptive immunity and is involved in the pathogenesis of various cancers. However, conflicting findings on the relationship between MIF polymorphisms and breast cancer (BC) have been reported in earlier research. We investigated the clinical value of serum MIF levels and the association between MIF rs1049829 and rs755622 variants with their serum levels and propensity to develop BC. METHODS: A total of 133 treatment-naïve Egyptian BC females and 126 apparently healthy controls were matriculated in this case-control study. The serum MIF protein levels were quantified by ELISA, whereas the genotyping was executed utilizing the TaqMan® allelic discrimination assay. RESULTS: A significant increase in the serum MIF level in BC cases was observed in comparison to control subjects (P < 0.0001), with a diagnostic potential to discriminate BC with 92.5% sensitivity and 73.7% specificity at a cut-off value > 9.47 ng/mL. Besides, a significant difference in serum MIF level was observed in BC cases with progesterone receptor (PR) negativity compared to those with PR positivity (P = 0.046). Moreover, a significant association was depicted between the rs1049829 variant of MIF gene and the protective effect against BC meanwhile the rs755622 variant demonstrated no significant link with BC risk. CONCLUSIONS: This study revealed that serum MIF levels may be regarded as a promising serum tumor marker for BC. Also, the rs1049829 variant of the MIF gene is considered a protective candidate against BC.

Increased risk of atypical antipsychotics-induced metabolic syndrome associated with MIF CATT >5/6 among females with chronic schizophrenia.

The utilization of atypical antipsychotics (AAPs) often leads to metabolic syndrome (MetS) in schizophrenia (SZ) patients. Macrophage migration inhibitory factor (MIF) is an important MetS-related cytokine. To investigate the potential association between the MIF-794 CATT5-8 polymorphism and AAP-induced MetS in SZ patients, data from 375 chronic SZ patients who received AAP treatment for a minimum of one year were included. MIF-794 CATT polymorphism genotyping and plasma MIF quantification was performed. The metabolism status of all patients was assessed according to the NCEP-ATP III criteria. Individuals who displayed at least three of the five risk factors (waist circumference, high-density lipoprotein cholesterol, triglycerides, fasting glucose levels, and blood pressure) were diagnosed with MetS. The prevalence of MetS in SZ patients with MIF CATT >5/6 was significantly higher than in those with CATT 5/5-5/6. In female patients, MIF CATT >5/6 was associated with an elevated risk of AAP-induced MetS after adjusting for covariates, particularly regarding abdominal obesity, and the mediating effect of plasma MIF levels was significant. In conclusion, MIF CATT >5/6 increased the risk of AAP-induced MetS among females with chronic SZ. The MIF-794 CATT5-8 microsatellite polymorphism may be a unique indicator for AAP-induced metabolic adverse effects in female SZ patients.

Early predictive value of lipocalin-type prostaglandin D synthase for 28-day mortality in cardiac arrest patients: study protocol for a prospective study.

INTRODUCTION: Public training in cardiopulmonary resuscitation and treatment in emergency and intensive care unit have made tremendous progress. However, cardiac arrest remains a major health burden worldwide, with brain damage being a significant contributor to disability and mortality. Lipocalin-type prostaglandin D synthase (L-PGDS), which is mainly localised in the central nervous system, has been previously shown to inhibit postischemia neuronal apoptosis. Therefore, we aim to observe whether serum L-PGDS can serve as a potential biomarker and explore its role in determining the severity and prognosis of patients who have achieved restoration of spontaneous circulation (ROSC). METHODS AND ANALYSIS: This is a prospective observational study. The participants (n = 60) who achieve ROSC will be distributed into two groups (non-survivor and survivor) based on 28-day survival. Healthy volunteers (n = 30) will be enrolled as controls. Each individual's relevant information will be extracted from Electronic Medical Record System in Xinhua Hospital, including demographic characteristics, clinical data, laboratory findings and so on. On days 1, 3 and 7 after ROSC, blood samples will be drawn and batch tested on the level of serum neuron-specific enolase, soluble protein 100ß, L-PGDS, procalcitonin, tumour necrosis factor-alpha and interleukin-6. The cerebral performance category score was assessed on the 28th day after ROSC. ETHICS AND DISSEMINATION: This study was performed with the approval of the Clinical Ethical Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-C-2023-130-1). The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2300078564).

