Showing papers by "Richard Bucala published in 2014"
TL;DR: Exogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses, and data indicate that levels of MIF, AMP-activated protein kinase activation, and Autophagy were elevated concurrently in human failing hearts.
Abstract: The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be cardioprotective under various pathological conditions. However, the underlying mechanisms still remain elusive. In this study, we revealed that MIF deficiency overtly exacerbated abdominal aorta constriction-induced cardiac hypertrophy and contractile anomalies. MIF deficiency interrupted myocardial autophagy in hypertrophied hearts. Rapamycin administration mitigated the exacerbated hypertrophic responses in MIF(-/-) mice. Using the phenylephrine-induced hypertrophy in vitro model in H9C2 myoblasts, we confirmed that MIF governed the activation of AMP-activated protein kinase-mammalian target of rapamycin-autophagy cascade. Confocal microscopic examination demonstrated that MIF depletion prevented phenylephrine-induced mitophagy in H9C2 myoblasts. Myocardial Parkin, an E3 ubiquitin ligase and a marker for mitophagy, was significantly upregulated after sustained pressure overload, the effect of which was prevented by MIF knockout. Furthermore, our data exhibited that levels of MIF, AMP-activated protein kinase activation, and autophagy were elevated concurrently in human failing hearts. These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses.
85 citations
TL;DR: The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) as mentioned in this paper.
78 citations
TL;DR: Insight is provided into the lack of cooperativity by 4‐IPP and into tuning the properties of the covalent inhibitors of D‐DT and MIF that are necessary for the development of therapeutic small molecules against neutrophil damage from lung infections such as Pseudomonas aeruginosa in cystic fibrosis and immunocompromised patients.
Abstract: We report a new inflammatory activity for extracellular d-dopachrome tautomerase (D-DT), the recruitment of neutrophils to the lung on D-DT intratracheal installation of C57BL/6J mice with an EC50 of 5.6 μg. We also find that D-DT and macrophage migration inhibitory factor (MIF) have additive effects in neutrophil recruitment. Although the tautomerase site of D-DT and its homologue MIF are biophysically very different, 4-iodo-6-phenylpyrimidine (4-IPP) forms a covalent bond with Pro-1 of both proteins, resulting in a 6-phenylpyrimidine (6-PP) adduct. Recruitment of neutrophils to the lung for the 6-PP adducts of D-DT and MIF are reduced by ∼50% relative to the apo proteins, demonstrating that an unmodified Pro-1 is important for this activity, but there is no cooperativity in inhibition of the proteins together. The differences in the binding mode of the 6-PP adduct for D-DT was determined by crystallographic studies at 1.13 A resolution and compared to the structure of the MIF–6-PP complex. There are maj...
61 citations
TL;DR: The data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.
Abstract: The cellular response to stress involves the recruitment and coordination of molecular signaling pathways that prevent cell death. D-dopachrome tautomerase (DDT) is an enzyme that lacks physiologic substrates in mammalian cells, but shares partial sequence and structural homology with macrophage migration inhibitory factor (MIF). Here, we observed that DDT is highly expressed in murine cardiomyocytes and secreted by the heart after ischemic stress. Antibody-dependent neutralization of secreted DDT exacerbated both ischemia-induced cardiac contractile dysfunction and necrosis. We generated cardiomyocyte-specific DDT knockout mice (Myh6-Cre Ddtfl/fl), which demonstrated normal baseline cardiac size and function, but had an impaired physiologic response to ischemia-reperfusion. Hearts from Myh6-Cre Ddtfl/fl mice exhibited more necrosis and LV contractile dysfunction than control hearts after coronary artery ligation and reperfusion. Furthermore, treatment with DDT protected isolated hearts against injury and contractile dysfunction after ischemia-reperfusion. The protective effect of DDT required activation of the metabolic stress enzyme AMP-activated protein kinase (AMPK), which was mediated by a CD74/CaMKK2-dependent mechanism. Together, our data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.
58 citations
TL;DR: Global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation.
57 citations
TL;DR: A novel inhibitor is identified that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and it is demonstrated that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
Abstract: The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (MifP1G). Primary tumor growth was significantly attenuated in both Mif-KO and MifP1G mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
48 citations
TL;DR: This study investigates whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF, a proinflammatory protein implicated in the pathogenesis of rheumatoid arthritis.
