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1
Shi, Qizhen, Erin L. Kuether, Jocelyn A. Schroeder, Crystal L. Perry, Scot A. Fahs, and Robert R. Montgomery. "Factor VIII Inhibitors: Von Willebrand Factor Makes A Difference In Vitro and In Vivo." Blood 116, no. 21 (November 19, 2010): 709. http://dx.doi.org/10.1182/blood.v116.21.709.709.
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Abstract Abstract 709 The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on FVIII inhibitors is still controversial. Studies have demonstrated that some anti-FVIII inhibitory antibodies inhibit VWF-FVIII interaction, while others rely on the presence of VWF to inhibit FVIII activities. The influence of VWF on the Bethesda assay, which is routinely used in the clinic to determine the titer of FVIII-neutralizing inhibitors, is still uncertain because the plasma from hemophilia A patients with inhibitors contains normal levels of VWF. To explore the effect of VWF on the reactivity of FVIII inhibitors, we immunized VWF and FVIII double knockout (VWFnullFVIIInull) mice with recombinant human B-domain deleted FVIII (rhFVIII) to induce anti-FVIII inhibitory antibody development. Inhibitory plasma was collected and the titer of inhibitors was determined by Bethesda assay. Murine plasma-derived VWF (from FVIIInull mice) or recombinant human VWF (rhVWF) was used to study the influence of VWF on inhibitor inactivation of FVIII activity (FVIII:C). The remaining FVIII:C after inactivation was determined by chromogenic assay. When inhibitory plasma was incubated with rhFVIII in the presence of 1 U/ml VWF, the residual FVIII activity recovered was higher than in the absence of VWF, resulting in 6.82 ± 1.12 (n = 27) fold lower apparent inhibitor titers. This protective effect is VWF dose dependent. The source of VWF (plasma-derived murine VWF vs. rhVWF) did not affect its protection of FVIII from inhibitor inactivation and VWF does not affect FVIII:C measured in the chromogenic assay in the absence of inhibitors. Interestingly, we found that inhibitor inactivation of FVIII:C in the absence of VWF occurred much faster than in its presence. When the usual 2 hr. incubation at 37°C was omitted from the Bethesda assay, adding rhVWF to rFVIII before mixing with inhibitory plasma resulted in 67.29 ± 20.18 (n = 5) fold lower apparent inhibitor titers than without added VWF. In contrast, if VWF was added to inhibitory plasma first and then mixed with rhFVIII, the inhibitor titers were only 11.04 ± 3.56 (n = 5) fold lower than without added VWF. These results indicate that rhFVIII present in a preformed VWF-FVIII complex is protected from inhibitory antibody inactivation. Conversely, when VWF and inhibitory plasma are added to rhFVIII at the same time, the VWF and inhibitors appear to compete to bind to rhFVIII. Inhibitor titers were lower than in the absence of VWF, but the protective effect is not as efficient as when VWF and rhFVIII were already associated with one another before encountering inhibitors. To confirm the protective effect of VWF on FVIII from inhibitor inactivation, we infused FVIIInull or VWFnullFVIIInull mice with inhibitory plasma and rhFVIII followed by a tail clip survival test. When rhFVIII was infused into FVIIInull mice to 2% followed by inhibitory plasma infusion, all mice with inhibitor titer of 2.5 BU/ml (n = 4) survived tail clipping, and 2 of 4 survived with either 25 BU/ml or 250 BU/ml. If inhibitory plasma was infused first followed by rhFVIII infusion, then only 2 of 6 mice with inhibitor titers of 2.5 BU/ml survived tail clip challenge and none survived with 25 BU/ml and 250 BU/ml. In the first set of mice the infused FVIII was able to form a protective complex with endogenous VWF before encountering inhibitors, while in the second set FVIII is exposed to VWF and pre-infused inhibitory antibodies at the same time, a competitive binding that appears to reduce VWF's protective effect. In contrast, when rhFVIII was infused into VWFnullFVIIInull mice followed by inhibitory plasma infusion, no animals (n = 4 for each group) survived tail clipping with inhibitor titers of 2.5 BU/ml or higher. In summary, our studies demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo. While the role of VWF in stabilizing plasma FVIII in a milieu rich in proteases has been appreciated for decades, our results indicate that treatment utilizing products containing a complex of FVIII with VWF may be especially beneficial in hemophilia A patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Kreisberg, R., M. S. Detrick, A. P. Osmand, and R. N. Moore. "Cytokine mediation of the suppressive effect of ferritin on colony-stimulating factor-1-dependent monocytopoiesis." Journal of Immunology 150, no. 11 (June 1, 1993): 5094–103. http://dx.doi.org/10.4049/jimmunol.150.11.5094.
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Abstract Peptide-specific IgG from a rabbit immunized with an alanine-lysine-proline-arginine ((ALA1)-tuftsin) containing 14-mer "ferritin" peptide neutralized rat liver ferritin inhibition of in vitro CSF-1-dependent monocytopoiesis. Antiferritin IgG similarly neutralized the inhibitory effect of ferritin but did not neutralize peptide inhibition of the in vitro myelopoietic response. No cross-reactivity between the respective antibodies and Ag was detected either by Western immunoblot or by competitive ELISA. Depletion of adherent cells before marrow cell culture significantly reduced the inhibitory effect of ferritin but did not influence peptide inhibition of CSF-1-stimulated colony formation. Adherent marrow cells and P388D1 cells treated with both CSF-1 and ferritin, but not either alone, produced inhibitory supernatant culture media that were neutralized by antipeptide but not antiferritin IgG. High resolution molecular sieve chromatography of the inhibitory adherent marrow cell and P388D1 supernatants resolved two peaks of 50 to 60 kDa and approximately 30 kDa in each. The inhibitory activity in all four peaks was neutralized by antipeptide but not antiferritin IgG. The ferritin/CSF inhibitors were not further characterized although identity with IL-6, IL-8, TNF-alpha, transforming growth factor-beta, and IFN-alpha/beta could be eliminated. The results indicate that ferritin inhibition of CSF-1-dependent monocytopoiesis is mediated by an endogenously produced inhibitor, or inhibitors, that shares antigenic similarity with the (ALA1)-tuftsin-containing 14-mer peptide and that adherent marrow cells, most likely monocytes or macrophages, produce the endogenous inhibitors in response to both CSF-1 and ferritin.