High circulating MIF levels indicate the association with atypical antipsychotic-induced adverse metabolic effects.

Atypical antipsychotics (AAPs) are primary medications for schizophrenia (SZ). However, their use is frequently associated with the development of adverse metabolic effects, and the mechanisms behind these negative effects remain inadequately elucidated. To investigate the role of macrophage migration inhibitory factor (MIF) in regulating antipsychotic-induced metabolic abnormalities, between 2017 and 2020, a cross-sectional study was conducted, involving 142 healthy individuals and 388 SZ patients undergoing treatment with either typical antipsychotic (TAP) or AAP medications. Symptoms of SZ patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), and measurements of metabolic indices and plasma MIF levels were performed on all individuals. A significant increase in plasma MIF levels was observed in groups receiving five major AAP monotherapies in comparison to healthy controls (all p < 0.0001). There was no such increase shown in the group receiving TAP treatment (p > 0.05). Elevated plasma MIF levels displayed a notable correlation with insulin resistance (ß = 0.024, p = 0.020), as well as with the levels of triglycerides (ß = 0.019, p = 0.001) and total cholesterol (ß = 0.012, p = 0.038) in the groups receiving AAPs. However, while the TAP group also displayed certain metabolic dysfunction compared to healthy controls, no significant association was evident with plasma MIF levels (all p > 0.05). In conclusion, plasma MIF levels exhibit a distinctive correlation with metabolic abnormalities triggered by AAPs. Hence, there is potential for further development of MIF as a distinctive marker for monitoring adverse metabolic effects induced by AAPs in clinical settings.

Correlation of Serum High-Sensitivity C-Reactive Protein, Homocysteine, and Macrophage Migration Inhibitory Factor Levels With Symptom Severity and Cognitive Function in Patients With Schizophrenia.

OBJECTIVE: This trial analyzed high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), and macrophage migration inhibitory factor (MIF) level in serum and their correlation with symptom severity and cognitive function in patients with schizophrenia (SP). METHODS: Sixty-eight SP patients were enrolled in the SP group, and 68 healthy volunteers were in the control (CN) group. Serum hs-CRP, Hcy, and MIF were measured, and symptom severity was assessed with the Positive and Negative Symptom Scale (PANSS). Cognitive function was determined with the MATRICS Consensus Cognitive Battery (MCCB). The SP group was divided into high PANSS score (PANSS ≥70 points) and low PANSS score (PANSS <70 points), or the mild cognitive dysfunction group and severe cognitive dysfunction group according to the median MCCB score. The correlation between serum hs-CRP, Hcy, and MIF levels and PANSS and MCCB scores in SP patients was examined by Pearson correlation analysis. RESULTS: SP patients had higher serum hs-CRP, Hcy, and MIF levels and showed higher PANSS scores and lower MCCB total score. Serum hs-CRP, Hcy, and MIF levels in the high PANSS group were higher than those in the low PANSS group and in the severe cognitive dysfunction group than in the mild cognitive dysfunction group. Serum hs-CRP, Hcy, and MIF levels in SP patients were positively correlated with PANSS total score and negatively correlated with MCCB total score. CONCLUSION: High serum hs-CRP, Hcy, and MIF levels in SP patients are correlated with symptom severity and cognitive dysfunction.

Association of Serum Macrophage Migration Inhibitory Factor with 3-Month Poor Outcome and Malignant Cerebral Edema in Patients with Large Hemispheric Infarction.

BACKGROUND: We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). METHODS: Patients with LHI within 24 h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3 months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5 mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. RESULTS: Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82 ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144-6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841-10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56 ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236-6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534-9.637, p = 0.004). CONCLUSIONS: Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies.