Abstract: Objective
Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF.
Methods
GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function.
Results
GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release.
Conclusion
MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity.
45 citations
TL;DR: It is demonstrated that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury in high‐fat or methionine‐ and choline‐deficient diet mouse models of NASH.
Abstract: MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif−/− mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif−/−, 103±7 mg/g liver; P<0.05) and a 2–3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif−/−mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80+ macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50–90% in white adipose tissue (WAT) of Mif−/− mice. Subset analysis showed that macrophage phenotypes in livers of Mif−/− mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80+ macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.—Heinrichs, D., Berres, M.-L., Coeuru, M., Knauel, M., Nellen, A., Fischer, P., Philippeit, C., Bucala, R., Trautwein, C., Wasmuth, H. E., Bernhagen, J. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.
45 citations
TL;DR: It is shown that MIF expression is down‐regulated by 0.75 ± 0.10‐fold and that down‐regulation of MIF by NFκB‐mediated signaling under hypoxia accelerates neuronal loss during stroke.
Abstract: Neuronal apoptosis is one of the major causes of poststroke neurological deficits. Inflammation during the acute phase of stroke results in nuclear translocation of NFκB in affected cells in the infarct area. Macrophage migration inhibitory factor (MIF) promotes cardiomyocyte survival in mice following heart ischemia. However, the role of MIF during stroke remains limited. In this study, we showed that MIF expression is down-regulated by 0.75 ± 0.10-fold of the control in the infarct area in the mouse brains. Two functional cis-acing NFκB response elements were identified in the human MIF promoter. Dual activation of hypoxia and NFκB signaling resulted in significant reduction of MIF promoter activity to 0.86 ± 0.01-fold of the control. Furthermore, MIF reduced caspase-3 activation and protected neurons from oxidative stress- and in vitro ischemia/reperfusion-induced apoptosis. H2O2 significantly induced cell death with 12.81 ± 0.58-fold increase of TUNEL-positive cells, and overexpression of MIF blocked the H2O2-induced cell death. Disruption of the MIF gene in MIF-knockout mice resulted in caspase-3 activation, neuronal loss, and increased infarct development during stroke in vivo. The infarct volume was increased from 6.51 ± 0.74% in the wild-type mice to 9.07 ± 0.66% in the MIF-knockout mice. Our study demonstrates that MIF exerts a neuronal protective effect and that down-regulation of MIF by NFκB-mediated signaling under hypoxia accelerates neuronal loss during stroke. Our results suggest that MIF is an important molecule for preserving a longer time window for stroke treatment, and strategies to maintain MIF expression at physiological level could have beneficial effects for stroke patients.—Zhang, S., Zis, O., Ly, P. T. T., Wu, Y., Zhang, S., Zhang, M., Cai, F., Bucala, R., Shyu, W.-C., Song, W. Down-regulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke.
44 citations
TL;DR: It is suggested that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
Abstract: The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of t...
44 citations
TL;DR: It is shown that MIF mediates the pathogenic inflammatory immune response and increases the recruitment of inflammatory monocytes and neutrophils to contribute to liver injury in Trypanosoma brucei infected mice, and contributes more significantly than monocyte-derived MIF to increased pathogenic liver TNF production and liver injury during trypanosome infection.
Abstract: African trypanosomiasis is a chronic debilitating disease affecting the health and economic well-being of many people in developing countries. The pathogenicity associated with this disease involves a persistent inflammatory response, whereby M1-type myeloid cells, including Ly6Chigh inflammatory monocytes, are centrally implicated. A comparative gene analysis between trypanosusceptible and trypanotolerant animals identified MIF (macrophage migrating inhibitory factor) as an important pathogenic candidate molecule. Using MIF-deficient mice and anti-MIF antibody treated mice, we show that MIF mediates the pathogenic inflammatory immune response and increases the recruitment of inflammatory monocytes and neutrophils to contribute to liver injury in Trypanosoma brucei infected mice. Moreover, neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to increased pathogenic liver TNF production and liver injury during trypanosome infection. MIF deficient animals also featured limited anemia, coinciding with increased iron bio-availability, improved erythropoiesis and reduced RBC clearance during the chronic phase of infection. Our data suggest that MIF promotes the most prominent pathological features of experimental trypanosome infections (i.e. anemia and liver injury), and prompt considering MIF as a novel target for treatment of trypanosomiasis-associated immunopathogenicity.