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Mihelič, Marko, and Dušan Turk. "Two decades of thyroglobulin type-1 domain research." Biological Chemistry 388, no. 11 (November 1, 2007): 1123–30. http://dx.doi.org/10.1515/bc.2007.155.
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Abstract Thyroglobulin type-1 repeats are primarily found in thyroglobulin and several other functionally unrelated proteins. Because a few of them exhibit inhibitory activity against cysteine proteases they were named thyropins (thyroglobulin type-1 domain protease inhibitors). In contrast to cystatins, the best-characterized group of papain-like protease inhibitors, they exhibit greater selectivity in their interactions with target proteases. Interestingly, a few members inhibit aspartic protease cathepsin D and metalloproteases. In contrast to the inhibitory fragment of the major histocompatibility complex class II-associated p41 form of invariant chain, whose structural integrity appears mandatory for its inhibitory properties, short polypeptides derived from insulin-like growth factor-binding proteins exhibit the same activity as the structure of the whole fragment. Taken together, the results indicate that the thyroglobulin type-1 repeat is a structural motif occasionally employed as an inhibitor of proteases.
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Buzzelli, Mark D., Murali Nagarajan, John F. Radtka, Margaret L. Shumate, Maithili Navaratnarajah, Charles H. Lang, and Robert N. Cooney. "Nuclear Factor-κB Mediates the Inhibitory Effects of Tumor Necrosis Factor-α on Growth Hormone-Inducible Gene Expression in Liver." Endocrinology 149, no. 12 (August 21, 2008): 6378–88. http://dx.doi.org/10.1210/en.2007-1574.
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TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and IGF-I gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and nuclear factor-κB (NFκB) inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for c-Jun N-terminal kinase), treated with or without TNF, and then stimulated with recombinant human GH. The 5- to 6-fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant-negative inhibitor-κBα (IκBα) expression vectors (IκBαS/A or IκBαTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFκB pathway. IκBαS/A and IκBαTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection with a C-terminal p65 deletion (1–450) enhanced GH-inducible promoter activity, whereas the N-terminal deletion (31–551) was inhibitory for IGF-I but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFκB, especially p65, by a mechanism that does not require protein synthesis.
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Pehlivan, Melek, Ceyda Caliskan, Zeynep Yuce, and Hakkı Ogun Sercan. "Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors." Tumor Biology 39, no. 5 (May 2017): 101042831770165. http://dx.doi.org/10.1177/1010428317701654.
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Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/β-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/β-catenin pathway antagonists—secreted frizzled-related protein 1 and Wnt inhibitory factor 1—on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular β-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total β-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.
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Zozulya, N. I., V. M. Chernov, I. S. Tarasova, and A. G. Rumyantsev. "Unsolved issues of providing medical care to patients with hemophilia with inhibitors in Russia." Russian Journal of Pediatric Hematology and Oncology 6, no. 2 (April 24, 2019): 48–53. http://dx.doi.org/10.21682/2311-1267-2019-6-2-48-53.
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The implementation of the state program “7 highcost nosologies” and the active work of Russian hematologists have significantly improved the specialized care for children and adults with Hemophilia. Russian hemophilia patient registry as of 10.25.2018 contained information about 7433 patients, of whom with hemophilia A – 6525 people. About 400 people were diagnosed with hemophilia with inhibitors. The inhibitor predominantly appeared at child and young age (up to 20 years). There is a high supply of coagulation factors concentrates for the treatment of hemophilia in the Russian Federation – 8.1 IU of coagulation factor VIII per capita in 2018, which corresponds to the graduation “full integration into society” according to the scale proposed by the World Hemophilia Federation. Due to the sufficient availability of coagulation factors, it is possible to conduct elimination of inhibitors by immune tolerance induction. Treatment with antiinhibitor coagulant complex and eptacog alfa (activated) requires a good venous access and is not always effective. Treatment results remain unsatisfactory in 67 % of adult patients with severe hemophilia with low inhibitor titer due to the number of bleeding per year exceeds 4. Unsatisfactory treatment results are noted in more than 1/ 3 patients with a high inhibitor titer, despite the ongoing prophylaxis with bypassing agents. Currently, clinical studies of fundamentally new drugs for hemophilia treatment, including the inhibitory form, are ongoing. One such drug is emicizumab, which is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII Emicizumab is not neutralized by inhibitors to FVIII, which allows it to be successfully used in the inhibitory form of hemophilia A. The results of HAVEN 1 and HAVEN 2 studies showed the advantages of using emicizumab in prophylactic regimen in children and adults with the inhibitory form of hemophilia A compared with bypassing agents.
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E, Jingwen, Ye Liu, Shanshan Guan, Zhijian Luo, Fei Han, Weiwei Han, Song Wang, and Hao Zhang. "How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study." Molecules 25, no. 4 (February 18, 2020): 895. http://dx.doi.org/10.3390/molecules25040895.
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Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.
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Batsuli, Glaivy, Courtney Cox, John F. Healey, Pete Lollar, and Shannon L. Meeks. "Anti-Factor VIII C1 Domain Antibodies Are Present in the Plasmas of Patients with Hemophilia and Inhibitors." Blood 124, no. 21 (December 6, 2014): 1482. http://dx.doi.org/10.1182/blood.v124.21.1482.1482.