Soluble Factors CD14, CD163, and Migration Inhibitory Factor Are Associated with Endometriosis-Related Infertility.

OBJECTIVES: Myeloid cell-derived factors contribute to the immunopathology of endometriosis. Soluble CD14 (sCD14), CD163 (sCD163), and MIF serve as in vivo markers of myeloid function. However, these soluble molecules are largely unexplored in women with endometriosis-related infertility cases. We investigated three soluble markers, namely sCD14, sCD163, and MIF, in cases of infertility associated with endometriosis and correlated its level to the stage of endometriosis. DESIGN: Eighty-seven women newly diagnosed with endometriosis or other benign gynecologic control cases linked to infertility were prospectively recruited and underwent diagnostic laparoscopy. PARTICIPANTS: Forty-four patients with endometriosis were included in this study, comprising 19 patients with early-endometriosis (stages I and II) and 25 late-endometriosis (stages III and IV) based on the revised American Society for Reproductive Medicine (rASRM) classification. The remaining 43 patients constituted a control group with infertility due to other causes. METHODS: The levels of sCD14, sCD163, and MIF in serum and peritoneal fluid were assessed using ELISA. RESULTS: Endometriosis women exhibited significantly higher serum levels of sCD163 and MIF levels compared to the control group. Both sCD163 and MIF levels displayed a positive correlation with the rASRM adhesion score. Moreover, the MIF level in serum had a positive correlation with the rASRM endometriosis score. In receiver operating characteristic analysis, serum sCD163 and MIF could significantly discriminate endometriosis and non-endometriosis in infertility cases. LIMITATIONS: Some limitations of the current study deserve to be underlined. First, the sensitive ELISA method was the sole-validated tool for detecting the markers in patient samples. Second, healthy or fertile women were not involved as the control group. CONCLUSIONS: The elevated systemic levels of sCD163 and MIF correlated with the severity of endometriosis. These soluble molecules have a potential diagnostic capacity as a non-invasive biomarker. Furthermore, our data warrants future studies on the underlying mechanism of sCD163 and MIF in endometriosis-related infertility.

Glomerular Filtration Rate Estimation Using ß2-Microglobulin and ß-Trace Protein in Adults With Solid Tumors: A Prospective Cross-Sectional Study.

RATIONALE & OBJECTIVE: ß2-Microglobulin (B2M) and ß-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFRcr-cys), but they have not been assessed in patients with cancer. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017. EXPOSURE: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR). OUTCOME: Performance of equations compared with eGFRcr-cys and non-GFR determinants of serum B2M and BTP (SB2M, and SBTP, respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). ANALYTICAL APPROACH: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P30). Linear regression was used to assess association of clinical and laboratory variables with SB2M, and SBTP after adjustment for mGFR. RESULTS: Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m2, respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys (lesser bias and 1-P30). Performance of 2-marker panel equations was as good as eGFRcr-cys (lesser bias and similar 1-P30). SB2M and SBTP were not strongly influenced by cancer site. LIMITATIONS: Participants may have had better clinical performance status than the general population of patients with solid tumors. CONCLUSIONS: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine. PLAIN-LANGUAGE SUMMARY: The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFRcr-cys). We studied whether using ß2-microglobulin (B2M) and/or ß-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys. Performance of 2-marker panel equations was as good as eGFRcr-cys. We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine.

