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Background: The role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma. Methods: A cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization. Results: Our study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout. Conclusions: Our findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF. Highlights: EAF2 is associated with the progression of prostate cancer. EAF2 is correlated with Gleason score of prostate cancer. EAF2 is closely related to macrophages recruitment and polarition. EAF2 recruits M2 macrophages through upregulation of MIF. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is an adaptive response to stressors such as high cardiac workload, which might lead to abnormal cardiac function and heart failure. Previous studies have indicated that macrophage migration inhibitory factor (MIF) might play a protective role in cardiac hypertrophy. Here, we aimed to illustrate the mechanism of MIF in protecting against pressure overload‐induced cardiac hypertrophy. Transverse aortic constriction (TAC) mouse model was established and we found that overexpression of MIF protected against pressure overload‐induced cardiac hypotrophy in TAC treated mice, as evidenced by significantly decreased the heart weight. In addition, transthoracic echocardiography showed that overexpression of MIF restored ejection fraction in TAC‐treated mice. While TAC treatment resulted in a much larger cardiomyocyte size in mice, MIF overexpression notably decreased the cardiomyocyte size. Next, we demonstrated that MIF overexpression promoted the expression of miR‐29b‐3p which further downregulated the expression of its downstream target HMG box protein 1 (HBP1). Overexpression of HBP1 reversed the effect of MIF in alleviating Ang‐II induced oxidative stress in cardiomyocytes. In conclusion, our findings suggest that MIF could attenuate pressure overload‐induced cardiac hypertrophy through regulating the miR‐29b‐3p/HBP1 axis. [ABSTRACT FROM AUTHOR]

To investigate the relationship between serum irisin (Irisin), trimethylamine oxide (TMAO), macrophage migration inhibitory factor (MIF) and the prognosis of patients with chronic heart failure (CHF) and atrial fibrillation (AF) and its predictive value. 175 patients with CHF and AF admitted to Gansu Provincial People's Hospital from January 2020 to January 2023 were selected and included in combined AF group, patints were divided into poor prognosis group and good prognosis group according to the prognosis. And 100 CHF patients without AF during the same period were included in non-combined AF group. The levels of serum Irisin, TMAO and MIF were detected by enzyme-linked immunosorbent assay. The prognostic influencing factors of patients with CHF and AF were analyzed by multivariate logistic regression, the predictive value of serum Irisin, TMAO and MIF in the poor prognosis of patients with CHF and AF were analyzed by receiver operating characteristic (ROC) curve. Compared with non-combined AF group, the serum Irisin level in AF group was decreased, and the serum TMAO and MIF levels were increased (P<0. 05). Compared with good prognosis group, the serum Irisin level in poor prognosis group was decreased, and the serum TMAO and MIF levels were increased (P<0.05). After 6 months of follow-up, the incidence of poor prognosis in 175 patients with CHF and AF was 26.29%. Multivariate Logistic regression analysis showed that, New York Heart Association (NYHA) classification of cardiac function III～IV level and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), TMAO, and MIF were independent risk factors for poor prognosis in patients with CHF and AF, and elevated Irisin was an independent protective factor (P<0.05). ROC curve analysis showed that, the area under the curve (AUC) of serum Irisin, TMAO and MIF combined prediction for poor prognosis of patients with CHF and AF was 0.919, which was greater than 0.787, 0.780 and 0.777 predicted by serum Irisin, TMAO and MIF alone. The level of serum Irisin in patients with CHF and AF was decreased, and the levels of TMAO and MIF were increased, which were closely relate to the poor prognosis. The combine detection of serum Irisin, TMAO and MIF levels had a high predictive value for the poor prognosis of patients with CHF and AF. [ABSTRACT FROM AUTHOR]

Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD‐1) and cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Macrophage migration inhibitory factor (MIF) is a cytokine in the immune system, participated in both innate and adaptive immune responses. Except from immune cells, MIF is also secreted by a variety of non-immune cells, including hematopoietic cells, endothelial cells (ECs), and neurons. MIF plays a crucial role in various diseases, such as sepsis, rheumatoid arthritis, acute kidney injury, and neurodegenerative diseases. The role of MIF in the neuropathogenesis of cognitive impairment disorders is emphasized, as it recruits multiple inflammatory mediators, leading to activating microglia or astrocyte-derived neuroinflammation. Furthermore, it contributes to the cell death of neurons and ECs with the binding of apoptosis-inducing factor (AIF) through parthanatos-associated apoptosis-inducing factor nuclease (PAAN) / MIF pathway. This review comprehensively delves into the relationship between MIF and the neuropathogenesis of cognitive impairment disorders, providing a series of emerging MIF-targeted pharmaceuticals as potential treatments for cognitive impairment disorders. [Display omitted] • MIF modulates neuronal and glial function in brain. • MIF-induced neuroinflammation and cell death contributed to cognitive impairment. • MIF inhibitors are promising to prevent cognitive impairment disorders. [ABSTRACT FROM AUTHOR]

Objective: To explore the diagnostic value of transvaginal ultrasound combined with serum alpha fetoprotein (AFP), plasminogen activator inhibitor-1 (PAI-1), and macrophage migration inhibitory factor (MMIF) in endometriosis. Methods: A retrospective analysis was conducted on 150 patients with endometriosis admitted to our hospital from August 2021 to August 2023. The imaging features of transvaginal ultrasound were analyzed, and pathological diagnosis was used as the "gold standard" to analyze the positive detection rate of vaginal ultrasound for endometriosis. According to the staging of endometriosis, it was divided into stage I-II group (n=77) and stage III-IV group (n=73) . In addition, 150 healthy women who came to our hospital for physical examination during the same period were selected as the control group. Analyze the expression levels of serum AFP, PAI-1, and MMIF in three groups of subjects, and use Spearman correlation analysis to analyze the correlation between AFP, PAI-1, and MMIF and endometriosis. Finally, a receiver characteristics (ROC) working curve was established to analyze the diagnostic efficacy of transvaginal ultrasound combined with serum AFP, PAI-1, and MMIF for endometriosis. Results: All 150 patients with endometriosis were diagnosed by pathology, and 128 patients (85.33%) were diagnosed with endometriosis through transvaginal ultrasound examination. Among them, 75 patients were ovarian type, and ultrasound showed a huge chocolate cyst with a large amount of fine dotted echoes and separated light bands inside. 53 patients were of uterine type, and ultrasound showed a posterior wall adenomyoma with uneven internal echoes and visible patchy anechoic areas; There were significant differences in the expression levels of serum AFP, PAI-1, and MMIF among the three groups of subjects. The levels of serum AFP, PAI-1, and MMIF in the stage III-IV group were significantly higher than those in the stage I-II group and the control group, and the difference was statistically significant (P＜0.05) ; Spearman correlation analysis showed that AFP, PAI-1, and MMIF were positively correlated with endometriosis (P＜0.05) ; The diagnostic sensitivity and specificity from low to high were MMIF (52.58%, 64.32%), PAI-1 (60.03%, 67.53%), AFP (65.24%, 71.27%), transvaginal ultrasound (73.25%, 86.36%), transvaginal ultrasound combined with serum AFP, PAI-1, and MMIF (84.26%, 98.63%) . The diagnostic sensitivity of transvaginal ultrasound combined with serum AFP, PAI-1, and MMIF was significantly higher than that of single indicator diagnosis (P＜0.05) . Conclusion: Transvaginal ultrasound combined with serum AFP, PAI-1, and MMIF has a high diagnostic value for endometriosis, with sensitivity and specificity of 84.26% and 98.63%, respectively. Through combined diagnosis, it can further assist in reducing the probability of misdiagnosis and missed diagnosis of endometriosis, providing important reference for the diagnosis and treatment of endometriosis. [ABSTRACT FROM AUTHOR]

Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration. [ABSTRACT FROM AUTHOR]

The cellular mechanisms of burn conversion of heat damaged tissue are center of many studies. Even if the molecular mechanisms of heat-induced cell death are controversially discussed in the current literature, it is widely accepted that caspase-mediated apoptosis plays a central role. In the current study we wanted to develop further information on the nature of the mechanism of heat-induced cell death of fibroblasts in vitro. We found that heating of human fibroblast cultures (a 10 s rise from 37 °C to 67 °C followed by a 13 s cool down to 37 °C) resulted in the death of about 50% of the cells. However, the increase in cell death started with a delay, about one hour after exposure to heat, and reached the maximum after about five hours. The lack of clear evidence for an active involvement of effector caspase in the observed cell death mechanism and the lack of observation of the occurrence of hypodiploid nuclei contradict heat-induced cell death by caspase-mediated apoptosis. Moreover, a dominant heat-induced increase in PARP1 protein expression, which correlated with a time-delayed ATP synthesis inhibition, appearance of double-strand breaks and secondary necrosis, indicate a different type of cell death than apoptosis. Indeed, increased translocation of Apoptosis Inducing Factor (AIF) and Macrophage Migration Inhibitory Factor (MIF) into cell nuclei, which correlates with the mentioned enhanced PARP1 protein expression, indicate PARP1-induced, AIF-mediated and MIF-activated cell death. With regard to the molecular actors involved, the cellular processes and temporal sequences, the mode of cell death observed in our model is very similar to the cell death mechanism via Parthanatos described in the literature. • Results contradict heat-induced cell death by caspase-mediated apoptosis. • Results indicate a different heat induced cell death of fibroblasts than apoptosis. • Results indicate a heat-induced cell death via Parthanatos. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. Methods: We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. Result: Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. Conclusions: Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. Methods: A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. Results: A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19 + MIF + epithelial cells and via epithelial-stromal crosstalk. Conclusions: Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs. [ABSTRACT FROM AUTHOR]

Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no bladder inflammation. Persistent BHA is mediated by spinal macrophage migration inhibitory factor (MIF), and is associated with changes in lumbosacral proteomics. We investigated the contribution of individual spinal MIF receptors to persistent bladder pain as well as the spinal proteomics changes associated with relief of persistent BHA by spinal MIF antagonism. Female mice with persistent BHA received either intrathecal (i.t.) MIF monoclonal antibodies (mAb) or mouse IgG1 (isotype control antibody). MIF antagonism temporarily reversed persistent BHA (peak effect: 2 h), while control IgG1 had no effect. Moreover, i.t. antagonism of the MIF receptors CD74 and C-X-C chemokine receptor type 4 (CXCR4) partially reversed persistent BHA. For proteomics experiments, four separate groups of mice received either repeated intravesical scrambled peptide and sham i.t. injection (control, no pain group) or repeated intravesical PAR4 and: sham i.t.; isotype IgG1 i.t. (15 μg); or MIF mAb (15 μg). L6-S1 spinal segments were excised 2 h post-injection and examined for proteomics changes using LC-MS/MS. Unbiased proteomics analysis identified and relatively quantified 6739 proteins. We selected proteins that showed significant changes compared to control (no pain group) after intravesical PAR4 (sham or IgG i.t. treatment) and showed no significant change after i.t. MIF antagonism. Six proteins decreased during persistent BHA (V-set transmembrane domain-containing protein 2-like confirmed by immunohistochemistry), while two proteins increased. Spinal MIF antagonism reversed protein changes. Therefore, spinal MIF and MIF receptors mediate persistent BHA and changes in specific spinal proteins. These novel MIF-modulated spinal proteins represent possible new targets to disrupt spinal mechanisms that mediate persistent bladder pain. [ABSTRACT FROM AUTHOR]

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/β-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Lysophospholipid acyltransferase (LPCAT) is crucial for surfactant biosynthesis. It is encoded by LPCAT genes. We investigated the LPCAT1-rs9728 genotypes in neonatal respiratory distress syndrome (NRDS) cases and their possible association with the cord arterial serum interleukin-10 (IL-10), macrophage migration inhibitory factor (MIF), and vascular endothelial growth factor (VEGF) levels. Methods: The study included 160 neonates grouped into G1: 60 healthy neonates and G2: 100 NRDS cases. IL-10, MIF, and VEGF levels were measured by their corresponding kits. The Gene JETTM Whole Blood Genomic DNA Purification Mini Kit was used to extract the DNA from the newborn venous blood. The quantitative real-time polymerase chain reaction was carried out for LPCAT1-rs9728 genotyping. Results: The IL-10 and MIF levels were significantly higher, while VEGF levels were significantly lower in G2 than in G1. The percentages of LPCAT1-rs9728 AA and LPCAT1-rs9728 AG genotypes were significantly higher in G2 than in G1. The IL-10 and MIF levels were significantly higher, while the VEGF levels, birth weight, and APGAR score at 1 and 5 min were significantly lower in neonates with LPCAT1-rs9728 AA genotype than in neonates with LPCAT1-rs9728 AG and LPCAT1-rs9728 GG genotypes and in neonates with LPCAT1-rs9728 AG genotype than in neonates with LPCAT1-rs9728 GG genotype. Conclusion: There is an association between the LPCAT1-rs9728 AA genotype and its A allele and the NRDS development and severity. Further research may provide a better understanding of this association to help future management. [ABSTRACT FROM AUTHOR]

Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage‐based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii, a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor‐transgenic macrophage (Mφtgmif) shows stable fibrinolysis and strong chemotactic capacity. Mφtgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6Chi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6Clo macrophage through the secretion of CX3CL1. Remarkably, Mφtgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN‐γ‐treated macrophages, making macrophage‐based immune therapy more efficient and safer. Mechanistically, TgMIF promotes CCL2 expression by activating the ERK/HMGB1/NF‐κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment. [ABSTRACT FROM AUTHOR]

Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease, which is characterized by amyloid plaques and neurofibrillary tangles in the brain tissue, many components such as acute phase proteins, cytokines, and proteases contribute to the progression of the disease or are part of the pathological process. The macrophage migration inhibitory factor (MIF) gene encodes a cytokine, which is secreted by lymphocytes, and has a role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis. The purpose of this study to investigate the association between Alzheimer disease and MIF gene promoter polymorphisms. The 205 patients with Alzheimer disease (AD) and 130 age-sex matched healthy individuals were investigated in terms of MIF -173 G/C and MIF −794 CATT polymorphisms. The genotyping of MIF -173 G/C was determined using the RT-PCR method. MIF-794 CATT polymorphism was analyzed using PCR and DNA Sequencing. In terms of binary genotypes and haplotypes, the 5/5-GC (p = 0.004), 6/7-GG (p = 0.02) and, 6/6-GG (p = 0.026) binary genotypes, and 5-C (p = 0.003), 7-G (p = 0.026) and 6-G (p = 0.025) haplotypes were differed significantly between the patients and the controls. This is the first study investigating the relationship between AD and MIF in terms of different genotypes, haplotypes and, alleles. The fact that the binary genotype and allele distributions are significantly different between the patient and control group, suggests that this MIF variants may play a role in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

The research investigated on observation of eosinophilic leukocytes in the lungs of white laboratory rats under the effect of a Macrophage migration inhibition factor (MIF) by light and electron microscopy. The object of the study was 60 white male rats subdivided into 3 groups: control, placebo (saline injection), and main (MIF injection). The eosinophilic leukocytes are detected by specific cytoplasmic eosinophilic granules and ultrastructurally visible distinctive osmiophilic granules. The subpopulations of indicated cells in the lungs were identified as "stromal-interstitial", within "BALT", "perivascular" and "bronchial". It was found that in the experiment, the administration of MIF induces the migration of eosinophilic leukocytes into the alveoli and respiratory tract. It is necessary to note that the introduction of MIF has a gradual effect on the quantification and functional activity of eosinophilic leukocytes in the lungs of laboratory white rats: an increase in the first 2-7 days and stabilization at a higher level in the next 15-30 days. At least two ways of the effect of MIF on eosinophilic leukocytes have been evaluated: 1) by direct reception of MIF and 2) by indirect mechanisms. After injection of MIF, eosinophilic leukocytes probably have a regulatory effect in various microzones of the lung. The obtained results show that research in this direction may be promising in modeling immunopathological lung diseases. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and nonmotor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Purpose: The following study aimed to determine the existence of blood biomarkers in symptomatic patients with or without lumbar Modic changes (MC). Methods: A cross-sectional sub-analyses of a prospective cohort was performed. Fasting blood samples were collected from patients with and without lumbar MC who had undergone spinal fusion or microdiscectomy. An 80-plex panel and CCL5/RANTES were used to assess preoperative plasma cytokine concentrations. Patient demographics and imaging phenotypes were also assessed. Results: Thirty-one subjects were analysed (n = 18 no MC; n = 13 MC). No significant differences were found in age, sex, body mass index, smoking and alcohol history, and surgical procedure (i.e. fusion, decompression) between the two groups (p > 0.05). Several statistically significant blood biomarkers in MC patients were identified, including elevated levels of C–C Motif Chemokine Ligand 5 (CCL5, p = 0.0006), while Macrophage Migration Inhibitory Factor (MIF) was significantly lower (p = 0.009). Additionally, C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 0.052), Pentraxin 3 (PTX3, p = 0.06) and Galectin-3 (Gal-3, p = 0.07) showed potential relevance. Moreover, MC patients exhibited significantly higher levels of disc degeneration (p = 0.0001) and displacement severity (p = 0.020). Based on multivariate analyses and controlling for disc degeneration/displacement, CCL5 (OR 1.02; 95% CI 1.002–1.033; p = 0.028) and MIF (OR 0.60; 95% CI 0.382–0.951; p = 0.030) were independently associated with MC patients. Conclusion: This "proof-of-concept" study is the first to identify specific and significantly circulating blood biomarkers associated with symptomatic patients with lumbar MC, independent of disc alterations of degeneration and/or bulges/herniations. Specifically, differences in CCL5 and MIF protein levels were significantly noted in MC patients compared to those without MC. [ABSTRACT FROM AUTHOR]

High level expression of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow‐derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF‐dependent, as administration of a small molecule MIF inhibitor, SCD‐19, blocked the induction of this pro‐inflammatory M1‐like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro‐inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM‐induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8). [ABSTRACT FROM AUTHOR]

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. Methods: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose. Results: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. Conclusions: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity. [ABSTRACT FROM AUTHOR]

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment. [ABSTRACT FROM AUTHOR]

Wnt1-inducible signaling protein 1 (WISP1/CCN4) is a secreted matricellular protein that is implicated in lung and airway remodeling. The macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been associated with chronic lung diseases. In this study, we aimed to investigate the WISP1 signaling pathway and its ability to induce the expression of MIF in primary cultures of fibroblasts from normal human lungs (HLFs). Our results showed that WISP1 significantly stimulated the expression of MIF in a concentration- and time-dependent fashion. In WISP1-induced expression of MIF, αvβ5-integrin and chondroitin sulfate proteoglycans as well as Src tyrosine kinases, MAP kinases, phosphatidylinositol 3-kinase/Akt, PKC, and NF-κB were involved. WISP1-induced expression of MIF was attenuated in the presence of the Src kinase inhibitor PP2 or the MIF tautomerase activity inhibitor ISO-1. Moreover, WISP1 significantly increased the phosphorylation and activation of EGF receptor (EGFR) through transactivation by Src kinases. WISP1 also induced the expression of MIF receptor CD74 and coreceptor CD44, through which MIF exerts its effects on HLFs. In addition, it was found that MIF induced its own expression, as well as its receptors CD74/CD44, acting in an autocrine manner. Finally, WISP1-induced MIF promoted the expression of cyclooxygenase 2, prostaglandin E2, IL-6, and matrix metalloproteinase-2 demonstrating the regulatory role of WISP1-MIF axis in lung inflammation and remodeling involving mainly integrin avβ5, Src kinases, PKC, NF-κB, and EGFR. The specific signaling pathways involved in WISP1-induced expression of MIF may prove to be excellent candidates for novel targets to control inflammation in chronic lung diseases. [ABSTRACT FROM AUTHOR]