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Abstract Hemophilia A is an X-linked disorder characterized by a deficiency or absence of blood coagulation protein factor VIII (fVIII). Treatment involves replacement of fVIII through infusions for acute bleeding episodes or prevention of bleeding events. Approximately 30% of individuals with severe hemophilia A will develop antibodies to fVIII. Many studies have characterized the antigenic properties of the C2 and A2 domains as these domains are considered the predominant immunogenic domains of the fVIII protein. However, there is increasing evidence that the C1 domain contributes to fVIII function and immune response to fVIII. Our laboratory has produced and purified a murine IgG2ak anti-human C1 domain monoclonal antibody (MAb), designated 2A9. In this study, we characterized the functional properties of MAb 2A9 using standard coagulation testing including its anti-fVIII inhibitor titer by Bethesda assay and its ability to inhibit fVIII binding to von Willebrand factor (VWF) by competition ELISA. In the Bethesda assay, 2A9 has an inhibitor titer of 97 BU/mg and is a type II inhibitor. In addition, MAb 2A9 inhibits fVIII binding to VWF in an ELISA assay with a 50% inhibitory concentration (IC50) of 1 µg/ml. This is in comparison to the potent high-titer inhibitory anti-C2 MAb I89 (IC50 0.02 µg/ml) and a control non-inhibitory anti-A2 MAb ID4 (IC50 > 10 µg/ml). We tested 11 plasma samples from patients with congenital hemophilia with inhibitors in the Emory IRB-approved inhibitor bank. The plasma samples have inhibitory titers ranging from 1 - 188 BU/ml with a median inhibitory titer of 54 BU/ml and mean inhibitory titer 59 BU/ml. The plasmas were tested for the presence of antibodies that compete with anti-C1 domain MAb 2A9 using competition ELISA with fVIII as the antigen. Biotinylated MAb 2A9 was serially diluted and the concentration of antibody required to produce an absorbance at 405 nm of 0.3 was compared between control severe hemophilia A plasma and inhibitor plasma samples. Inhibitor plasma samples that reduced the ELISA titer of MAb 2A9 were considered a competitive inhibitor. Of the 11 inhibitor plasma samples, 4 were found to compete with MAb 2A9. Our study demonstrates that anti-C1 domain antibodies are present in the plasma of patients with hemophilia A and inhibitors. Given the increasing evidence that the C1 domain is important in fVIII function it is likely that these anti-C1 antibodies are clinically relevant. Therefore, domains other than A2 and C2 need to be included in future studies of fVIII B cell epitopes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Kawai, Misato, Tomohiro Osanai, Makoto Tanaka, Koji Magota, Hirofumi Tomita, and Ken Okumura. "Mitochondrial Inhibitory Factor Protein 1 Functions as an Endogenous Inhibitor for Coupling Factor 6." Journal of Cellular Biochemistry 117, no. 7 (January 15, 2016): 1680–87. http://dx.doi.org/10.1002/jcb.25461.
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Tenan, Mirna, Giulia Fulci, Michele Albertoni, Annie-Claire Diserens, Marie-France Hamou, Michèle El Atifi-Borel, Jean-Jacques Feige, Michael S. Pepper, and Erwin G. Van Meir. "Thrombospondin-1 Is Downregulated by Anoxia and Suppresses Tumorigenicity of Human Glioblastoma Cells." Journal of Experimental Medicine 191, no. 10 (May 15, 2000): 1789–98. http://dx.doi.org/10.1084/jem.191.10.1789.
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Angiogenesis, the sprouting of new capillaries from preexisting blood vessels, results from a disruption of the balance between stimulatory and inhibitory factors. Here, we show that anoxia reduces expression of thrombospondin-1 (TSP-1), a natural inhibitor of angiogenesis, in glioblastoma cells. This suggests that reduced oxygen tension can promote angiogenesis not only by stimulating the production of inducers, such as vascular endothelial growth factor, but also by reducing the production of inhibitors. This downregulation may significantly contribute to glioblastoma development, since we show that an increase in TSP-1 expression is sufficient to strongly suppress glioblastoma cell tumorigenicity in vivo.
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Na, Bon Hyang, Thi Xoan Hoang, and Jae Young Kim. "Hsp90 Inhibition Reduces TLR5 Surface Expression and NF-κB Activation in Human Myeloid Leukemia THP-1 Cells." BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/4319369.
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Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin. Flagellin-induced nuclear factor-κB (NF-κB) activation was significantly reduced by treatment with GA or VER155008. To elucidate the underlying mechanism of this effect, mRNA and cell surface expression of TLR5 was examined. TLR5 mRNA expression was enhanced by both GA and VER155008, whereas cell surface expression of TLR5 was reduced by three different Hsp90 inhibitors, including GA, 17-(allylamino)-17-demethoxygeldanamycin, and radicicol, and an Hsp70 inhibitor. The inhibitory effect of Hsp90 inhibitors was much higher than that of Hsp70 inhibitor. Our results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF-κB in THP-1 cells in response to TLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp90 inhibitors suppress myeloid leukemia.
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Sen, Prosenjit, Andrey Komissarov, Usha R. Pendurthi, Steven Idell, and L. Vijaya Mohan Rao. "Plasminogen Activator Inhibitor-1 Inhibits Factor VIIa Bound to Tissue Factor." Blood 112, no. 11 (November 16, 2008): 1023. http://dx.doi.org/10.1182/blood.v112.11.1023.1023.
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Abstract The tissue factor (TF) pathway of coagulation plays a primary role in hemostasis but the aberrant activation of TF-mediated coagulation leads to thrombus formation, the precipitating event in acute myocardial infarction, unstable angina and ischemic stroke. Tissue factor-mediated coagulation also contributes to the pathogenesis of acute lung injury by generating extravascular fibrin deposition in lung parenchyma. Pleural fibrin deposition is a common complication of pleural inflammation and occurs in a wide variety of pleural diseases. Thus, a proper regulation of TF activity is critical for maintenance of hemostatic balance. Tissue factor pathway inhibitor (TFPI) is the primary inhibitor for TF-mediated coagulation whereas antithrombin (AT) may function as an auxiliary second physiologic regulator. In pleural injury, concentrations of plasminogen activator inhibitor (PAI)-1, the predominant inhibitor of tissue-type and urokinase-type plasminogen activators, were increased about 1000-fold in exudative pleural fluids. In addition to inhibiting uPA and tPA, PAI-1 was also shown to inhibit thrombin and activated protein C. In the present study we investigated whether PAI-1 inhibits FVIIa activity. Free FVIIa or FVIIa complexed with relipidated TF (10 nM) was incubated with PAI-1 (1 μM) ± heparin (10 U/ml) or vitronectin (1 μM) for varying time periods and the extent of FVIIa inactivation was measured in a clotting assay. PAI-1 or PAI-1 + heparin exhibited no significant inhibitory effect on free factor VIIa coagulant activity. PAI-1, combined with equimolar concentration of vitronectin, inhibited free FVIIa activity, albeit very slowly (~15% inhibition in 2 h). However if FVIIa was complexed with relipidated TF, it was inhibited much more rapidly by PAI-1. The time required for 50% inactivation of FVIIa/TF by PAI-1 was about 85 min. Heparin increased the rate of PAI-1 inactivation of FVIIa/TF by about 2-fold whereas vitronectin enhanced PAI-1 inactivation of FVIIa/TF by 4 to 5-fold, inhibiting 50% of the FVIIa coagulant activity in less than 20 min. Heparin or vitronectin alone had no inhibitory effect on FVIIa/TF. To compare the efficiency of PAI-1 and PAI-1/vitronectin with AT/heparin to inhibit FVIIa/TF activity, we determined the loss of FVIIa coagulant activity in the presence of varying concentrations of PAI-1 ± vitronectin (1 μM) or AT ± heparin (10 U/ml). The IC50 values as follow; AT, > 5 μM; PAI-1, 817 nM; AT/heparin, 25 nM; PAI-1/vitronectin, 125 nM. A 1:1 stochiometric complex between PAI-1 and FVIIa, with an apparent molecular weight of 100,000 was detected by SDS-PAGE. In additional studies, we investigated the ability of PAI-1 to inactivate FVIIa bound to TF on lung fibroblasts. PAI-1 inhibited FVIIa bound to cell surface TF, but to a lesser extent than FVIIa bound to relipidated TF. However, in the absence of heparin, PAI-1 and not AT is capable of inactivating FVIIa bound to TF. Interestingly, in contrast to the data observed with FVIIa bound to relipidated TF, heparin or vitronectin failed to accelerate PAI-1 inactivation of FVIIa bound to cell surface TF. At present, it is unclear why heparin and vitronectin failed to enhance the PAI-1 inhibitory effect on FVIIa bound to cell surface TF. Overall the data presented here in show that PAI-1 is capable of modulating FVIIa/TF activity. Further studies are needed evaluate whether PAI-1 inhibition of FVIIa/TF plays an important role in pathophysiology, particularly in lung inflammation.