Elevated MIF identified by multiple cytokine analyses facilitates macrophage M2 polarization contributing to postoperative recurrence in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by tissue heterogeneity and high postoperative recurrence risk. This study aims to employ cytokine analyses to identify serum biomarkers associated with postoperative CRSwNP recurrence and elucidate underlying recurrent mechanisms. METHODS: A prospective cohort study was conducted on CRSwNP patients undergoing functional endoscopic sinus surgery. Serum and tissue samples were collected and analyzed for multiple cytokines. Participants were followed for 3 years and categorized into recurrent and non-recurrent groups. Cytokine profiles were compared, and potential markers for recurrence were further assessed. Macrophage migration inhibitory factor (MIF) expression in macrophages was modulated, and their polarization and cytokine secretion were assessed. RESULTS: In the discovery cohort (21 recurrent and 40 non-recurrent patients), circulating cytokine profiles differed significantly, with 8 cytokines showing differential expression between the two groups. Among them, serum eotaxin, MIF, RANTES, and TRAIL exhibited promise in predicting recurrence. In the validation cohort (24 recurrent and 44 non-recurrent patients), serum eotaxin, MIF, and TRAIL levels were higher in recurrent cases. Tissue MIF was elevated in recurrent cases and had a strong predictive value for recurrence. Moreover, tissue MIF was co-expressed with CD206 in recurrent cases. Mechanistically, MIF overexpression promoted macrophage M2 polarization and TGF-ß, CCL-24, and MIF secretion, and MIF recombinant protein facilitated M2 polarization, and TGF-ß1 and CCL-24 production, contributing to CRSwNP recurrence. CONCLUSIONS: Serum-specific cytokine signatures were associated with postoperative recurrence risk in CRSwNP. Elevated MIF enhanced macrophage M2 polarization and cytokine secretion, contributing to the recurrent mechanisms of CRSwNP.

The role of serum macrophage migration inhibitory factor in preoperative prediction of chronic rhinosinusitis with nasal polyps endotypes.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease and can be categorized into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP). Exploring effective biomarkers to distinguish endotypes is important for personalized therapies. The present study aims to evaluate the predictive value of serum MIF in CRSwNP endotypes. METHODS: One hundred and twenty CRSwNP patients, including 51 eCRSwNP and 69 neCRSwNP, 40 chronic rhinosinusitis without nasal polyps (CRSsNP) patients and 40 healthy controls (HC) were enrolled. Serum MIF levels were determined by enzyme-linked immunosorbent assay (ELISA). The patients' clinical variables were analyzed for correlations with serum MIF. Receiver operating characteristic (ROC) curve and multivariate analysis were utilized to assess the predictive value of serum MIF in CRSwNP endotypes. RESULTS: The serum MIF levels were significantly higher in CRSwNP group than CRSsNP group and HC group (P < 0.001), and the serum MIF levels were increased in eCRSwNP compared to neCRSwNP group (P = 0.006). Elevated serum MIF levels were significantly correlated with blood eosinophil (B-EOS) count (r = 0.411, P < 0.001), B-EOS percentage (r = 0.377, P < 0.001), visual analog scale score (r = 0.204, P = 0.025), tissue eosinophil (T-EOS) count (r = 0.705, P < 0.001) and T-EOS percentage (r = 0.671, P < 0.001) in CRSwNP patients. ROC curve demonstrated that serum MIF exhibited good preoperative prediction in CRSwNP endotypes (area under the curve = 0.925, P < 0.001). Multivariate regression analysis showed that serum MIF was an independent factor associated with CRSwNP endotypes. CONCLUSIONS: This was the first study identifying serum MIF as a possible specific biomarker for preoperatively distinguishing CRSwNP endotypes. Furthermore, the serum MIF levels were found to be closely associated with the degree of mucosal eosinophil infiltration.

Anti-Mullerian Hormone and Macrophage Migration Inhibitory Factor Determine the Reproductive Health of Ladakhi Women Residing at 3,500 m.

