Preliminary study on the expression of MIF in HCC tissues and its relationship with ERK1/2 signaling pathway / 中华内科杂志

Objective:To investigate the expression of Macrophage migration-inhibitory factors (MIF) in hepatocellular carcinoma (HCC) tissues and its interaction with ERK1/2 signaling pathway, so as to establish a theoretical basis for further studying the molecular mechanism of MIF promoting HCC.Methods:From February 2020 to August 2021, 52 cases of hepatocellular carcinoma (HCC) tissues based on hepatitis B cirrhosis (HBV-LC) and 52 cases of adjacent tissues in Tianjin Medical University Cancer Hospital and 940th Hospital of Joint Logistic Support Force of PLA were collected as the experimental group, including 39 males and 13 females, aged 35-65 years. And 20 cases of normal liver tissue were selected as the control group. Immunohistochemistry was used to detect the expression of MIF, ERK1/2 and p-ERK1/2 proteins in liver tissues of the two groups, and in situ hybridization was used to detect the expression of ERK1/2 nucleic acid in liver tissues of the two groups.HepG2 HCC cells and L-02 normal hepatocytes were co-cultured with different concentrations of rMIF, the expression and phosphorylation levels of ERK1/2 and JNK1 proteins in the two kinds of liver cells were detected by Western-blot, and the expression levels of ERK1/2 nucleic acids in the two kinds of liver cells were detected by RT-PCR. One-way ANOVA was used for measurement data and χ 2 test was used for counting data. Results:The expressions of MIF, ERK1/2, p-ERK1/2 and ERK1/2 mRNA were significantly increased in HCC and para-cancer tissues (the expression of MIF in HCC group was 78.8%, and that in adjacent group was 75.0%; ERK1/2 80.8% in HCC group and ERK1/2 71.8% in paracancerous group. The expression of p-ERK1/2 75.0 % in HCC group and 46.2% in paracancerous group were respectively detected. ERK1/2 mRNA was expressed in HCC group 76.9%, ERK1/2 mRNA expression in paracancerous group 78.8%), and the differences were statistically significant compared with normal liver tissues ( P<0.05), but there was no significant difference between HCC and para-cancer tissues ( P>0.05). The expressions of ERK1/2, p-ERK1/2 and ERK1/2 mRNA in HepG2 HCC cells were significantly increased with the increase of rMIF concentration, and the increase was most obvious when rMIF concentration was 200 ng/ml, and the difference was statistically significant compared with L-02 normal hepatocytes ( P<0.05). Conclusion:MIF, ERK1/2 and p-ERK1/2 are highly expressed in HCC tissues and HepG2 HCC cells, suggesting that MIF promotes the occurrence and development of hepatocellular carcinoma through ERK1/2 signaling pathway.

Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats / Antagonista (p425) do fator de inibição da migração de macrófagos (MIF) melhora as alterações histopatológicas e funcionais renais em ratos diabéticos

Abstract Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.

Resumo Introdução: Supõe-se que elevações da expressão do fator de inibição da migração de macrófagos (MIF) possam contribuir para a patogênese da nefropatia diabética (ND). O objetivo do presente estudo foi investigar os efeitos renais da inibição do MIF em um modelo experimental diabético. Métodos: Dezoito ratos Wistar machos (230 ± 20g) foram divididos em três grupos: 1) controle, 2) diabético (STZ 50 mg/kg dissolvida em soro fisiológico, IP), 3) diabético + antagonista do MIF (p425 1 mg/kg por dia IP no 21o dia por 21 dias consecutivos). O tratamento começou após a identificação de aumento significativo na albuminúria nos ratos diabéticos em relação aos controles. Os ratos foram mantidos individualmente em gaiolas metabólicas (8h-14h) e amostras de urina foram colhidas no 21o e no 42o dia. Ao final do estudo, amostras de sangue e tecido foram colhidas para análises bioquímicas (BS, excreção urinária de proteína, excreção urinária de GAGs, BUN, Cr, Na e K) e histológicas. Resultados: O presente estudo demonstrou que o antagonista do MIF (p425) diminuiu significativamente proteinúria, excreção urinária de GAGs , relação proteína/creatinina na urina, BUN e Cr no grupo com ND induzida por estreptozotocina. As alterações patológicas foram significativamente abrandadas nos ratos com ND que receberam antagonista do MIF (p425). Conclusão: Coletivamente, os dados sugerem que o antagonista do MIF (p425) teve efeito protetor contra lesões funcionais e histopatológicas da ND.