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Bilan, Philip J., Jonathan B. Weitzman, Tracey Pflieger, C. Roy D. Lancaster, Alan Stafford, and Richard M. Epand. "Potent inhibitors of glucagon-stimulated adenylate cyclase associated with serum lipoprotein particles." Biochemistry and Cell Biology 67, no. 11-12 (November 1, 1989): 759–62. http://dx.doi.org/10.1139/o89-114.
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Lipoprotein fractions from some individuals have inhibitory effects on rat liver adenylate cyclase. Precipitation of the lipoprotein fractions with acetone released an inhibitory factor, which was soluble in acetone–H2O (3:1, v/v). The inhibition was greater against glucagon-stimulated activity than against basal activity. Acetone extraction increased the potency of inhibition. All three lipoprotein fractions, i.e., very low, low, and high density lipoproteins, released some inhibitory component after acetone extraction. The inhibitor was concentrated in the lipoprotein fractions, since acetone extraction of plasma did not release an inhibitor. The acetone extract from the very low density liproprotein was the most inhibitory. This material was further purified and partially characterized. The inhibitor had a molecular mass of about 500. It was inhibitory at micromolar concentrations. The material was sufficiently hydrophobic to migrate in normal-phase thin-layer chromatography (TLC). Nuclear magnetic resonance results indicated that it was not a polar lipid. There were several different inhibitory factors that were separable by TLC. The sequestration of these inhibitors into lipoproteins reduced their effectiveness in inhibiting the action of counter-regulatory hormones, such as glucagon.Key words: glucagon, adenylate cyclase, lipoprotein, diabetes mellitus.
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Ahamed, Jasimuddin, Mattias Belting, and Wolfram Ruf. "Regulation of tissue factor–induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1." Blood 105, no. 6 (March 15, 2005): 2384–91. http://dx.doi.org/10.1182/blood-2004-09-3422.
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AbstractTissue factor (TF) triggers upstream coagulation signaling via the activation of protease-activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor 1 (TFPI-1) is the physiologic inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TF-mediated signaling through PARs. In endothelial cells transduced with TF to mimic exacerbated TF expression in vascular cells, TF-VIIa-Xa ternary complex-dependent activation of PAR1 remained intact when TF-mediated Xa generation was blocked with 2.5 to 5 nM recombinant TFPI-1 (rTFPI-1). Concordantly, inhibition of signaling in PAR1-expressing Chinese hamster ovary (CHO) cells required about 30-fold higher rTFPI-1 concentrations than necessary for anticoagulation. Studies with proteoglycan-deficient CHO cells document a crucial role of accessory receptors in supporting the anticoagulant and antisignaling activities of rTFPI-1. Coexpression of PAR2 with TF enhanced rTFPI-mediated inhibition of TF-VIIa-Xa–mediated PAR1 signaling, suggesting an unexpected role of PAR2 in the inhibitory control of TF signaling. These experiments are of potential significance for the limited therapeutic benefit of rTFPI-1 in systemic inflammation and recommend caution in using anticoagulant potency as a measure to predict how efficacious TF-directed inhibitors block cell signaling during initiation of coagulation.
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Dimitrov, Jordan D., Suryasarathi Dasgupta, Ana-Maria Navarrete, Sandrine Delignat, Yohann Repesse, Yann Meslier, Cyril Planchais, et al. "Induction of heme oxygenase-1 in factor VIII–deficient mice reduces the immune response to therapeutic factor VIII." Blood 115, no. 13 (April 1, 2010): 2682–85. http://dx.doi.org/10.1182/blood-2009-04-216408.
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Abstract Replacement therapy with exogenous factor VIII (FVIII) to treat hemorrhages induces anti-FVIII inhibitory immunoglobulin G in up to 30% of patients with hemophilia A. Chronic inflammation associated with recurrent bleedings is a proposed risk factor for FVIII inhibitor development. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory activity. Here, we demonstrate that induction of HO-1 before FVIII administration drastically reduces the onset of the anti-FVIII humoral immune response. The protective effect was specific for HO-1 because it was reproduced on administration of the end products of HO-1 activity, carbon monoxide, and bilirubin, and prevented by the pharmacologic inhibition of HO-1 using tin mesoporphyrin IX. HO-1 induction was associated with decreased major histocompatibility complex class II expression by splenic antigen-presenting cells and reduced T-cell proliferation. Triggering the endogenous anti-inflammatory machinery before FVIII administration may represent a novel therapeutic option for preventing the development of FVIII inhibitors in hemophilia A patients.
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Meeks, Shannon, John F. Healey, Ernest T. Parker, Rachel T. Barrow, and John (Pete) Lollar. "Non-Classical Anti-Factor VIII C2 Domain Antibodies Are Pathogenic in a Murine in Vivo Bleeding Model." Blood 112, no. 11 (November 16, 2008): 2027. http://dx.doi.org/10.1182/blood.v112.11.2027.2027.