Shaw, Snigdha, Himashree Gidugu, Gopinath Bhaumik, Maramreddy Prasanna Kumar Reddy, Usha Panjwani, and Dishari Ghosh. Anti-Mullerian hormone and macrophage migration inhibitory factor determine the reproductive health of Ladakhi women residing at 3,500 m. High Alt Med Biol. 22:317-326, 2021. Background: Reproductive health of Ladakhi high-altitude (HA) native females was investigated for the first time in this study. Available literature suggest that, female reproductive cycle and hormonal profile varies in different HA populations due to heterogeneity. Although these studies illustrate some progress on the role of HA hypoxia, it still leaves scope for evaluation of the remaining mechanisms involved in the maintenance of reproductive health in this contemporary population. Materials and Methods: Menstrual details, phasic variations in circulatory steroid hormones, and gonadotropins along with oxytocin in sea level (SL) and HA (∼3,500 m) native females of India were assessed. Moreover, ovarian reserve marker anti-Mullerian hormone (AMH) and proinflammatory cytokine macrophage migration inhibitory factor (MIF) were measured. Results: A difference in Ladakhi women was registered compared to SL, regarding luteinizing hormone (LH) (2.6 mIU/ml vs. 4.4 mIU/ml, p < 0.05) and progesterone (P) (4.1 ng/ml vs. 9.4 ng/ml, p < 0.05) levels in their luteal phase. Reduced LH might contribute to poor development of the ovarian corpus luteum, subsequently diminish P level. Decreased AMH level in three age groups: 21-30 years (1.4 ng/ml vs. 3.2 ng/ml, p < 0.01), 31-40 years (0.6 ng/ml vs. 2.1 ng/ml, p < 0.01), and >40 years (0.4 ng/ml vs. 1.7 ng/ml, p < 0.01) of Ladakhi women were recorded than their SL counterpart. Elevated oxytocin (83.5 ng/ml vs. 76.3 ng/ml, p < 0.05) and MIF levels (70.2 ng/ml vs. 49.7 ng/ml, p < 0.01) along with low P and AMH levels delineated the reason for recorded early menopause (43.9 years), shorter reproductive span (∼29 years), and history of miscarriage in HA dwellers compared to SL. Conclusion: Therefore, the findings insinuated that the response of the reproductive system to hypoxia in Ladakhi women differs from SL women, and the adaptive response in these women might be in favor of their reproductive health.

Evaluation of the relationship between macrophage migration inhibitory factor level and clinical course in patients with COVID-19 pneumonia.

The COVID-19 pandemic, which has ravaged our world for more than a year, still shapes our agenda with a scale of intensity that fluctuates over time. In our study, we aimed to determine the correlation between serum migration inhibitory factor (MIF) level and disease severity in COVID-19 with different prognoses. Between 15 October 2020 and 20 January 2021, 110 patients over the age of 18 who were diagnosed with COVID-19 and 40 volunteer healthcare personnel were included in our study. MIF levels were measured by enzyme-linked immunosorbent assay. In the comparison of serum MIF values in the patient and control group, it was observed that the MIF level was significantly higher in patients with both moderate and severe COVID-19 levels compared to the control group (p = 0.001, 0.001). In the comparison of serum MIF values of moderate to severe COVID-19 patients, it was observed that MIF level was higher in severe patients (p = 0.001). In the receiver operating characteristic curve analysis performed to differentiate between severe and moderate COVID-19 patients with MIF levels, the area under the curve was observed as 0.78. When the cutoff value of the MIF level was taken as 4.455 ng/ml, the sensitivity was 83% and the specificity was 62%. Failure to adequately balance the pro-inflammatory cytokines synthesized in COVID-19 with anti-inflammatory effect is the most important reason for the aggravation of the disease course. Playing a role in pro-inflammatory cytokine synthesis, MIF can provide important information about the disease prognosis in the early period.

Does Macrophage Migration Inhibitory Factor predict the prognosis of COVID-19 disease?