TL;DR: This review discusses CD74 and its ligand macrophage migration inhibitory factor (MIF) and their central position in linking these two components of the immune response by controlling survival of macrophages and B cells.
Abstract: Molecules that link innate and adaptive immunity and regulate immune response in health and disease are now the focus of many studies. This review discusses CD74 and its ligand macrophage migration inhibitory factor (MIF), and their central position in linking these two components of the immune response by controlling survival of macrophages and B cells.
TL;DR: It is found that DRα1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), resulting in a novel therapeutic, DR α1–MOG-35–55, that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis.
Abstract: CD74, the cell-surface form of the MHC class II invariant chain, is a key inflammatory factor that is involved in various immune-mediated diseases as part of the macrophage migration inhibitory factor (MIF) binding complex. However, little is known about the natural regulators of CD74 in this context. In order to study the role of the HLA-DR molecule in regulating CD74, we used the HLA-DRα1 domain, which was shown to bind to and downregulate CD74 on CD11b(+) monocytes. We found that DRα1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Potency of the DRα1 domain could be destroyed by trypsin digestion but enhanced by addition of a peptide extension (myelin oligodendrocyte glycoprotein [MOG]-35-55 peptide) that provided secondary structure not present in DRα1. These data suggest a conformationally sensitive determinant on DRα1-MOG that is responsible for optimal binding to CD74 and antagonism of MIF effects, resulting in reduced axonal damage and reversal of ongoing clinical and histological signs of EAE. These results demonstrate natural antagonist activity of DRα1 for MIF that was strongly potentiated by the MOG peptide extension, resulting in a novel therapeutic, DRα1-MOG-35-55, that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis.
TL;DR: A significant association of genotypes carrying the -794 CATT7 and -173(∗)C risk alleles with susceptibility to SLE and with a significant increase of TNF-α is found in a Mexican-Mestizo population.
TL;DR: It is suggested that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococCal disease susceptibility.
Abstract: Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.
TL;DR: Taken together, MIF appears to antagonize CS-induced toxicity in the lung and resultant emphysematous tissue remodeling by suppressing EC DNA damage and controlling p53-mediated apoptosis, highlighting a critical role of MIF in EC homeostasis within the lung.
Abstract: Cigarette smoke (CS) is the most common cause of chronic obstructive pulmonary diseases (COPD), including emphysema. CS exposure impacts all cell types within the airways and lung parenchyma, causing alveolar tissue destruction through four mechanisms: (1) oxidative stress; (2) inflammation; (3) protease-induced degradation of the extracellular matrix; and (4) enhanced alveolar epithelial and endothelial cell (EC) apoptosis. Studies in human pulmonary ECs demonstrate that macrophage migration inhibitory factor (MIF) antagonizes CS-induced apoptosis. Here, we used human microvascular ECs, an animal model of emphysema (mice challenged with chronic CS), and patient serum samples to address both the capacity of CS to alter MIF expression and the effects of MIF on disease severity. We demonstrate significantly reduced serum MIF levels in patients with COPD. In the murine model, chronic CS exposure resulted in decreased MIF mRNA and protein expression in the intact lung. MIF deficiency (Mif−/−) potentiated the ...
TL;DR: There is sufficient evidence that the EQ-5D displays construct and criterion validity for use in SLE patients, and disease-specific measures of HRQoL used alongside may be a better choice.
Abstract: Objective
To investigate the construct and criterion validity of the Euro Qol-5D (EQ-5D), which allows quality-adjusted life-years to be calculated, in patients with systemic lupus erythematosus (SLE).
Methods
Consecutive SLE patients who had been followed at the Renji Hospital, School of Medicine, Shanghai Jiao Tong University were recruited. Cross-sectional correlations of the EQ-5D with equivalent domains in disease-specific health-related quality of life (HRQoL), LupusQol, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) measures, the Systemic Lupus International Collaborating Clinics Damage Index (SDI), and patient characteristics were tested. Discriminant validity to assess the ability to distinguish between patients of different disease severity was assessed. There also were evaluations of ceiling and floor effects.