Clinical application of combined detection of serum macrophage inhibitory cytokine-1, carcinoembryonic antigen and carbohydrate antigens for the diagnosis and prognosis of colorectal cancer in the elderly / 中华老年医学杂志

Objective@#To explore the application value of combined detection of serum macrophage inhibitory cytokine-1(MIC-1), carcinoembryonic antigen(CEA)and carbohydrate antigens in the diagnosis and prognosis of elderly patients with colorectal cancer.172 elderly patients with colorectal cancer were selected retrospectively as the observation group, 175 elderly patients with benign colorectal lesions were enrolled as the benign lesion group and 166 healthy elderly subjects as the control group.@*Methods@#The levels of MIC-1, CEA, carbohydrate antigens of 199(CA199), 724(CA724), 242(CA242), 125(CA125), and 50(CA50)were compared among the three groups, and the diagnostic efficacy was calculated.The difference in the above-mentioned indicators between patients with different stages and prognosis in the observation group were compared.@*Results@#Levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 were higher in the observation group than in the benign lesion group and the control group, and the above indexes were higher in the benign lesion group than in the control group.The sensitivity, positive predictive value and negative predictive value of MIC-1 were the highest in single index test(68.6%, 72.8% and 84.6%, respectively). The specificity of CA199 was the highest(91.2%). The combined detections greatly improved sensitivity, positive predictive value and negative predictive value(89.0%, 79.3% and 94.1%, respectively). In the observation group, levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 in the elderly colorectal cancer patients were higher in stage Ⅲ and Ⅳ than in stage Ⅰ and Ⅱ.The levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 in elderly patients with recurrence and metastasis of colorectal cancer were higher than those in patients without recurrence and metastasis.@*Conclusions@#Combined detection of multiple indicators can improve the sensitivity of diagnosis, and is more conducive to the early diagnosis of elderly patients with colorectal cancer.

Clinical application of combined detection of serum mcrophage inhibitory cytokine-1, carcinoembryonic antigen and carbohydrate antigens for the diagnosis and prognosis of colorectal cancer in the elderly / 中华老年医学杂志

Objective To explore the application value of combined detection of serum macrophage inhibitory cytokine-1 (MIC-1),carcinoembryonic antigen (CEA) and carbohydrate antigens in the diagnosis and prognosis of elderly patients with colorectal cancer.172 elderly patients with colorectal cancer were selected retrospectively as the observation group,175 elderly patients with benign colorectal lesions were enrolled as the benign lesion group and 166 healthy elderly subjects as the control group.Methods The levels of MIC-1,CEA,carbohydrate antigens of 199(CA199),724 (CA724),242 (CA242),125 (CA125),and 50 (CA50) were compared among the three groups,and the diagnostic efficacy was calculated.The difference in the above-mentioned indicators between patients with different stages and prognosis in the observation group were compared.Results Levels of MIC-1,CEA,CA199,CA242,CA724,CA125 and CA50 were higher in the observation group than in the benign lesion group and the control group,and the above indexes were higher in the benign lesion group than in the control group.The sensitivity,positive predictive value and negative predictive value of MIC-1 were the highest in single index test (68.6 ％,72.8％ and 84.6 ％,respectively).The specificity of CA199 was the highest(91.2 ％).The combined detections greatly improved sensitivity,positive predictive value and negative predictive value(89.0％,79.3％ and 94.1 ％,respectively).In the observation group,levels of MIC-1,CEA,CA199,CA242,CA724,CA125 and CA50 in the elderly colorectal cancer patients were higher in stage Ⅲ and Ⅳ than in stage Ⅰ and Ⅱ.The levels of MIC-1,CEA,CA199,CA242,CA724,CA125 and CA50 in elderly patients with recurrence and metastasis of colorectal cancer were higher than those in patients without recurrence and metastasis.Conclusions Combined detection of multiple indicators can improve the sensitivity of diagnosis,and is more conducive to the early diagnosis of elderly patients with colorectal cancer.