INTRODUCTION: The aim of this study is to investigate whether macrophage migration inhibitory factor (MIF) predicts the prognosis of COVID-19 disease. METHODOLOGY: This descriptive and cross-sectional study was conducted on 87 confirmed COVID-19 patients. The patients were separated into two groups according to the admission in the ICU or in the ward. MIF was determined batchwise in plasma obtained as soon as the patients were admitted. Both groups were compared with respect to demographic characteristics, biochemical parameters and prediction of requirement to ICU admission. RESULTS: Forty seven patients in ICU, and 40 patients in ward were included. With respect to MIF levels and biochemical biomarkers, there was a statistically significant difference between the ICU and ward patients (p< 0.024). In terms of ICU requirement, the cut-off value of MIF was detected as 4.705 (AUC:0.633, 95%CI:0.561-0.79, p= 0.037), D-dimer was 789 (AUC:0.779, 95%CI: 0.681-0.877, p= 0.000), troponin was 8.15 (AUC: 0.820, 95%CI:0.729-0.911, p= 0.000), ferritin was 375 (AUC: 0.774, 95%CI:0.671-0.876, p= 0.000), and lactate dehydrogenase (LDH) was 359.5 (AUC:0.843, 95%CI: 0.753-0.933, p= 0.000). According to the logistic regression analysis; when MIF level > 4.705, the patient's requirement to ICU risk was increased to 8.33 (95%CI: 1.73-44.26, p= 0.009) fold. Similarly, elevation of troponin, ferritin and, LDH was shown to predict disease prognosis (p< 0.05). CONCLUSIONS: Our study showed that MIF may play a role in inflammatory responses to COVID-19 through induction of pulmonary inflammatory cytokines, suggesting that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of COVID-19 pneumonia.

Macrophage migration inhibitory factor predicts an unfavorable outcome after transarterial chemoembolization for hepatic malignancies.

Transarterial chemoembolization (TACE) is a therapeutic option for patients with intermediate-stage hepatocellular carcinoma (HCC) or metastatic liver cancers. Identifying those patients who particularly benefit from TACE remains challenging. Macrophage migration inhibitory factor (MIF) represents is an inflammatory protein described in patients with liver cancer, but no data on its prognostic relevance in patients undergoing TACE exist. Here, we evaluate MIF serum concentrations as a potential biomarker in patients undergoing TACE for primary and secondary hepatic malignancies. MIF serum concentrations were measured by multiplex immunoassay in 50 patients (HCC: n = 39, liver metastases: n = 11) before and 1 day after TACE as well as in 51 healthy controls. Serum concentrations of MIF did not differ between patients and healthy controls. Interestingly, in the subgroup of patients with larger tumor size, significantly more patients had increased MIF concentrations. Patients with an objective tumor response to TACE therapy showed comparable concentrations of serum MIF compared to patients who did not respond. MIF concentrations at day 1 after TACE were significantly higher compared to baseline concentrations. Importantly, baseline MIF concentrations above the optimal cutoff value (0.625 ng/ml) turned out as a significant and independent prognostic marker for a reduced overall survival (OS) following TACE: patients with elevated MIF concentrations showed a significantly reduced median OS of only 719 days compared to patients below the cutoff value (median OS: 1430 days, p = 0.021). Baseline MIF serum concentrations are associated with tumor size of intrahepatic malignancies and predict outcome of patients with liver cancer receiving TACE.

IL-8, MSPa, MIF, FGF-9, ANG-2 and AgRP collection were identified for the diagnosis of colorectal cancer based on the support vector machine model.

Colorectal cancer (CRC) is one of the most common cancer, and the early detection of CRC is essential to improve the survival rate of patients. To identify diagnostic markers for colorectal cancer (CRC) by screening differentially expressed proteins (DEPs) in CRC. The DEPs were initially obtained from 12 CRC samples and 12 healthy control samples, and verification analysis was performed in another 34 CRC samples and 34 normal controls. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment with DEPs was analyzed by the R package clusterProfiler (Version 3.2.11), and the DEP-associated protein-protein interaction (PPI) network was created from the STRING database. Additionally, Support Vector Machine (SVM) model prediction and survival analyses were conducted on the key DEPs. Preliminary screening and functional analysis showed that the DEPs mainly overrepresented in pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, Rap1, Ras, and MAPK signaling pathways. The key DEPs, including AgRP, ANG-2, Dtk, EOT3, FGF-4, FGF-9, HCC-4, IL-16, IL-8, MIF, MSPa, TECK, TPO, TRAIL R3, and VEGF-D, were used to construct a custom chip. The drug-gene interaction network suggested that TPO was a key drug target. ROC curve showed the SVM diagnostic model with the DEPs IL-8, MSPa, MIF, FGF-9, ANG-2, and AgRP had better diagnostic performance with an AUC of 0.933. Survival analysis showed the expression of FGF9, TPO, TRAIL R3, Dtk, TECK and FGF4 were associated with prognosis. This study revealed the important serum proteins in the pathogenesis of CRC, which might serve as useful and noninvasive predictors for the diagnosis of CRC.