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Abstract Approximately 30% of patients with severe hemophilia A will develop inhibitory antibodies to factor VIII (fVIII inhibitors). In addition, autoimmune antibodies to fVIII can develop in non-hemophiliacs, producing acquired hemophilia A, which frequently produces life- or limb-threatening bleeding. Patients with congenital hemophilia who develop inhibitors usually have a polyclonal antibody response directed against the A2 and C2 domains of fVIII. Patients with acquired hemophilia typically have a more limited B-cell epitope response with antibodies directed against the A2 or C2 domain not both. Classical anti-C2 antibodies inhibit the binding of fVIII to phospholipid membranes and to von Willebrand factor. We recently have identified anti-C2 antibodies that inhibit the activation of fVIII, but do not inhibit the binding of fVIII to phospholipid membranes or to von Willebrand factor. These non-classical inhibitors are found in the plasmas of most inhibitor patients (Meeks, S.L. et al. Blood112, 1151-1153, 2008). The pathogenicity of classical and non-classical murine anti-human fVIII monoclonal antibodies (MAbs) was tested in a murine in vivo bleeding model. MAbs were injected into the tail veins of –hemophilia A mice to a peak plasma concentration of 60 nM followed by an injection human B domain-deleted fVIII to a concentration of 2 nM. At 2 hours the mice were anesthetized and a 4 mm tail snip was made. The amount of blood lost into a collection tube of normal saline over 40 minutes was measured. 4A4 is a type I anti-A2 inhibitor with an inhibitory titer of 40,000 Bethesda units (BU)/mg IgG. I54 and 1B5 are classical type I anti-C2 inhibitors with inhibitory titers of 1300 and 930 BU/mg IgG, respectively. 2-77 is a non-classical type II anti-C2 inhibitor that produces a residual fVIII level of 40% at saturating concentrations and whose titer is 21,000 BU/mg IgG. 2-117 is a non-classical anti-C2 MAb with inhibitory activity less than 0.4 BU/mg IgG. All of these MAbs except 2-117 significantly increased blood loss over control mice injected with fVIII alone (p= 0.01-0.02, Mann-Whitney Test) (Fig .1). The amount of blood loss was similar at these saturating concentrations of antibody despite inhibitory titers ranging from 930-40,000 BU/mg IgG. Increasing the dose of fVIII to 4 nM could overcome the bleeding diathesis produced by the non-classical MAb 2-77, but not the type I antibodies, 4A4 and I54. Similar results were seen in the in vitro Bethesda assay where 4A4 completely inhibited both 1 U/ml and 3 U/ml fVIII at saturating concentrations, while 2-77 had 40% residual activity with either 1 or 3 U/ml fVIII (0.4 U and 1.2 U respectively) (Fig. 2). These results suggest that high-dose fVIII rather than bypassing agents may be warranted in patients with an inhibitor response dominated by non-classical anti-C2 antibodies. FIGURE 1. FIGURE 1. FIGURE 2. FIGURE 2.
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Dubois, C. M., F. W. Ruscetti, E. W. Palaszynski, L. A. Falk, J. J. Oppenheim, and J. R. Keller. "Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action." Journal of Experimental Medicine 172, no. 3 (September 1, 1990): 737–44. http://dx.doi.org/10.1084/jem.172.3.737.
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Transforming growth factor beta (TGF-beta) acts as a potent inhibitor of the growth and functions of lymphoid and hemopoietic progenitor cells. Cell proliferation depends not only on the presence of growth factors, but also on the development of specific receptor-signal transducing complexes. We therefore investigated whether the inhibitory actions of TGF-beta could be mediated by inhibition of growth factor receptors. TGF-beta inhibited the constitutive level of interleukin 1 receptor (IL-1R) expression on several murine lymphoid and myeloid progenitor cell lines, as well as IL-1R expression induced by interleukin 3 (IL-3) on normal murine and human bone marrow cells. Furthermore, treatment of bone marrow progenitor cells with TGF-beta concomitantly inhibited the ability of IL-1 to promote high proliferative potential (HPP) colony formation as well as blocked IL-1-induced IL-2 production by EL-4 6.1 cells. These findings provide the first evidence that the inhibitory action of TGF-beta on the growth and functional activities of hematopoietic and T cells is associated with a reduction in the cell surface receptor expression for IL-1.
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Tiku, K., M. L. Tiku, S. Liu, and J. L. Skosey. "Normal human neutrophils are a source of a specific interleukin 1 inhibitor." Journal of Immunology 136, no. 10 (May 15, 1986): 3686–92. http://dx.doi.org/10.4049/jimmunol.136.10.3686.
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Abstract In the course of our study on neutrophil production of an interleukin 1 (IL-1)-like factor, we found that the addition of polymorphonuclear neutrophils (PMN) to monocytes cultured in the presence of zymosan resulted in decreased IL 1 activity of the resultant supernatant, suggesting that PMN may contain an inhibitor of IL 1. The objective of this investigation was to study this IL 1 inhibitor which normal human PMN contain. The inhibitor is constitutively present in the PMN because 0 hr PMN lysates and unstimulated PMN supernatants also show inhibitory activity. The PMN inhibitor inhibits IL 1 (crude and partially purified) in a dose-response manner and does not affect basal [3H]thymidine incorporation in the presence or absence of PHA-P. The PMN inhibitor does not have any effect on interleukin 2 (IL 2)-induced proliferation of the IL 2-dependent CTLL cells. The inhibitor can be generated in the absence of serum and is not produced as a result of proteolytic activity from PMN enzymes. The inhibitor is heat-labile and is most stable at neutral pH. Gel filtration studies on Sephadex G-200 indicate that the inhibitor is heterogeneous in size. Two inhibitory peaks, at 45,000 to 70,000 m.w. and at greater than 160,000 m.w., were observed. When zymosan-stimulated PMN supernatant was chromatographed, there was separation of inhibitory factor from a 17,000 m.w. proliferating factor. Presence of this PMN inhibitor may be important in negative regulation of IL 1.
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Ahamed, Jasimuddin, Mattias Belting, and Wolfram Ruf. "Regulation of Tissue Factor Signaling by Tissue Factor Pathway Inhibitor." Blood 104, no. 11 (November 16, 2004): 1930. http://dx.doi.org/10.1182/blood.v104.11.1930.1930.