Nematode infections are common in both humans and livestock, with major adverse planetary health and economic impacts. Wuchereria bancrofti is a parasitic nematode that causes lymphatic filariasis, a neglected tropical disease that can lead to severe disability and deformity worldwide. For the long-term survival of the bancroftian parasites in the host, a complex immune invasion strategy is involved through immunomodulation. Therefore, immunomodulation can serve as a site of research and innovation for molecular targets. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine crucial to the host antimicrobial alarm system and stress response. Interestingly, the nematode parasite W. bancrofti also produces two homologs of MIF (Wba-MIF1 and 2). Using a mass spectrometry-based phosphoproteomics approach, we report new findings on the immunomodulatory effect and signaling mechanism of Wba-MIF2 in macrophage cells. Accordingly, we observed 1201 phosphorylated sites on 467 proteins. Out of the 1201 phosphorylated sites, 1075, 117, and 9 were found on serine (S), threonine (T), and tyrosine (Y) residues, respectively. Our bioinformatics analysis led to identification of major pathways, including spliceosomes, T cell receptor signaling pathway, Th17 differentiation pathway, interleukin-17 signaling pathway, and insulin signaling pathway upon Wba-MIF2 treatment. Wba-MIF2 treatment also enriched CDK4, CDK1, and DNAPK kinases. The comparison of the signaling pathway of Wba-MIF2 with that of human-MIF suggests both share similar signaling pathways. These findings collectively offer new insights into the role and mechanism of Wba-MIF2 as an immunomodulator and inform future diagnostics and drug discovery research for W. bancrofti. [ABSTRACT FROM AUTHOR]

Background: More than 800 000 people die by suicide annually. The heritability of suicide is 30%–50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia‐inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single‐nucleotide polymorphism (SNP), in suicide completers and controls. Methods: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). Results: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. Conclusion: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF‐related genetic studies, including those of rs17004038, are necessary with larger sample sizes. [ABSTRACT FROM AUTHOR]

Background. Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Methods. Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. Results. The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52–0.96, P = 0.027; OR: 1.18, 95%CI: 1.01–1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04–1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Conclusion. Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD. [ABSTRACT FROM AUTHOR]

To explore the relationship between fertility index (EFI) score, serum macrophage migration inhibitory factor (MMIF), Chitin enzyme protein 40 (YKL-40), ovarian function and clinical stage of patients with Endometriosis. Eighty patients with Endometriosis admitted to our hospital from June 2020 to June 2023 were selected as the study subjects, and they were dividedinto an observation group. Eighty healthy female volunteers who came to our hospital for physical examination at the same time were selected as the control group. The EFI score, serum MMIF, YKL-40 and the expression level of ovarian function indicators of the twogroups were compared. Eighty patients with Endometriosis were classified according to the American Association of ReproductiveMedicine Endometriosis staging criteria (r-AFS), including 15 patients with stage I, 23 patients with stage II, 25 patients with stage III, and 17 patients with stage IV. The EFI scores, serum MMIF, and YKL-40 expression levels in patients with different r-AFS stages were compared. And the Spearman correlation analysis method was used to analyze the correlation between EFI score, serum MMIF, YKL-40, and ovarian function indicators. The EFI score of the observation group was lower than that of the control group, and the expression levels of serum MMIF and YKL-40 were higher than those of the control group (P<0.05); The expression levels of anti M俟llerianhormone (AMH), Luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the observation group were lower than those in the control group, and the level of estradiol (E2 ) was higher than that in the control group (P<0.05); The EFI scores of patients with Endometriosis in different stages from high to low were stage I, stage II, stage III, and stage IV, and the levels of MMIF and YKL-40 from high to low were stage IV, stage III, stage II, and stage I. The EFI scores, serum MMIF, and YKL-40 expression levels in different stages were significantly different (P<0.05); The Spearman correlation analysis showed that the EFI score was positively correlated with AMH, LH, FSH, and negatively correlated with E2 (P<0.05). MMIF and YKL-40 were negatively correlated with AMH, LH, FSH, and positively correlated with E2 (P<0.05). EFI score, serum MMIF, and YKL-40 levels are significantly correlated with the ovary of Endometriosis patients, and there are significant differences between the EFI score, serum MMIF, and YKL-40 levels of different Endometriosis patients. Clinical application of EFI score, serum MMIF, and YKL-40 levels can be considered to assist in judging the ovarian function and disease severity of Endometriosis patients. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is a progressive manifestation of nonalcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Despite the growing knowledge of NASH and HCC, the association between the two conditions remains to be fully explored. Bioinformatics has emerged as a valuable approach for identifying disease-specific feature genes, enabling advancements in disease prediction, prevention, and personalized treatment strategies. Materials and methods: In this study, we utilized CellChat, copy number karyotyping of aneuploid tumors (CopyKAT), consensus Non-negative Matrix factorization (cNMF), Gene set enrichment analysis (GSEA), Gene set variation analysis (GSVA), Monocle, spatial co-localization, single sample gene set enrichment analysis (ssGSEA), Slingshot, and the Scissor algorithm to analyze the cellular and immune landscape of NASH and HCC. Through the Scissor algorithm, we identified three cell types correlating with disease phenotypic features and subsequently developed a novel clinical prediction model using univariate, LASSO, and multifactor Cox regression. Results: Our results revealed that macrophages are a significant pathological factor in the development of NASH and HCC and that the macrophage migration inhibitory factor (MIF) signaling pathway plays a crucial role in cellular crosstalk at the molecular level. We deduced three prognostic genes (YBX1, MED8, and KPNA2), demonstrating a strong diagnostic capability in both NASH and HCC. Conclusion: These findings shed light on the pathological mechanisms shared between NASH and HCC, providing valuable insights for the development of novel clinical strategies. [ABSTRACT FROM AUTHOR]

Progressive brain diseases create a huge social and economic burden on modern societies as a major cause of disability and death. Incidence of brain diseases has a significantly increasing trend and merits new therapeutic strategies. At the base of many progressive brain malfunctions is a process of unresolved, chronic inflammation. Macrophage migration inhibitory factor, MIF, is an inflammatory mediator that recently gained interest of neuro-researchers due to its varied effects on the CNS such as participation of nervous system development, neuroendocrine functions, and modulation of neuroinflammation. MIF appears to be a candidate as a new biomarker and target of novel therapeutics against numerous neurologic diseases ranging from cancer, autoimmune diseases, vascular diseases, neurodegenerative pathology to psychiatric disorders. In this review, we will focus on MIF's crucial role in neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and glioblastoma (GBM). [ABSTRACT FROM AUTHOR]

Background: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). Objective: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. Methods: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. Results: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = −0.113%, 95% confidence interval (CI): −0.204% to −0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. Conclusions: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect. [ABSTRACT FROM AUTHOR]