Role of the Macrophage Migration Inhibitory Factor in the Pathophysiology of Pre-Eclampsia.

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE.

Measurement of multiple cytokines for discrimination and risk stratification in patients with Chagas' disease and idiopathic dilated cardiomyopathy.

Chagas' disease (CD), caused by the hemoflagellate protozoan, Trypanosoma cruzi, is endemic in most countries of Latin America. Heart failure (HF) is often a late manifestation of chronic CD, and is associated with high morbidity and mortality. Inflammatory processes mediated by cytokines play a key role in the pathogenesis and progression of CD. Keeping in view the inflammatory nature of CD, this study investigated the possible role of 21 different inflammatory cytokines as biomarkers for prediction and prognosis of CD. The plasma concentration of these cytokines was measured in a group of patients with CD (n = 94), and then compared with those measured in patients with dilated cardiomyopathy (DCM) from idiopathic causes (n = 48), and with control subjects (n = 25). Monovariately, plasma levels of cytokines such as stem cell growth factor beta (SCGF beta), hepatocyte growth factor (HGF), monokine induced by interferon gamma (CXCL9), and macrophage inhibitory factor (MIF) were significantly increased in CD patients with advanced HF compared to control group. None of the cytokines could demonstrate any prognostic potency in CD patients, and only MIF and stromal derived factor-1 alpha (CXCL12) showed significance in predicting mortality and necessity for heart transplant in DCM patients. However, multivariate analysis prognosticated a large proportion of CD and DCM patients. In CD patients, HGF and Interleukin-12p40 (IL-12p40) together separated 81.9% of 3-year survivors from the deceased, while in DCM patients, CXCL12, stem cell factor (SCF), and CXCL9 together discriminated 77.1% of survivors from the deceased. The significant increase in plasma concentrations of cytokines such as HGF and CXCL9 in CD patients, and the ability of these cytokines to prognosticate a large proportion of CD and DCM patients multivariately, encourages further studies to clarify the diagnostic and prognostic potential of cytokines in such patients.

Beta-trace protein as a potential biomarker of residual renal function in patients undergoing peritoneal dialysis.

BACKGROUND: Residual renal function is closely linked to quality of life, morbidity and mortality in dialysis patients. Beta-trace protein (BTP), a low molecular weight protein, has been suggested as marker of residual renal function, in particular in patients on hemodialysis. We hypothesized that BTP also serves as a marker of residual renal function in pertioneal dialysis patients. METHODS: In this study 34 adult patients on peritoneal dialysis were included. BTP, creatinine, cystatin C and urea concentrations were analyzed simultaneously in serum and dialysate to calculate renal and peritoneal removal of the analytes. RESULTS: In peritoneal dialysis patients with residual diuresis, mean serum BTP was 8.16 mg/l (SD ± 4.75 mg/l). BTP correlated inversely with residual diuresis (rs = - 0.58, p < 0.001), residual creatinine clearance (ClCr) (rs = - 0.69, p < 0.001) and total urea clearance (Clurea) (rs = - 0.56, p < 0.001). Mean peritoneal removal of BTP was 3.36 L/week/1.73m2 (SD ± 1.38) and mean renal removal 15.14 L/week/1.73m2 (SD ± 12.65) demonstrating a significant renal contribution to the total removal. Finally, serum BTP inversely correlated with alterations in residual diuresis (r = - 0.41, p = 0.035) and renal creatinine clearance over time (r = - 0.79, p = p < 0.001). CONCLUSION: BTP measurement in the serum may be a simple tool to assess residual renal function in peritoneal dialysis patients.