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Abstract Tissue factor initiates the coagulation cascade as well as cellular signaling through the activation of cell surface protease activated receptors (PARs), relevant to inflammation, tumor metastasis and angiogenesis. Tissue factor pathway inhibitor-1 (TFPI-1) is the major regulator of TF initiated coagulation, but recombinant TFPI-1 (rTFPI-1) has shown limited efficacy on sepsis-associated inflammatory responses and mortality. In TNF-stimulated human umbilical vein endothelial cells (HUVECs), we demonstrate with specific blocking antibodies that endogenous TFPI effectively controls TF procoagulant activity as well as TF-dependent signaling through PAR1 and PAR2. The effect of rTFPI-1 on coagulation and signaling was tested in TF-transfected CHO-cells or in HUVECs transduced with TF to overcome the inhibitory threshold of endogenous TFPI-1. Under conditions that specifically measure signaling of the ternary TF-VIIa-Xa complex, 2.5–5 nM rTFPI-1 inhibited TF-dependent Xa generation by >80% but the signaling of the ternary complex through PAR1 at these concentrations of rTFPI-1 was only marginally inhibited. Moreover, studies with proteoglycan-deficient CHO cells provided genetic evidence that PG binding facilitates the inhibitory activities of rTFPI-1 on coagulation and signaling. In HUVECs that co-expressed PAR2 with TF, three different signaling responses of the ternary TF-VIIa-Xa complex were inhibited by ~ 50% at 1.2–2.5 nM rTFPI-1, but the inhibitory potency of rTFPI-1 to block Xa generation was consistently higher relative to its effect on signaling. These data demonstrate that coagulation initiation phase signaling can occur in the absence of the activation of coagulation. The results also establish that endogenously expressed TFPI-1, known to be entirely GPI-anchored in endothelial cells, is a potent, negative regulator of ternary complex-mediated PAR signaling. The efficacy of rTPFI-1 appears to be influenced by the presence of PAR2, further emphasizing the close reciprocal signaling linkage of PAR2 and TF demonstrated in angiogenesis and cellular signaling targeting the TF cytoplasmic domain by phosphorylation.
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Tang, Liang, Clark Pan, Harpartap Atwal, Jennifer Nixon, Thomas Barnett, John E. Murphy, Baisong Mei, and Michael Fournel. "PEGylation of Factor VIII Reduces the Inhibitory Effects of Human Antibody Inhibitors on the Factor VIII Molecule." Blood 108, no. 11 (November 16, 2006): 4017. http://dx.doi.org/10.1182/blood.v108.11.4017.4017.
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Abstract Replacement therapy with plasma-derived or recombinant Factor VIII (FVIII) has successfully reduced mortality and morbidity and improved the quality of life for patients with hemophilia A. However, up to 30% of patients develop antibody inhibitors to the FVIII molecule. Inhibitors reduce the efficacy of FVIII, increase the cost of treatment, and greatly increase the risk for life-threatening bleeding events in these patients. In the hopes of developing a more efficacious FVIII therapeutic for hemophilia A patients with inhibitors, we initiated studies on the PEGylation of B-region deleted FVIII (FVIII-BDD) with different sizes of polyethylene glycol (PEG) and investigated the inhibitory effects of anti-FVIII inhibitors on the activity of PEGylated FVIII-BDDs. Applying a site-specific mutagenesis technique to the FVIII-BDD molecule, an amino-acid residue at the inhibitor binding site was changed to cysteine. Mutated FVIII-BDD was purified and PEG molecules of different sizes were added at the mutation sites through a chemical reaction with the maleimide group on the activated PEG. PEGylated FVIII-BDD molecules were further purified and tested for FVIII activity using the chromogenic assay. To investigate the effects of antibody inhibitors on the PEGylated FVIII-BDD, studies were carried out utilizing inhibitory plasmas collected from 8 hemophilia A patients with confirmed inhibitors and different monoclonal antibodies as controls. Of the 8 patient plasmas tested, 43 kD PEGylated FVIII-BDD was more resistant to antibody inhibitors in 4 patient plasma samples than unmodified FVIII-BDD. In one sample, pre-incubation of FVIII-BDD with inhibitor patient plasma (1:15 dilution) reduced FVIII activity to 5% of the originally activity added, according to the chromogenic assay. By contrast, approximately 20% of original activity was retained for monoPEGylated FVIII-BDD and >40% activity was retained for diPEGylated FVIII-BDD. Overall, the results suggest that PEGylated FVIII-BDDs may retain more FVIII activity in the presence of some FVIII antibody inhibitors compared to FVIII-BDD. It is important to note that there was a positive correlation between the size of PEG added to FVIII-BDD and the amount of FVIII activity retained. This study indicates that the addition of PEG to FVIII molecules through site-specific PEGylation has the potential to increase the resistance of FVIII to the effects of some antibody inhibitors in patients with hemophilia A.
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He, Enqi, Wei Quan, Jie Luo, Chuxin Liu, Wanting Zheng, and Qingwu Shen. "Absorption and Transport Mechanism of Red Meat-Derived N-glycolylneuraminic Acid and Its Damage to Intestinal Barrier Function through the NF-κB Signaling Pathway." Toxins 15, no. 2 (February 6, 2023): 132. http://dx.doi.org/10.3390/toxins15020132.
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N-glycolylneuraminic acid (Neu5Gc) is a specific factor in red meat that induces intestinal disease. Our aim was to investigate the effect of Neu5Gc on the intestinal barrier as well as its mechanism of endocytosis and exocytosis. Ten specific inhibitors were used to explore the mechanism of Neu5Gc endocytosis and exocytosis by Caco-2 cells. Amiloride hydrochloride and cytochalasin D had the strongest inhibitory effect on the endocytosis of Neu5Gc. Sodium azide, dynasore, chlorpromazine hydrochloride, and nystatin also inhibited Neu5Gc endocytosis. Dynasore exhibited a stronger inhibitory effect than that of chlorpromazine hydrochloride or nystatin alone. Exocytosis inhibitors, including nocodazole, brefeldin A, monensin, and bafilomycin A, inhibited the transmembrane transport of Neu5Gc. Monensin promoted the exocytosis of Neu5Gc from Caco-2 cells. In another experiment, we observed no significant inhibitory effects of monensin and brefeldin A. Dietary concentrations of Neu5Gc induced prominent damage to intestinal tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-1 and promoted the phosphorylation of IκB-α and P65 to activate the canonical Nuclear Factor kappa-B (NF-κB) pathway. Neu5Gc increased the RNA levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α and inhibited those of anti-inflammatory factors TGF-β and IL-10. BAY, an NF-κB signaling pathway inhibitor, attenuated these changes. Reductions in the levels of ZO-1, occludin, and claudin-1 were recovered in response to BAY. Our data reveal the endocytosis and exocytosis mechanism of Neu5Gc and prove that Neu5Gc can activate the canonical NF-κB signaling pathway, regulate the transcription of inflammatory factors, thereby damaging intestinal barrier function.