Background: High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross‐sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood‐based proteins. Methods: We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio‐Plex Pro™ Human Cytokine Screening Panel, ICAM‐1 set and VCAM‐1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio‐Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ‐standardized cytokine levels on the log2‐scale. Results: Stromal‐cell‐derived‐factor 1 alpha (SDF‐1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin‐6 (IL‐6) (β = −0.53; 95% CI −0.84; −0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = −0.52; 95% CI −0.84; −0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Conclusions: Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested the involvement of an activated inflammatory process in major depressive disorder (MDD), as altered expression of inflammatory cytokines is observed in depression. This alteration can be the cause or a consequence of MDD. However, acknowledging inflammatory cytokines as prospective biomarkers would aid in diagnosing or guiding better therapeutic options. Therefore, we designed this study to assess the macrophage migration inhibitory factor (MIF) in depression. Method: We collected blood samples from 115 MDD patients and 113 healthy controls (HCs) matched by age and sex. MDD patients were diagnosed by a qualified psychiatrist based on the symptoms mentioned in the diagnostic and statistical manual of mental disorders (DSM-5). We applied the Hamilton depression (Ham-D) rating scale to assess the severity of depression. We assessed serum levels of MIF using ELISA kit (Boster Bio, USA). Result: We detected increased serum MIF levels in MDD patients compared to HCs (6.15 ± 0.23 ng/mL vs 3.95 ± 0.21 ng/mL, P < 0.001). Moreover, this increase is more among female patients than female controls. Also, we noticed a positive correlation between altered MIF levels and the Ham-D scores (r = 0.233; P = 0.012), where we found that patients who scored higher on the Ham-D scale had higher MIF levels in serum. Moreover, the area under the curve (AUC) of receiver operating characteristic (ROC) curve represented the good diagnostic performance of altered serum MIF. Conclusion: Our study findings indicate the association of pro-inflammatory cytokine MIF in the pathophysiology of depression as we identified elevated serum MIF levels in depressive patients compared to HCs. However, more researches are required to confirm whether this alteration of cytokine is the causative factor or a consequence of depression. We recommend conducting further studies to understand the pattern of this alteration of MIF levels in MDD patients. [ABSTRACT FROM AUTHOR]

Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms. [ABSTRACT FROM AUTHOR]

Lumbar intervertebral disc degeneration(IDD) is a prevalent inflammatory disease caused by many proinflammatory factors, such as TNF and IL‐1β. Migration inhibitory factor (MIF) is an upstream inflammatory factor widely expressed in vivo that is associated with a variety of inflammatory diseases or malignant tumors and has potential therapeutic value in many diseases. We explored the role of MIF in intervertebral disc degeneration by regulating the content of exogenous MIF or the expression of MIF in cells. Upon inducing degeneration of nucleus pulposus (NP) cells with IL‐1β, we found that the increase in intracellular and exogenous MIF promoted the catabolism induced by proinflammatory factors in NP cells, while silencing of the MIF gene alleviated the degeneration to some extent. In a mouse model, the intervertebral disc degeneration of MIF‐KO mice was significantly less than that of wild‐type mice. To explore the treatment of intervertebral disc degeneration, we selected the small‐molecular MIF inhibitor CPSI‐1306. CPSI‐1306 had a therapeutic effect on intervertebral disc degeneration in the mouse model. In summary, we believe that MIF plays an important role in intervertebral disc degeneration and is a potential therapeutic target for the treatment of intervertebral disc degeneration.The migration inhibitory factor (MIF) trimer binds to membrane CD74‐CD44, leading to the generation of CD74‐ICD, which then associates with cytoplasmic RelA. This binding facilitates the nuclear translocation of RelA, thereby activating downstream signaling pathways. Under CPSI‐1306 treatment, interference with MIF trimer formation reduces the generation of CD74‐ICD, subsequently decreasing the nuclear translocation of RelA, thereby inhibiting the activation of the NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Background: Macrophage migration inhibitory factor (MIF) is an important mediator of neuropathology in various central nervous system (CNS) diseases. However, little is known about its inducers for production from the nerve cells, as well as the underlying regulatory mechanism. Injury‐induced HIF‐1α has been shown to exacerbate neuroinflammation by activating multiple downstream target molecules. It is postulated that HIF‐1α is involved in the regulation of MIF following spinal cord injury (SCI). Methods: SCI model of Sprague–Dawley rats was established by cord contusion at T8–T10. The dynamic changes of HIF‐1α and MIF protein levels at lesion site of rat spinal cord were determined by Western blot. The specific cell types of HIF‐1α and MIF expression were examined by immunostaining. Primary astrocytes were isolated from the spinal cord, cultured and stimulated with various agonist or inhibitor of HIF‐1α for analysis of HIF‐1α‐mediated expression of MIF. Luciferase report assay was used to determine the relationship between HIF‐1α and MIF. The Basso, Beattie, and Bresnahan (BBB) locomotor scale was used to assess the locomotor function following SCI. Results: The protein levels of HIF‐1α and MIF at lesion site were significantly elevated by SCI. Immunofluorescence demonstrated that both HIF‐1α and MIF were abundantly expressed in the astrocytes of the spinal cord. By using various agonists or inhibitors of HIF‐1α, it was shown that HIF‐1α sufficiently induced astrocytic production of MIF. Mechanistically, HIF‐1α promoted MIF expression through interaction with MIF promoter. Inhibition of HIF‐1α activity using specific inhibitor markedly reduced the protein levels of MIF at lesion site following SCI, which in turn favored for the functional recovery. Conclusion: SCI‐induced activation of HIF‐1α is able to promote MIF production from astrocytes. Our results have provided new clues for SCI‐induced production of DAMPs, which may be helpful for clinical treatment of neuroinflammation. [ABSTRACT FROM AUTHOR]