Promoting migration and apoptosis of glioma cells by macrophage migration inhibitory factor / 中华病理学杂志

Objective@#To investigate the effect of macrophage migration inhibitory factor (MIF) on the biology of glioma U87MG and U251 cells.@*Methods@#Silencing MIF gene expression in U87MG cells by RNA interference was monitored by Western blot. MIF low expressing U251 cells were treated at different concentrations of recombinant human MIF (rhMIF) and scratching test and flow cytometry were used to detect cell migration and apoptosis. The protein expression of bcl-2, bax, AKT, p-AKT was detected by Western blot.@*Results@#The ability of migration and anti-apoptosis of U87MG cells silenced by siRNA decreased significantly, and the expression levels of p-AKT and anti-apoptotic protein bcl-2 also decreased; in contrast, the expression level of apoptosis protein bax increased. With increase of rhMIF treatment concentration, the expression levels of MIF protein, p-AKT and bcl-2 in U251 cells were gradually enhanced, whereas the level of apoptosis protein bax was inhibited.@*Conclusion@#MIF promotes cell migration and inhibits apoptosis of both U87MG and U251 cells, likely through the regulation of PI3K/AKT signaling pathway.

Macrophage migration inhibitory factor as an incriminating agent in vitiligo

Abstract: Background: Vitiligo is an autoimmune skin disorder in which the loss of melanocytes is mainly attributed to defective autoimmune mechanisms and, lately, there has been more emphasis on autoinflammatory mediators. Among these is the macrophage migration inhibitory factor, which is involved in many autoimmune skin diseases. However, little is known about the contribution of this factor to vitiligo vulgaris. Objective: To determine the hypothesized role of migration inhibitory factor in vitiligo via estimation of serum migration inhibitory factor levels and migration inhibitory factor mRNA concentrations in patients with vitiligo compared with healthy controls. We also aimed to assess whether there is a relationship between the values of serum migration inhibitory factor and/or migration inhibitory factor mRNA with disease duration, clinical type and severity in vitiligo patients. Methods: Evaluation of migration inhibitory factor serum level and migration inhibitory factor mRNA expression by ELISA and real-time PCR, respectively, were performed for 50 patients with different degrees of vitiligo severity and compared to 15 age- and gender-matched healthy volunteers as controls. Results: There was a highly significant increase in serum migration inhibitory factor and migration inhibitory factor mRNA levels in vitiligo cases when compared to controls (p<0.001). There was a significant positive correlation between both serum migration inhibitory factor and migration inhibitory factor mRNA concentrations in vitiligo patients, and each of them with duration and severity of vitiligo. In addition, patients with generalized vitiligo have significantly elevated serum migration inhibitory factor and mRNA levels than control subjects. Study limitations: Small number of investigated subjects. Conclusions: Migration inhibitory factor may have an active role in the development of vitiligo, and it may also be a useful index of disease severity. Consequently, migration inhibitory factor may be a new treatment target for vitiligo patients.

The effect of abdominal Bevacizumab combined with hyperthermia chemotherapy on serum transforming growth factor beta 1 and migration-inhibitory factor levels in elderly patients with ovarian cancer / 中华老年医学杂志

Objective To investigate the effect of abdominal Bevacizumab combined with hyperthermia chemotherapy on serum transforming growth factor beta1 (TGF-β1) and macrophage migration-inhibitory factor (MIF) levels in elderly patients with ovarian cancer.Methods A hundred elderly patients diagnosed with ovarian cancer from December 2011 to December 2014 at our hospital were recruited.Participants were assigned into a joint therapy group (n =50) and a thermal therapy group (n =50) according to the received treatment.Both groups were given the abdominal hyperthermia chemotherapy treatment,while the joint therapy group was additionally given Bevacizumab treatment.The effectiveness of treatment,adverse reactions,pre-and post-treatment serum TGF-β1 and MIF levels,and the 2-year survival situation in all participants were collected and analyzed.Results The therapeutic response rate and 2-year survival rate in the joint therapy group (64.0％ and 60.0％) were significantly higher than those in the thermal therapy group (44.0％ and 40.0％) (both P ＜ 0.05).There were statistically significant differences between pre-and posttreatment levels of serum TGF-β1 [(346.15 ± 35.15) ng/L vs.(201.46 ± 23.75) ng/L] and MIF [(46.32±5.16)μg/L vs.(13.48±2.45)μg/L] in the thermal therapy group,and of serum TGF-β1 [(342.26±35.01) ng/L vs.(167.52±20.26) ng/L] and MIF [(46.97±5.24)μg/L vs.(4.87±1.02)μg/L] in the joint therapy group,with greater reductions observed in the joint therapy group (P＜0.05).No significant difference in the incidence of adverse reactions was found between the two groups (P ＞ 0.05).Conclusions Abdominal Bevacizumab combined with hyperthermia chemotherapy can effectively decrease the levels of serum TGF-β1 and MIF in elderly patients with ovarian cancer and achieve improved short-term and long-term effectiveness with good safety.