Results
240 patients were recruited in total. The EQ-5D correlated moderately to strongly with all domains of the LupusQoL (r: 0.44–0.7) apart from intimate relationships (r = 0.25) and body image (r = 0.18). There was moderate negative correlation between EQ-5D and clinical assessment of disease, SLEDAI (r = −0.589) and SDI (r = −0.509). When compared with equivalent domains on LupusQoL, there was good construct validity in EQ-5D (r: 0.631–0.812). EQ-5D could also discriminate patients with varied disease severity (according SLEDAI and SDI). There was no floor effect in EQ-5D but the ceiling effect remains strong (34%).
Conclusion
Our results provide sufficient evidence that the EQ-5D displays construct and criterion validity for use in SLE patients. Disease-specific measures of HRQoL used alongside may be a better choice.
TL;DR: Macrophage migration inhibitory factor of Ostertagia ostertagi, an abomasal parasite of cattle, was characterised in the present study and Immunostaining indicated that macrophages were able to internalise rOos-MIF-1.1, further supporting receptor-mediated transportation.
TL;DR: This work suggests that older adults with low expression of MIF may be predisposed to hyporesponsiveness to lipopolysaccharide and gram-negative bacterial infection.
Abstract: Macrophage migration inhibitory factor (MIF) is an immune mediator encoded in a functionally polymorphic locus. We found the genotype conferring low expression of MIF to be enriched in a cohort of 180 patients with gram-negative bacteremia, compared with 229 healthy controls (odds ratio [OR], 2.4; P = .04), an association that was more pronounced in older adults (OR, 4.6; P = .01). Among older subjects, those with low expression of MIF demonstrated 20% reduced MIF production from lipopolysaccharide-stimulated peripheral blood monocytes and 30% lower monocyte surface Toll-like receptor 4, compared with those with high expression. Our work suggests that older adults with low expression of MIF may be predisposed to hyporesponsiveness to lipopolysaccharide and gram-negative bacterial infection.
TL;DR: D-DT and its receptor are expressed in the murine tumors B16F10 and 4T1 and knock-down of D-DT through siRNA or blocking by antibodies reduced proliferation of B 16F10 tumor cells, qualifying D- DT for further evaluation as a therapeutic target.
Abstract: // Sebastian Kobold 1,* , Melanie Merk 1,* , Luisa Hofer 1 , Philip Peters 1 , Richard Bucala 2 and Stefan Endres 1 1 Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munich, Germany, Member of the German Center for Lung Research 2 Internal Medicine, Yale University School of Medicine, New Haven, United States of America * These authors contributed equally to this work Correspondence: Sebastian Kobold, email: // Keywords : Cytokine, MIF, cancer, apoptosis Received : October 31, 2013 Accepted : December 10, 2013 Published : December 12, 2013 Abstract The macrophage migration inhibitory factor (MIF)-homologue D- dopachrome tautomerase (D-DT) recently has been described to have similar functions as MIF. However, the role of D-DT, as opposed to MIF, in tumor biology remains unknown. We hypothesized that D-DT could represent a target for therapeutic interventions in cancer. We analyzed the production of D-DT in the murine melanoma model B16F10 and the murine breast cancer model 4T1 by western blot and ELISA. D-DT was released by tumor cells both in vitro and in vivo. RT-PCR revealed the expression of the D-DT receptor CD74 on both tumor cell lines. Tumor bearing mice had higher serum levels of D-DT compared to healthy controls. Remarkably, knock-down of D-DT by siRNA reduced proliferation of B16F10 cells in BrDU-assay and rendered them more prone to apoptosis induction, as shown by flow cytometry. In vivo neutralization of D-DT by antibodies reduced tumor progression in the B16F10 subcutaneous syngeneic tumor model. In summary, we could show that D-DT and its receptor are expressed in the murine tumors B16F10 and 4T1. Knock-down of D-DT through siRNA or blocking by antibodies reduced proliferation of B16F10 tumor cells. This qualifies D-DT for further evaluation as a therapeutic target.
TL;DR: This study reports the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor with nanomolar Ki’s and provides explanations regarding their selectivity of PfMIF versus human MIF.
Abstract: We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar Ki’s, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF These inhibitors were also found to selectively inhibit interactions between PfMIF and the human MIF receptor CD74 The results of this study provide the framework for the development of new therapeutics that target PfMIF
TL;DR: Progress made by an ILAR-supported project to enhance paediatric and adult rheumatology education and practice in Zambia underscores the suitability of the ILAR mission statement “think global, act local” demonstrating that even with minimum resources and networking, improvement of rheumatic care in developing countries is attainable.