This study was to comprehensively clarify the associations between single nucleotide polymorphisms (SNPs) in inflammatory genes and the susceptibility to childhood leukemia. Eligible articles were collected from the databases of PubMed, EMBASE, Cochrane Library, CNKI and Wan Fang. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate the association strength by using the STATA 15.0 software. Sixteen studies were enrolled. These studies mainly evaluated SNPs in 13 genes, including C-X-C motif chemokine ligand 12 (CXCL12), toll-like receptor (TLR)−4, TLR6, TLR9, CD14, interleukin (IL)−1β, NLR family pyrin domain containing 3, IL-4, interleukin 4 receptor, IL-10, IL-13, macrophage migration inhibitory factor (MIF) and tumor necrosis factor-α. The meta-analysis indicated that CXCL12 rs1801157 (AG vs GG: OR = 1.99; 95%CI = 1.20–3.30; p = 0.008; AA + AG vs GG: OR = 1.92; 95%CI = 1.18–3.12; p = 0.009), TLR6 rs5743810 (TC vs TT: OR = 0.58; 95%CI = 0.39–0.85; p = 0.005), IL-10 rs1800871 (TC vs CC: OR = 1.19; 95%CI = 1.01–1.41; p = 0.044), rs1800872 (AC vs AA: OR = 1.53; 95%CI = 1.22–1.92; p < 0.001) and MIF rs755622 (CG versus GG: OR = 1.33; 95%CI = 1.07–1.67; p = 0.012) polymorphisms were associated with the risk of childhood leukemia. No significant correlations were found between SNPs in other genes and the childhood leukemia risk. Subgroup analyses of rs1800871 and rs1800872 confirmed the conclusions obtained in their overall meta-analytical processes. CXCL12 rs1801157, TLR6 rs5743810, IL-10 rs1800871, rs1800872 and MIF rs755622 polymorphisms may represent candidate biomarkers for the risk prediction of childhood leukemia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cell replacement therapy is a very promising approach to treating Parkinson’s disease. The current main regimen for neural differentiation of human pluripotent stem cells is the “dual SMAD” inhibition regimen, which uses blockade of glycogen synthase kinase 3β to activate WNT pathway signaling, followed by a combination of hedgehog signaling and bone morphogenetic protein signaling regulation to precisely control the specific fate of human pluripotent stem cells from the basal to the parietal regions. Macrophage migration inhibitory factor (MIF), a class of pleiotropic immunomodulatory cytokines with a unique structure, has been shown to be important for neural development and differentiation in several studies. However, whether MIF is involved in the induction of stem cell differentiation is unknown. OBJECTIVE: On the basis of the “dual SMAD” inhibition regimen, different concentrations of MIF and its inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isothiazoleacetic acid methyl ester (ISO-1) were added to the culture medium to observe its effect on the differentiation of human embryonic stem cells into midbrain dopaminergic progenitor cells, to find a new way to solve the problem of heterogeneity during differentiation of human embryonic stem cells into midbrain dopaminergic progenitor cells. METHODS: CCK8 assay was performed to detect the survival of human embryonic stem cells cultured with the addition of different concentrations of MIF and ISO-1. The expression of MIF receptors CD74, CD44 and CXCR7 on human embryonic stem cells was detected by immunofluorescence. The expression levels of ventral midbrain markers LMX1A, FOXA2, EN1, forebrain marker FOXG1, hindbrain marker HOXA2, midbrain substrate marker PAX6 and transcription factor SOX6 of Wnt1/β-catenin signaling pathway were determined by RT-qPCR and western blotting, respectively, 16 days after differentiation of embryonic stem cells levels. Meanwhile, the expression levels of LMX1A, FOXA2, EN1 and MAP2 were measured by immunofluorescence assay. The expression of LMX1A, FOXA2, TH and GIRK2 in dopaminergic neurons was determined by immunofluorescence assay after continuing the differentiation of embryonic stem cells until day 42. RESULTS AND CONCLUSION: (1) MIF was expressed in human embryonic stem cells, and its associated receptors CD44 and CXCR7 were also expressed, but CD74 expression did not occur. (2) The addition of MIF promoted the protein expression of LMX1, FOXA2, and EN1, and promoted the gene expression of LMX1 and FOXA2. It also significantly inhibited the gene and protein expression of FOXG1 and HOXA2 and PAX6, effectively suppressing the heterogeneity of differentiation. (3) The addition of MIF did not result in high expression of SOX6 in dopaminergic neural progenitors as expected, but rather decreased expression at the gene level, while its inhibitor ISO-1 caused a mild increase in SOX6 expression at the gene level. (4) The present study demonstrates that MIF plays an important role in the dopaminergic differentiation potential and ventral midbrain fate determination of human embryonic stem cells and that MIF intervention further optimizes the regional localization of neural induction. [ABSTRACT FROM AUTHOR]

Switching to normal diet (ND) is the regular therapy for high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). Intermittent fasting (IF) is a unique treatment which may exhibits better therapeutic efficacy. Thus, we aim to investigate the therapeutic effects of these treatments and exploring the mechanisms. In the present study, NAFLD mouse model was induced by a 10-week HFD. Thereafter, mice adopted continued HFD, ND, or IF for the next 12 weeks. Finally, the liver was then harvested to assess lipid deposition, lipid metabolism, apoptosis, and autophagy, while blood was collected to determine blood glucose and insulin. The results showed that IF and ND treatment improved lipid deposition and metabolic disorder of NAFLD mice; the increasing body weight, liver weight, and HOMA-IR index of HFD mice were also alleviated by IF and ND. Furthermore, IF and ND treatment activated the macrophage migration inhibitory factor (MIF)/AMPK pathway and regulated its downstream autophagy and apoptosis. However, the efficacy of IF was better than ND. Both IF and ND activates MIF signaling and alleviate the lipotoxicity of NAFLD while IF therapy is more effective than ND. The different MIF up-regulation might be the underlying mechanism of why IF benefits more than ND. [ABSTRACT FROM AUTHOR]

Obacunone (OB) targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate osteoporosis. [Display omitted] • Obacunone (OB) effectively inhibits osteoclast formation and function in vitro. • OB attenuates RANKL-induced osteoclast differentiation signaling pathways. • Macrophage migration inhibitory factor (MIF) is identified as the molecular target of OB. • OB alleviates estrogen deficiency-induced bone loss by impeding excessive osteoclast activity. • OB may serve as an alternative therapeutic candidate for osteoporosis. Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB's therapeutic potential on osteoporosis and explore the rudimentary mechanisms. Osteoclast formation and osteoclastic resorption assays were carried out to examine OB's inhibitory effects in vitro , followed by the in-vivo studies of OB's therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Some cytokines are strongly implicated in the development of squamous cell carcinoma (SCC) such as the Macrophage migration inhibitory factor (MIF). The haplotype ‐794 (CATT)5–8/‐173G>C in MIF gene polymorphisms has been associated with some types of cancer. The aim of this study is to establish the possible association between the presence of this haplotype in the MIF gene and its subsequent soluble levels with the susceptibility of SCC in western Mexican population. Methods: This study included 175 SCC patients and 175 age–sex‐matched individuals as a reference group (RG) from western Mexico. Genomic DNA was extracted from peripheral blood leukocytes. Polymorphisms were genotyped by endpoint PCR and PCR‐RFLP, and the determination of MIF serum levels was measured by ELISA. Clinical characteristics were evaluated by a group of dermatologists. Results: Analysis of [‐794(CATT)5–8/‐173G>C] MIF gene polymorphisms showed that the 5C (OR = 2.7, p = 0.02) and the 7G (OR = 3.39, p < 0.01) haplotypes are associated with susceptibility in SCC. MIF soluble levels in SCC patients showed a median of 13.93 ng/mL, whereas the reference group showed 6.000 ng/mL. Conclusions: Our findings suggest that 5C and 7G [‐794(CATT)5–8/‐173G>C] MIF gene haplotypes are associated with susceptibility to SCC and that SCC patients present increased soluble levels of MIF. [ABSTRACT FROM AUTHOR]