Relationship between MIF expression and obese-induced abolition of sevoflurane preconditioning-in-duced cardioprotection in mice / 中华麻醉学杂志

Objective To evaluate the relationship between macrophage migration inhibitory factor ( MIF) expression and obese-induced abolition of sevoflurane preconditioning-induced cardioprotection in mice. Methods Forty-eight male C57BL∕6J mice, aged 4 weeks, were divided into 2 groups ( n=24 each) using a random number table method: normal diet group ( Lean group ) and high-fat diet group ( Obese group) . Lean group were fed a normal diet ( 10％ kcal) for 12 weeks, while Obese group were fed a high-fat diet ( 60％ kcal) for 12 weeks. The weight of mice was measured. Blood samples were collected from the tail vein for determination of blood glucose concentrations, and plasma concentrations of total cho-lesterol, triglyceride, insulin and leptin. After measurement of the parameters mentioned above, Lean group and Obese group were divided into 3 subgroups ( n=8 each) using a random number table method:sham operation groups (L-Sham group, O-Sham group), myocardial ischemia-reperfusion groups (L-IR group, O-IR group) and sevoflurane preconditioning groups (L-IR+Sev group, O-IR+Sev group). The mice were anesthetized and their hearts were immediately removed and retrogradely perfused in a Langendorff apparatus with an oxygenated K-H solution at 37 ℃. Hearts were continuously perfused with K-H solution for 115 min in L-Sham and O-Sham groups. Hearts were subjected to global ischemia for 25 min, followed by 60-min reperfusion after being retrogradely perfused with K-H solution in L-IR and O-IR groups. In L-IR+Sev and O-IR+Sev groups, hearts were subjected to 3 cycles of 5-min perfusion with sevoflurane-contai-ning K-H solution ( final concentration 0. 6 mmol∕L) and 5-min washout, and then hearts were subjected to global ischemia for 25 min, followed by 60-min reperfusion. Left ventricular developed pressure ( LVDP ) , left ventricular end-diastolic pressure ( LVEDP ) , and the maximum rate of increase or decrease in left ventricular pressure ( ±dp∕dtmax) were recorded at the end of reperfusion. Hearts were obtained at the end of reperfusion for determination of myocardial infarct size and expression of MIF ( by Western blot) . Results Compared with Lean group, the weight, blood glucose, levels of plasma total cholesterol, tri-glyceride, insulin and leptin were significantly increased in Obese group (P<0. 05). Compared with L-Sham group, the LVDP and +dp∕dtmax were significantly decreased, LVEDP and -dp∕dtmax were in-creased, myocardial infarct size was increased, and the expression of myocardial MIF was up-regulated in L-IR and L-IR+Sev groups, and the expression of myocardial MIF was up-regulated in O-Sham group ( P<0. 05) . Compared with L-IR group, LVDP and +dp∕dtmax were significantly increased, LVEDP and-dp∕dtmax were decreased, myocardial infarct size was decreased, and the expression of myocardial MIF was up-regulated in group L-IR+Sev, and the expression of myocardial MIF was significantly up-regulated in group O-IR (P<0. 05). Compared with O-Sham group, LVDP and +dp∕dtmax were significantly de-creased, LVEDP and-dp∕dtmax were increased, and myocardial infarct size was increased, and no signif-icant change was found in the expression of MIF in O-IR and O-IR+Sev groups ( P>0. 05) . Conclusion The mechanism by which obese abolishes sevoflurane preconditioning-induced cardioprotection may be relat-ed to inducing MIF over-expression in mice.

Correlation between the plasma level of MIF and its related gene-173G/C polymorphism and risk factors of atherosclerosis in pilots / 解放军医学杂志

Objective To investigate the relationship between the plasma level of macrophage migration inhibiting factor (MIF) and its related gene-173G/C polymorphism and risk factors of atherosclerosis in pilots for reducing the risk of adverse cardiovascular events in early stage. Methods Four hundred and fifty-eight military pilots undergoing medical examination (pilot group), 51 patients with coronary heart disease (CHD group), and 194 persons undergoing routine health examination (control group) were selected as the subjects under investigation. Subjects in pilot group were further grouped according to the different aircraft type they were flying and their flight time. General clinical data of the three groups were collected. ELISA was used to determine the plasma levels of MIF. MIF-173 G/C (rs755622) was detected by Taqman probe method. The differences of genotype and allele frequencies among the three groups were analyzed. Results No significant difference was found in plasma levels of MIF between pilot group and CHD group (P>0.05), but the levels were significantly higher in the both groups than in the control group (P0.05). There was no significant difference in genotype and allele frequencies among the three group (P>0.05). There was no significant difference of plasma MIF, TC, TG concentrations in the pilots who were with CC, GG and CG genotypes, respectively (P>0.05). Conclusions MIF-173G/C polymorphism may have no significant correlation to the early susceptibility of atherosclerosis. Elevated plasma MIF levels may be associated with the development of coronary heart disease.

Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis

Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients.

The Association of Higher Plasma Macrophage Migration Inhibitory Factor Levels with Lower Bone Mineral Density and Higher Bone Turnover Rate in Postmenopausal Women

BACKGROUND: Despite evidence from animal and clinical studies showing the detrimental effects of macrophage migration inhibitory factor (MIF) on bone metabolism, there are no clinical studies relating circulating MIF levels to osteoporosis-related phenotypes. This cross-sectional study investigated the association of plasma MIF with bone mineral density (BMD), bone turnover markers (BTMs), and prevalence of osteoporosis in postmenopausal Korean women. METHODS: A total of 246 women not taking any medications or diagnosed with any diseases that could affect bone metabolism were enrolled. BMD values at the lumbar spine, femoral neck, and total femur, and blood levels of MIF and BTMs were measured in all subjects. Osteoporosis was defined by World Health Organization criteria. RESULTS: Before and after adjustment for confounding variables, higher MIF levels were significantly associated with lower BMD values at all measured sites and higher levels of all BTMs. All BMD values and BTMs significantly changed in a dose-dependent fashion across increasing MIF quartile. When participants were divided into two groups according to osteoporosis status, postmenopausal women with osteoporosis demonstrated 24.2% higher plasma MIF levels than those without osteoporosis (P=0.041). The odds ratio per each standard deviation increment of MIF levels for prevalent osteoporosis was 1.32 (95% confidence interval, 1.01 to 1.73). CONCLUSION: This study provides the first epidemiological evidence that higher plasma MIF may be associated with higher risk of osteoporosis resulting from lower bone mass and higher bone turnover rate, and thus it could be a potential biomarker of poor bone health outcomes in postmenopausal women.

Effect of over-expressed macrophage migration Inhibitory factor on epithelial-mesenchymal transition in human cervical carcinoma SiHa cells / 中国医师杂志

Objective To investigate the effect of over-expressed macrophage migration inhibitory factor (MIF) on epithelial-mesenchymal transition (EMT) in human cervical carcinoma SiHa cells.Methods Recombinant eukaryotic expression plasmid liposome enhanced transfection of green fluorescent protein gene (pEGFP-N1)-MIF was constructed and then transfected into human cervical cancer SiHa cells.Experimental cells were classified into three groups (SiHa-pEGFP-N1-MIF,SiHa-pEGFP-N1,and SiHa).Western blot was used to detect the expression of MIF protein,and the expressions of EMT-related markers such as E-cadherin and vimentin in SiHa cells were determined before and after transfection.Results The eukaryotic expression vector pEGFP-N1-MIF significantly increased the expression of MIF protein in SiHa cells (P ＜ 0.05),and after overexpression of MIF gene in SiHa cells,the expression of E-cadherin protein in SiHa-pEGFP-N1-MIF group was significantly lower than that in control groups (P ＜0.05),while the expression of vimentin in SiHa-pEGFP-N1-MIF group was significantly higher than that in control groups (P ＜ 0.05).Conclusions Overexpression of MIF in cervical cancer SiHa cells can promote the EMT occurrence.

The relationship between mRNA level of glucocorticoid receptor α, heat shock protein 90, protein level of macrophage migration inhibitory factor and glucocorticoid resistance in systemic lupus erythematosus / 中华内科杂志

Objective To investigate the mRNA level of glucocorticoid receptor α (GRα) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance.Methods One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study.Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction.Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF.The association between these parameters and GC resistance was analyzed by Spearman correlation analysis.The multivariate logistic regression model was used to analyze the risk factors for GC resistance.Results The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18(3.12,17.20) vs 16.83(12.01,24.18), P =0.001;18.46(14.77,26.45) vs 25.84 (17.97,35.90), P =0.005].MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21 ±7.98) μg/L vs (18.34 ±6.29)μg/L;P =0.013].The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84,28.32) vs 26.64 (23.61,47.16);P =0.001], as well as HSP90/GRαratio(P =0.008).Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r =-0.275, P =0.004) and HSP90/GRα ratio(r =-0.341, P ＜ 0.001).SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23 ±2.86) μg./L vs (9.63 ± 3.48) μg/L;P =0.003].Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR =17.481, 95％ CI 1.747-174.903, P =0.015).Conclusions Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance.Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/ Grα.Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.