Abstract: The burden of non-communicable diseases such as musculoskeletal diseases in the developing world is often overshadowed by the more prevalent infectious diseases. Generally, there is gross underestimation of the burden of rheumatologic disease in the backdrop of scanty or indeed non-existent rheumatology services in these countries. Local studies conducted in the last two decades in Zambia have documented the increasing burden of rheumatologic conditions in the country. There are unfortunately negligible rheumatology services in the country both at tertiary or primary health-care facility levels. There is thus an urgent need to build capacity for these services so as to improve the care and management of rheumatic conditions. Here, we review progress made by an International League of Associations for Rheumatology (ILAR)-supported project that has run for the past 2 years (2012–2013) with the objective of enhancing paediatric and adult rheumatology education and practice so as to stimulate positive change in practice and related care services in Zambia. During this short time of the project, substantial progress has been made in the areas of paediatric and adult rheumatology services enhancement at the University Teaching Hospital, Lusaka: streamlining of referrals and follow-ups of rheumatology patients, laying foundations for short- and long-term medical education in rheumatology and raising public awareness of rheumatic diseases. The progress made by this grant underscores the suitability of the ILAR mission statement “think global, act local” demonstrating that even with minimum resources and networking, improvement of rheumatology care in developing countries is attainable.
TL;DR: Chinese Multidimensional Health Assessment Questionnaire (MDHAQ-C) is a reliable, valid instrument for functional measurement and a feasible, informative quantitative index for busy clinical settings in Chinese RA patients.
Abstract: Objective To evaluate the psychometric properties and clinical utility of Chinese Multidimensional Health Assessment Questionnaire (MDHAQ-C) in patients with rheumatoid arthritis (RA) in China. Methods 162 RA patients were recruited in the evaluation process. The reliability of the questionnaire was tested by internal consistency and item analysis. Convergent validity was assessed by correlations of MDHAQ-C with Health Assessment Questionnaire (HAQ), the 36-item Short-Form Health Survey (SF-36) and the Hospital anxiety and depression scales (HAD). Discriminant validity was tested in groups of patients with varied disease activities and functional classes. To evaluate the clinical values, correlations were calculated between MDHAQ-C and indices of clinical relevance and disease activity. Agreement with the Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI) was estimated. Results The Cronbach's alpha was 0.944 in the Function scale (FN) and 0.768 in the scale of psychological status (PS). The item analysis indicated all the items of FN and PS are correlated at an acceptable level. MDHAQ-C correlated with the questionnaires significantly in most scales and scores of scales differed significantly in groups of different disease activity and functional status. MDHAQ-C has moderate to high correlation with most clinical indices and high correlation with a spearman coefficient of 0.701 for DAS 28 and 0.843 for CDAI. The overall agreement of categories was satisfying. Conclusion MDHAQ-C is a reliable, valid instrument for functional measurement and a feasible, informative quantitative index for busy clinical settings in Chinese RA patients.
01 Jan 2014
TL;DR: J Immunol€ published online 28 March 2014Material Supplementary8.DCSupplemental.
Abstract: Arthur A. VandenbarkHalina Offner, Yoram Reiter, Gregory G. Burrows andMooney, Rony Dahan, Nerri Duvshani, Richard Bucala, Roberto Meza-Romero, Gil Benedek, Xiaolin Yu, Jeffery L.ol.1303118http://www.jimmunol.org/content/early/2014/03/28/jimmunJ Immunol€ published online 28 March 2014MaterialSupplementary8.DCSupplemental.htmlhttp://www.jimmunol.org/content/suppl/2014/03/30/jimmunol.130311Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:
01 Jan 2014
TL;DR: MIFKO mice had a significantly lower incidence of post-MI cardiac rupture and amelioration of cardiac remodelling and were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators' expression, and reduced activity of M MP-2, MMP-9, p38 and JNK MAPK.
Abstract: article i nfo Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators' expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissecttheroleofMIFderivedfromdifferentcellular sources in post-MIcardiacremodelling, we generatedchimeric mice with MIF deficiency either in bone marrow derived-cells (WT KO