Summary: The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid‐derived suppressor cells (M‐MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M‐MDSC induction. This study demonstrates that miR‐106a‐5p and miR‐146a‐5p delivered by tumour‐derived exosomes (TEXs) from myeloma cells play essential roles in M‐MDSC induction in MM. MiR‐106a‐5p and miR‐146a‐5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death‐ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)‐α response, IFN‐γ response, inflammatory response, tumour necrosis factor‐α signalling and Interleukin‐6‐JAK–STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co‐cultured with myeloma cells. MiR‐106a‐5p and miR‐146a‐5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M‐MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX‐mediated sequential cellular and molecular events underlying M‐MDSC induction, potentially improving the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Vitiligo pathogenesis is related to the macrophage migration inhibitory factor (MIF) protein. This study aimed to assess the lesional MIF levels and gene polymorphisms (rs755622G>C) in patients with vitiligo. To assess the consequences of combining narrow-band ultraviolet B with oral minipulse prednisolone as opposed to a combination with oral methotrexate on MIF levels in vitiligo patients, 50 unstable vitiligo patients and 50 controls were randomly chosen for comparison. MIF levels in skin homogenates and MIF (rs755622G>C) single nucleotide polymorphisms were assessed using the ELISA and the polymerase chain reaction restriction fragment length polymorphism (RFLP-PCR) techniques. We found significantly higher lesional MIF levels, a higher frequency of both (GC) and (CC) genotypes, and a significantly more frequent mutant allele (C) in patients than in controls. In addition, there was a significantly lower frequency of the allele (C) among patients who exhibited moderate to marked therapeutic improvement than among those who showed minimal to mild improvement. In conclusion, tissue MIF and gene polymorphisms were associated with vitiligo. In addition, oral corticosteroids, narrow-band ultraviolet B, methotrexate-targeted tissue MIF, and gene polymorphisms can improve unstable vitiligo. [ABSTRACT FROM AUTHOR]

Background: Four-chambered stomach including the forestomachs (rumen, reticulum, and omasum) and abomasum allows ruminants convert plant fiber into high-quality animal products. The early development of this four-chambered stomach is crucial for the health and well-being of young ruminants, especially the immune development. However, the dynamics of immune development are poorly understood. Results: We investigated the early gene expression patterns across the four-chambered stomach in Hu sheep, at 5, 10, 15, and 25 days of age. We found that forestomachs share similar gene expression patterns, all four stomachs underwent widespread activation of both innate and adaptive immune responses from d 5 to 25, whereas the metabolic function were significantly downregulated with age. We constructed a cell landscape of the four-chambered stomach using single-cell sequencing. Integrating transcriptomic and single-cell transcriptomic analyses revealed that the immune-associated module hub genes were highly expressed in T cells, monocytes and macrophages, as well as the defense-associated module hub genes were highly expressed in endothelial cells in the four-stomach tissues. Moreover, the non-immune cells such as epithelial cells play key roles in immune maturation. Cell communication analysis predicted that in addition to immune cells, non-immune cells recruit immune cells through macrophage migration inhibitory factor signaling in the forestomachs. Conclusions: Our results demonstrate that the immune and defense responses of four stomachs are quickly developing with age in lamb's early life. We also identified the gene expression patterns and functional cells associated with immune development. Additionally, we identified some key receptors and signaling involved in immune regulation. These results help to understand the early life immune development at single-cell resolution, which has implications to develop nutritional manipulation and health management strategies based on specific targets including key receptors and signaling pathways. [ABSTRACT FROM AUTHOR]

Trichinellosis caused by Trichinella spiralis (T. spiralis) is a major food‐borne parasitic zoonosis worldwide. Prevention of trichinellosis is an effective strategy to improve patient quality of life. Macrophage migration inhibitory factor (MIF) is closely related to the occurrence and development of several parasitic diseases. Studying the impact of MIF deficiency (Mif−/−) on the alterations in host fecal microbiota due to T. spiralis infection may contribute to proposing a novel dual therapeutic approach for trichinellosis. To reveal the diversity and differences in fecal microbial composition, feces were collected from T. spiralis‐uninfected and T. spiralis‐infected wild‐type (WT) and MIF knockout (KO) C57BL/6 mice at 0, 7, 14, and 35 days post‐infection (dpi), and the samples were sent for 16S rRNA amplicon sequencing on the Illumina NovaSeq platform. Flow cytometry was used to determine the expression levels of IFN‐γ and IL‐4 in the CD4+/CD8+ T‐cell sets of mouse spleens. The results showed that operational taxonomic unit (OTU) clustering, relative abundance of microbial composition, alpha diversity, and beta diversity exhibited significant changes among the eight groups. The LEfSe analysis selected several potential biomarkers at the genus or species level, including Akkermansia muciniphila, Lactobacillus murinus, Coprococcus catus, Firmicutes bacterium M10_2, Parabacteroides sp. CT06, and Bacteroides between the KTs and WTs groups. The predicted bacterial functions of the fecal microbiota were mainly involved in metabolism, such as the metabolism of carbohydrates, amino acids, energy, cofactors, vitamins, nucleotides, glycans, and lipids. Flow cytometry revealed an increased CD3+CD8−/CD3+CD8+ T‐cell ratio and increased IFN‐γ and IL‐4 levels in CD3+CD8− T‐cell sets from WT and MIF KO mice at 7 dpi. The results indicated that both MIF KO and infection time have a significant influence on the CD3+CD8−IFN‐γ+ and CD3+CD8−IL‐4+ response in mice after T. spiralis. In conclusion, this research showed alterations of the fecal microbiota and immune response in both WT and MIF KO mice before and after T. spiralis infection. These results revealed a potential role of MIF in regulating the pathogenesis of trichinellosis related to the intestinal microbiota. Importantly, the selected potential biomarkers combined with MIF will also offer a novel therapeutic approach to treat trichinellosis in the future. [ABSTRACT FROM AUTHOR]

Dysregulation of innate immune responses can result in chronic inflammatory conditions. Glucocorticoids, the current frontline therapy, are effective immunosuppressive drugs but come with a trade‐off of cumulative and serious side effects. Therefore, alternative drug options with improved safety profiles are urgently needed. Sulforaphane, a phytochemical derived from plants of the brassica family, is a potent inducer of phase II detoxification enzymes via nuclear factor‐erythroid factor 2–related factor 2 (NRF2) signaling. Moreover, a growing body of evidence suggests additional diverse anti‐inflammatory properties of sulforaphane through interactions with mediators of key signaling pathways and inflammatory cytokines. Multiple studies support a role for sulforaphane as a negative regulator of nuclear factor kappa‐light chain enhancer of activated B cells (NF‐κB) activation and subsequent cytokine release, inflammasome activation and direct regulation of the activity of macrophage migration inhibitory factor. Significantly, studies have also highlighted potential steroid‐sparing activity for sulforaphane, suggesting that it may have potential as an adjunctive therapy for some inflammatory conditions. This review discusses published research on sulforaphane, including proposed mechanisms of action, and poses questions for future studies that might help progress our understanding of the potential clinical applications of this intriguing molecule. [ABSTRACT FROM AUTHOR]