Expression and significance of VEGF,MIF in colorectal cancer / 重庆医学

Objective Todetecttheexpressionofvascularendothelialgrowthfactor(VEGF)andmigrationinhibitoryfactor (MIF) in colorectal cancer .Methods The immunohistochemical staining (SP method) was used to measure the expression of VEGF and MIF in 80 samples of colorectal cancer and 80 samples of normal colorectal tissues at 5 cm apart from the tumor edge . The relationship between VEGF and MIF with the clinical pathologic characteristics of colorectal cancer was anlyzed .Results The positive rates of VEGF and MIF in the colorectal cancer tissues were 77 .50% and 82 .50% respectively ,but which in the normal colorectal tissues were 22 .50% and 27 .50% respectively ,the positive rate of VEGF and MIF expression in the colorectal cancer tis‐sues were higher than that in the normal colorectal tissue with statistical difference (P<0 .05) .The expression of VEGF and MIF had correlation with the tumor infiltration depth ,lymph node metastasis ,and clinical stage ,but no correlation with gender ,age and histodifferentiation .Conclusion VEGF and MIF are highly expressed in the colorectal cancer tissues .

miR-451 inhibits migration and invasion of gastric cancer cells by targeting migration inhibitory factor / 中国医师杂志

Objective To explore whether miR-451 suppresses cell migration and invasion by targeting macrophage migration inhibitory factors (MIF),thus to reveal molecular mechanism that miR-451 functions as a tumor suppressor in gastric cancer.Methods A quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to detect the expression of miR-451 in gastric cancer and normal stomach mucosa.Western blotting was performed to detect the expressions of MIF protein regulated by miR-451 in MGC 803 cells.The migration and invasion abilities of MGC-803 cell were evaluated with wound-healing and transwell invasion assays.Results miR-451 was down-regulated in gastric cancer tissues.The expressions of miR-451 were negatively correlated with the clinical stage and lymph node metastasis in gastric cancer patients.Western blot showed that a notable reduction of the protein level of MIF by restoring miR-451 in MGC-803 cells.Overexpression of miR-451 inhibited the migration and invasion of MGC-803 cells.Conclusions miR-451 suppresses cell migration and invasion by targeting MIF in gastric cancer.

Effect of Macrophage Migration Inhibitory Factor on Corneal Sensitivity after Laser In Situ Keratomileusis in Rabbit

PURPOSE: To investigate the effect of macrophage migration inhibitory factor (MIF) on corneal sensitivity after laser in situ keratomileusis (LASIK) surgery. METHODS: New Zealand white rabbits were used in this study. A hinged corneal flap (160-microm thick) was created with a microkeratome, and -3.0 diopter excimer laser ablation was performed. Expressions of MIF mRNA in the corneal epithelial cells and surrounding inflammatory cells were analyzed using reverse transcription polymerase chain reaction at 48 hours after LASIK. After LASIK surgery, the rabbits were topically given either 1) a balanced salt solution (BSS), 2) MIF (100 ng/mL) alone, or 3) a combination of nerve growth factor (NGF, 100 ug/mL), neurotrophine-3 (NT-3, 100 ng/mL), interleukin-6 (IL-6, 5 ng/mL), and leukemia inhibitory factor (LIF, 5 ng/mL) four times a day for three days. Preoperative and postoperative corneal sensitivity at two weeks and at 10 weeks were assessed using the Cochet-Bonnet esthesiometer. RESULTS: Expression of MIF mRNA was 2.5-fold upregulated in the corneal epithelium and 1.5-fold upregulated in the surrounding inflammatory cells as compared with the control eyes. Preoperative baseline corneal sensitivity was 40.56 +/- 2.36 mm. At two weeks after LASIK, corneal sensitivity was 9.17 +/- 5.57 mm in the BSS treated group, 21.92 +/- 2.44 mm in the MIF treated group, and 22.42 +/- 1.59 mm in the neuronal growth factors-treated group (MIF vs. BSS, p < 0.0001; neuronal growth factors vs. BSS, p < 0.0001; MIF vs. neuronal growth factors, p = 0.815). At 10 weeks after LASIK, corneal sensitivity was 15.00 +/- 9.65, 35.00 +/- 5.48, and 29.58 +/- 4.31 mm respectively (MIF vs. BSS, p = 0.0001; neuronal growth factors vs. BSS, p = 0.002; MIF vs. neuronal growth factors, p = 0.192). Treatment with MIF alone could achieve as much of an effect on recovery of corneal sensation as treatment with combination of NGF, NT-3, IL-6, and LIF. CONCLUSIONS: Topically administered MIF plays a significant role in the early recovery of corneal sensitivity after LASIK in the experimental animal model.