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Dahiya, Raivir. "PP-543 The Functional Significance of Wnt Inhibitory Factor-1 (WIF-1) Gene in Kidney Cancer." Japanese Journal of Urology 101, no. 2 (2010): 504. http://dx.doi.org/10.5980/jpnjurol.101.504_3.
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Yada, Koji, Keiji Nogami, Kenichi Ogiwara, Katsumi Nishiya, Masahiro Takeyama, and Midori Shim. "Effects of Anti-FVIII Inhibitors On Factor VIIa/Tissue Factor-Catalyzed Activation and Inactivation of Factor VIII." Blood 114, no. 22 (November 20, 2009): 3169. http://dx.doi.org/10.1182/blood.v114.22.3169.3169.
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Abstract Abstract 3169 Poster Board III-110 Factor (F)VIIa with tissue factor (TF) is a primary trigger of blood coagulation. We have recently demonstrated that FVIIa/TF rapidly activated FVIII by proteolysis of the heavy chain (HCh), and served physiologically as a potent activator for up-regulation of FVIII activity in very early-timed phase (ASH #1036, 2008). FVIII inhibitors develop as alloantibodies in multi-transfused patients with hemophilia A and also arise as autoantibodies in normal individuals. FVIII inactivation by inhibitors is associated with impairment of FVIII(a) cofactor function through the binding to functional crucial epitopes in FVIII. Anti-C2 inhibitors prevent FVIII binding to phospholipid, von Willebrand factor, and FXa. Anti-A2 inhibitors prevent FVIII binding to FIXa and thrombin. However, effects of these inhibitors on FVIIa action for FVIII have remained to be studied. In this study, we prepared 13 of anti-FVIII inhibitor IgGs (2 of anti-A2, 7 of anti-C2 with type 1 behavior, and 4 of anti-C2 with type 2). We first examined FVIIa/TF-catalyzed FVIII activation in the presence of anti-FVIII inhibitors in one-stage clotting assay. The levels of FVIII activity (10 nM) elevated rapidly by ∼2.0-fold within 30 sec after adding of FVIIa/TF (1 nM), and subsequently decreased to the initial level within 20 min. The presence of anti-FVIII inhibitors did not significantly affect FVIIa/TF-catalyzed FVIII activation (by 1.7∼2.2-fold) compared to normal IgG. This action was independent of the difference of inhibitor epitopes. In addition, FVIIa-catalyzed FVIIIa inactivation with anti-A2 or anti-C2 with type 2 inhibitors was little affected, similar to that with normal IgG. However, of note, all of anti-C2 with type 1 significantly inhibited FVIIa-catalyzed inactivation of FVIIIa. Inactivation rates of FVIIa with anti-C2 with type 1 (k ∼0.15) was ∼40% less than that with control IgG (k ∼0.24), supporting that the presence of anti-C2 with type 1 might persist the activity of FVIIIa generated by FVIIa. To clarify this inhibitory mechanism of anti-C2 with type 1, we performed FVIIa-catalyzed FVIII cleavage in Western blotting. FVIIa/TF (1 nM) proteolyzed the HCh of FVIII (10 nM) rapidly by cleavages at Arg372 (and Arg740), whilst cleavage at Arg336 in the A1 domain was appeared at ∼2.5 min, supporting that cleavages at Arg372 and Arg336 by FVIIa contribute to the up- and down-regulation of FVIII(a) activity, respectively. All inhibitors, independent of recognizing epitopes, did not affect FVIIa-catalyzed cleavage at Arg372. However, the presence of anti-C2 type 1 delayed the cleavage at Arg336 in timed- and dose-dependent manners, whilst either anti-A2 or anti-C2 type 2 did not affect, consistent with the functional inactivation results. FVIIa binds to the A2, A3, and C2 domains in FVIII. Based on our findings, FVIIa-interactive sites on FVIII unlikely overlapped with anti-A2 and -C2 inhibitor epitopes, and inhibition of Arg336 cleavage may be due to conformational change caused by antibody binding. Furthermore, FVIIa indeed activates FVIII even in the presence of anti-FVIII inhibitors, different from thrombin, FXa, etc, and it would be important to predict the effect of FVIIa for FVIII to determine the characteristics of anti-FVIII inhibitors. Disclosures No relevant conflicts of interest to declare.
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Sun, Xuemei, Judith E. Layton, Andrew Elefanty, and Graham J. Lieschke. "Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL–expressing cells, demonstrating synergy between AG490 and STI571." Blood 97, no. 7 (April 1, 2001): 2008–15. http://dx.doi.org/10.1182/blood.v97.7.2008.
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Abstract STI571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145abland its oncogenic derivative p210bcr-abl. AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210bcr-abl-expressing factor-independent derivatives. STI571 was a more potent inhibitor of3H-thymidine incorporation in p210bcr-abl-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210bcr-abl-expressing derivatives. Assays performed with and without growth factor demonstrated that STI571 but not AG957 reversed the p210bcr-abl-driven factor independence of cell lines. p210bcr-abl-expressing cells were less sensitive to AG490 than to AG957 or STI571. However, for p210bcr-abl-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between STI571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of STI571 that reversed the p210bcr-abl factor-independent phenotype, STI571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) STI571 is a more potent and more selective inhibitor of a p210bcr-abl-dependent phenotype than AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory effect on p210bcr-abl-driven proliferation; and (3) the combination of p210bcr-abl-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells.
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Negrier, Claude, Shannon L. Meeks, Johannes Oldenburg, Uri Martinowitz, Jean-Claude Bordet, Bernd Poetzsch, Raed Al Dieri, et al. "Recombinant Porcine Factor VIII Corrects Thrombin Generation and Improves Clot Structure In Vitro in Plasma Containing Anti-Factor VIII Inhibitory Antibodies." Blood 118, no. 21 (November 18, 2011): 2282. http://dx.doi.org/10.1182/blood.v118.21.2282.2282.