The course of coronavirus disease-2019 (COVID-19) differs from person to person. The relationship between the genetic variations of the host and the course of COVID-19 has been a matter of interest. In this study, we investigated whether Angiotensin-Converting Enzyme (ACE) ID, Methylenetetrahydrofolate Reductase (MTHFR) C677T, and Macrophage Migration Inhibitory Factor (MIF)-173GC variants are risk factors for the clinical course of COVID-19 disease in Turkish patients. One hundred COVID-19 patients were included in the study. The diagnosis of COVID-19 was made using Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Chest Computed Tomography (CT). The patients were evaluated in 3 groups: intensive care, service, and outpatient treatment. ACE ID, MTHFR C677T, and MIF-173GC variants were genotyped by PCR-Restriction Fragment Length Polymorphism (RFLP) methods. When the genotype distribution between the groups was examined, it was found that the frequency of the ACE DD genotype and the D allele was higher in the intensive care group compared to the hospitalized and outpatient groups. MTHFR C677T CT genotype T allele and MIF-173GC, CC genotype C allele were more prevalent in the intensive care group compared to other groups. Patients with PCR-positive results had a higher MTHFR C677T C/C genotype and C allele. In CT-positive patients, the MTHFR C677T CT genotype and the MIF-173GC, G allele were more common. It is predicted that genetic predisposition may contribute to COVID-19 morbidity and mortality. Our results show that ACE ID, MTHFR C677T, and MIF-173GC variants affect the course of COVID-19 disease in the Turkish population. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify the key genes involved in the development of multiple primary lung cancers. Methods: Differential expression analysis was performed, followed by comparing the infiltration levels of 22 immune cell types between multiple and single primary lung adenocarcinomas. Marker genes for epithelial cells with different proportions between the two types of lung adenocarcinomas were identified. The common genes between the marker genes and differentially expressed genes were identified. Finally, the effects of the key genes were tested on the in vitro proliferation, migration and morphology. Results: The infiltration levels of helper follicular T cells, resting NK cells, activated NK cells, M2 macrophages and resting mast cells were higher in the patients with multiple than in those with single primary lung adenocarcinomas. A total of 1553 differentially expressed genes and 4414 marker genes of epithelial cells were identified. Logistic regression analysis was performed on the 164 resulting genes. The macrophage migration inhibitory factor expression was positively associated with the occurrence of multiple primary lung adenocarcinomas. Moreover, its signalling pathway was the key pathway among the epithelial cells and multiple and single primary lung adenocarcinoma cells, and it was upregulated in lung adenocarcinoma cells. It also increased the expression of lung cancer markers, including NES and CA125, induced morphological changes in alveolar epithelial type II cells, and promoted their proliferation, migration and invasion. Conclusions: Multiple and single primary lung adenocarcinomas have different tumour immune microenvironments, and migration inhibitory factor may be a key factor in the occurrence of multiple primary lung adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background: To explore the effect of calcium dobesilate combined with hypoglycemic drugs in the treatment of cataract complicated with non-proliferative diabetic retinopathy (NPDR) and its effects on fundus microcirculation, intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), and macrophage migration inhibitory factor (MIF). Mathods: From March 2019 to January 2021, a total of 114 patients with cataract and NPDR were included, and the patients were assigned into the control and the observation groups by random number table method, with 57 cases/group. The control was given hypoglycemic drugs, and the observation was given calcium dobesilate combined therapy. The therapeutic efficacy, blood glucose and blood lipid levels, fluorescein fundus angiography results, fundus microcirculation indexes, retinal neovascularization- related factors, and ICAM-1, MCP-1, and MIF levels before and after treatment were compared between the two groups. Results: The total effective rate of treatment in the observation was higher vs. the control (P < 0.05); Fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL) in the observation after treatment were reduced vs. the control (P < 0.05); The number of micro-hemangiomas in the observation after treatment was less vs. the control, and the area of hemorrhage, the area of exudation and the thickness of the yellow plate were smaller vs. the control (P < 0.05); The resistance index (Rl) value of the observation after treatment was lower than the control, and the end-diastolic blood flow velocity (EDV) and the peak systolic blood flow velocity (PSV) of the observation were higher vs. the control (P < 0.05). ICAM-1, MCP-1, MIF, vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF- 1) in the observation after treatment were reduced vs. the control, but pigment epithelium-derived factor (PEDF) were higher vs. the control (P < 0.05); one case of gastrointestinal reaction took place in the observation, but no adverse reaction occurred in the control, and no clear difference exhibited in the incidence of adverse reactions between the two groups (P > 0.05). Conclusions: Calcium dobesilate combined with hypoglycemic drugs has good clinical efficacy in the treatment of cataract complicated with NPDR, which can effectively reduce the level of blood glucose and blood lipids, reduce inflammation, and mitigate the microcirculation of branch retinal vein occlusion lesions. [ABSTRACT FROM AUTHOR]

This paper presents a mathematical model of severe malarial anemia (SMA), which is a complication of malaria and is a major contributor to malaria-related deaths. SMA is characterized by a decrease in hemoglobin levels in the blood due to the suppression of red blood cell (RBC) recruitment by the protein macrophage migration inhibitory factor (MIF). Plasmodium falciparum, which is a malaria-causing parasite, secretes a specific form of MIF called plasmodium falciparum macrophage migration inhibitory factor (PFMIF), which affects immune cells. Artesunate, which is the primary treatment for SMA, reduces the parasite level but does not increase hemoglobin levels and can sometimes lead to hemolytic anemia, which requires a blood transfusion. To address this issue, the experimental drug Epoxyazadiradione (Epoxy) was explored as a potential treatment for SMA. Epoxy inhibits both MIF and PFMIF interactions with immune cells and has the potential to increase hemoglobin levels in SMA patients. Our model simulations support previous findings that the appropriate combination of Artesunate with Epoxy can reduce parasite load while preventing anemia by maintaining hemoglobin levels at an adequate level. Additionally, we explored the impact of immune boosters on the anti-malarial drugs Artesunate and Epoxy and discovered that an insufficient amount of drugs is ineffective, while an excessive amount may not be beneficial. [ABSTRACT FROM AUTHOR]

Mast cell extracellular traps (MCETs) released by mast cells contribute to host defense. In this study, we investigated the effects of MCETs released from mast cells after infection with a periodontal pathogen Fusobacterium nucleatum. We found that F. nucleatum induced MCET release from mast cells, and that MCETs expressed macrophage migration inhibitory factor (MIF). Notably, MIF bound to MCETs induced proinflammatory cytokine production by monocytic cells. These findings suggest that MIF expressed on MCETs, released from mast cells upon infection with F. nucleatum , promotes inflammatory responses that may be associated with the pathogenesis of periodontal disease. [Display omitted] • Fusobacterium nucleatum infection induces mast cell extracellular traps (MCETs). • MCETs express macrophage migration inhibitory factor (MIF). • LPS derived from F. nucleatum induces MIF expression on MCETs. • MIF-on MCETs induces proinflammatory cytokine production in monocytes. • These processes may be associated with periodontal disease progression. [ABSTRACT FROM AUTHOR]