Change in expression of macrophage migration inhibitory factor mRNA in a rat model of ventilator-induced lung injury / 中华麻醉学杂志

Objective To investigate the changes in the expression of macrophage migration inhibitory factor (MIF) mRNA in a rat model of ventilator-induced lung injury.Methods Thirty adult male Sprague-Dawley rats,weighing 2β5-260 g,were randomly divided into 3 groups (n =10 each) using a random number table:control group (group C),small tidal volume (VT) mechanical ventilation group (group S) and large tidal volume mechanical ventilation group (group L).The animals were anesthetized with intraperitoneal ketamine 100 mg/kg,midazolam 0.2 mg/kg and atropine 1.0 mg/kg.The rats were tracheostomized and spontaneous breathing was maintained in group C,while the rats were tracheostomized and mechanically ventilated for 4 h in groups S and L.The tidal volume was 7 ml/kg (group S) or 40 ml/kg (group L),I ∶ E was 1 ∶ 1,RR was 80 bpm and FiO2 was 100％.At 4 h of spontaneous breathing or mechanical ventilation,broncho-alveolar lung lavage fluid (BALF) was collected for determination of the total protein concentration,white blood cell (WBC) counts and concentrations of MIF,IL-6 and IL-1β (by ELISA).Then the rats were sacrificed and the lungs removed for microscopic examination and for determination of wet to dry lung weight ratio (W/D ratio) and expression of MIF mRNA (by RT-PCR).Results Compared with C and S groups,WBC counts,concentrations of total protein,MIF,IL-6 and IL-1β in BALF,and W/D ratio and expression of MIF mRNA in lung tissues were significantly increased in group L (P ＜ 0.05).There was no significant difference in the indexes mentioned above between group C and group S (P ＞ 0.05).The pathological changes occurred in group L.Conclusion The up-regulation of MIF mRNA expression in lung tissues may be involved in the development of ventilator-induced lung injury in rats.

Relationship between macrophage migration inhibitory factor-173G/C polymorphism and susceptibility to gout in Chinese male population / 中华风湿病学杂志

Objective To explore gene polymorphism of the G/C genotype of-173G/C(rs755622)in the promoter of macrophage migration inhibitory factor(MIF)gene in male population,and thus to investigate the relationship between gene polymorphism of MIF and gout.Methods A total of 380 gout patients and 378 healthy controls were enrolled.The possible association between the polymorphism of MIF-173G/C and gout in Chinese were investigated and genotype frequencies and allelic frequencies were analyzed by polymerase chain reaction with sequence-specific primers(PCR-SSP)method.Hardy-Weinberg was used to verify the representativeness of the samples.Comparisons between the groups were performed with x2 test.The gene polymorphism of MIF and gout was performed by t test.Results The frequencies of GG,GC,CC genotypes were 62.1％(236 cases),34.2％(130 cases)and 3.7％(14 cases),respectively among gout patients,while they were 66.5％(252 cases),29.8％(113 cases)and 3.7％(14 cases),respectively among the controls.There was no statistical difference in MIF-173G/C genotype frequencies between gout patients and controls(x2=1.713,P=0.425).The allele frequencies of G and C in gout cases were 79.2％(602 cases)and 20.8％(158cases),while the controls were 81.4％(617 cases)and 18.6％(141 cases),and no significant difference between them could be found(x2=1.148,P=0.302).Combine GG and GC of gout into GG+GC,the association analysis of the two groups showed that,mean age,leves of glucose,TG,TC,BUN,Cr and UA of the GG+GC group and the CC group were(51±13)and(50±15)t=0.369,P=0.712;(7.1±8.8)and(6.1±1.2)mmol/L,t=0.352,P=0.725;(2.3±1.6)and(2.9±3.4)mmol/L,t=-1.207,P=0.228;(5.3±1.2)and(5.7±1.4)mmol/L,t=-1.207,P=0.228;(5.8±2.9)and(6.2±2.2)mmol/L,t=-0.513,P=0.608;(92±52)and(84±17)μmol/L,t=0.537,P=0.592;(472±103)vs(557±154)μmol/L,t=-2.949,P=0.03 respectively;no significant difference was found in the two group.Moreover,no association between MIF-173G/C genotypes and risk factors for gout were detected in gout cases by t-test.Conclusion Results of the present study suggest that the G/C genotype of-173G/C in the promoter of MIF gene is not associated with gout in male population.

Association between single nucleotide polymorphism of macrophage migration inhibitory factorrs1007888 and the pathogenesis of gestational diabetes mellitus / 中华妇产科杂志

Objective To investigate the association between single nucleotide polymorphism (SNP) of macrophage migration inhibitory factor (MIF) gene-rs1007888 and the pathogenesis of gestational diabetes mellitus (GDM).Methods A total of 120 GDM pregnant women (GDM group) and 165 healthy pregnant women (control group) from Affiliated Hospital of Medical College,Qingdao University were recruited from June 2011 to July 2012.Their age,gestational week,height and weight were recorded.The levels of fasting blood glucose (FBG) and fasting insulin (FIN) were determined.Body mass index (BMI),the hemeostasis model assessment-insulin resistance (HOMA-IR) and hemeostasis model assessment-β cell function (HOMA-β) were calculated.DNA was extracted from fasting blood samples.SNP of MIFrs1007888G/A was determined by DNA sequencing.The FBG,FIN,HOMA-IR and HOMA-β were compared between GDM group and the control group.They were also compared among pregnancies withdifferent genotypes.Results (1) GDM group had higher FBG,FIN and HOMA-IR levels,but lower HOMA-β than the control group (all P ＜ 0.05).(2) MIF-rs1007888 SNP genotype frequencies of GG,GA and AA were 37.5％,45.8％ and 16.7％,and the allelic frequencies of G and A were 60.4％,39.6％ in GDM group; However,in the control group,the frequencies of GG,GA and AA were 26.1％,54.5％ and 19.4％,and the allelic frequencies of G and A were 53.3％,46.7％,respectively.The distributions of MIF genotypes in GDM patients were significantly different from the healthy subjects (P ＜ 0.05).No significant difference of MIF-rs1007888 allele distributions was observed between GDM group and the control group (P ＞0.05).(3) The FBG,FIN and HOMA-IR in pregnant women with GG genotype were statistically higher than those with GA or AA genotypes,while HOMA-β was lower in women with GG genotype (all P ＜0.05).Conclusions The SNP of MIF rs-1007888 was related to the insulin resistance and pancreatic β cell function of pregnant women.GG genotype of MIF-rsl007888 might be a genetic susceptible factor in the pathogenesis of GDM.

Expression and function of macrophage migration inhibitory factor in a rat tibia fracture model of complex regional pain syndrome type I / 第二军医大学学报

Objective To investigate the expression of macrophage migration inhibitory factor (MIF) in complex regional pain syndrome I (CRPS I) rat model and the possible efficacy of MIF blockage in treatment of CRPS I. Methods Fifty healthy male SD rats were randomly divided into the following 5 groups: control, sham, model, DMSO control, and ISO-1 (inhibitor of MIF) treatment. CRPSI models were created in the last 3 groups; rats in the ISO-1 treatment group were subcutaneously treated with ISO-1 dissolved in 10 μl 5% DMSO at 1 mg/(kg • d) for 14 d. DMSO control group was only given 10 μl 5% DMSO. The pain threshold and thickness of the hindpaws were measured before and after treatment and were compared. The levels of MIF protein were examined in the serum, skin, spinal cord, sciatic nerve, and cerebrospinal fluid using ELISA and Western blotting analysis. Results Rats in the model group had noticeable hindpaw edema and significantly decreased pain threshold compared with the baselihe and that of the control group(P<0. 01). The hindpaw edema and pain threshold were significantly improved in ISO-1 treatment group compared with those in the model group(P<0. 05). MIF levels in the serum, skin, spinal cord, cerebrospinal fluid and sciatic nerve were higher in the model, DMSO control, and ISO-1 groups compared with those in the control group (P<0. 05 or P<0. 01). Conclusion MIF is a key inflammatory factor of CRPS I, and anti-MIF treatment might be a new therapy for human CRPS I.