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Abstract Abstract 2282 Introduction: Treatment of bleeding episodes in patients with hemophilia A who have developed inhibitory antibodies can be challenging. Using human factor VIII (FVIII) and, historically, porcine FVIII in patients with a low inhibitor titer are therapeutic options, and provide ease of monitoring. A B-domain deleted recombinant porcine FVIII (rpFVIII; OBI-1), which may possess low cross-reactivity to anti-human FVIII antibodies, is being investigated for the treatment of bleeding episodes in individuals with congenital hemophilia A and inhibitors, and in those with acquired hemophilia. The in vitro capacity of this molecule to correct hemostasis has been further characterized. Methods: This is an international, multicenter in vitro study. Individuals with hemophilia A and inhibitor antibodies were recruited during routine out-patient visits between January 2011 and March 2011. Written and signed informed consent was obtained prior to venepuncture. Blood was obtained from volunteers with congenital hemophilia A and inhibitors attending routine visits at participating hemophilia treatment centers. A single blood sample was obtained from consenting individuals under protocols approved by Institutional Review Boards/Ethical Committees. In vitro spiking experiments with OBI-1 were conducted using FVIII-deficient plasma with and without anti-FVIII inhibitory activity. Three control inhibitor plasmas were provided, composed of FVIII deficient plasma to which the anti-C1 monoclonal antibody (MAb) to human FVIII (Sanquin, Amsterdam, the Netherlands) was added at two concentrations to reach anti-human FVIII inhibitory activity of 4.9 Bethesda Units (BU)/mL and 32.8 BU/mL with anti-porcine anti-FVIII inhibitory activity of 2.7 BU/mL and 19.1 BU/mL, respectively; and FVIII deficient plasma to which “polyclonal” mixture of the anti-C1 MAb, along with an anti-A2 and 2 anti-C2 MAbs was added. Plasma from eight patients with hemophilia A and inhibitors was tested. Hemostatic correction by OBI-1 was assessed by thrombin generation measurement (Calibrated Analytical Thrombography assay, Synapse BV, Maastricht, The Netherlands) and clot structure using electron microscopy. Epitope mapping of the inhibitor patient plasma was undertaken at a central laboratory (Atlanta, Georgia, USA) using an Enzyme-Linked Immunosorbent Assay (ELISA) with human/porcine FVIII hybrids as the antigen. Results: The results showed a dose-dependent and anti-porcine titer dependent correction of thrombin generation parameters (peak and ETP) with OBI-1 at concentrations equivalent to 100 IU/dL, 200 IU/dL, and 400 IU/dL, which paralleled a correction of the clot structure (number and diameter of fibrin fibres). These results were only dependent on the anti-porcine titer. In samples with high titers of anti-porcine inhibitor (>10 BU), little or no restoration of the diminished thrombin generation was observed when various OBI-1 concentrations were added to the plasma. In the plasmas with high anti-human titers (≥10 BU/mL) the dominant epitope was C2 in 3 plasmas, A2 in 1 plasma, and indeterminate in 3 plasmas. The plasmas with no restoration of the thrombin generation with even the highest dose of OBI-1 all had antibody detected to more than one domain of FVIII or were not able to be mapped due to high porcine cross-reactivity. Conclusion: In vitro data obtained with spiking experiments using OBI-1 indicate that it has the potential to correct surrogate markers of hemostasis depending on the anti-porcine FVIII titer which may translate into in vivo effectiveness. Further investigation into the epitope specificity of responsive and non-responsive inhibitor plasmas correlation with effectiveness is warranted. Disclosures: Negrier: Inspiration Biopharmaceuticals: Honoraria, Research Funding. Meeks:Inspiration Biopharmaceuticals: Research Funding. Oldenburg:SOBI: Membership on an entity's Board of Directors or advisory committees; Catalyst: Membership on an entity's Board of Directors or advisory committees; Inspiration: Consultancy, Honoraria, Research Funding; LFB: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria; Octapharma: Consultancy, Honoraria, Research Funding. Bordet:Inspiration Biopharmaceuticals: Research Funding. Poetzsch:Inspiration Biopharmaceuticals: Research Funding. Al Dieri:Synapse BV: Employment. Dargaud:Inspiration Biopharmaceuticals: Research Funding. Hemker:Synapse BV: Employment. Eckmann:Sanquin Diagnostic Services: Employment. Gomperts:Inspiration Biopharmaceuticals: Employment. Lee:Inspiration Biopharmaceuticals: Employment.
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Eubanks, Joshua, Wallace Hunter Baldwin, Rebecca Markovitz, Ernest T. Parker, and Shannon L. Meeks. "Anti-Factor VIII A2 Epitopes In a Murine Bleeding Model." Blood 122, no. 21 (November 15, 2013): 1100. http://dx.doi.org/10.1182/blood.v122.21.1100.1100.
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Abstract Up to 30% of patients with severe hemophilia A will develop inhibitory antibodies to factor VIII (fVIII inhibitors). In addition, autoimmune antibodies to fVIII can develop in non-hemophiliacs, producing acquired hemophilia A, which frequently produces life- or limb-threatening bleeding. Patients with congenital hemophilia who develop inhibitors usually have a polyclonal antibody response directed against the A2 and C2 domains of fVIII. Patients with acquired hemophilia typically have a more limited B-cell epitope response with antibodies directed against the A2 or C2 domain but not both. We have shown that within the C2 domain of fVIII antibody epitope is more important than inhibitory titer in predicting pathogenicity in a murine in vivo bleeding model. In this project we investigated the pathogenicity of a diverse panel of anti-A2 monoclonal antibodies (Mabs) in the murine in vivo bleeding model. We have previously characterized anti-A2 antibodies into groups A, AB, B, BCD, C, D, DE, and E based on the pattern of overlap on the B-cell epitopes in a competition ELISA. Table 1 shows the characteristics of the anti-A2 Mabs. Mabs were injected retro-orbitally into Exon 16 hemophilic (E16) mice at a dose of 0.5 umg per g body weight (∼ 65nM plasma concentration). Fifteen minutes later, mice were injected with B-domain deleted human fVIII at a dose of 180U/kg (∼ 2.5nM plasma concentration). In addition, a subset of Mabs has also been tested at a high dose of 360U/kg (∼5 nM). Two hours after fVIII injection, the mice were anesthetized and a 4mm tail snip was performed. Blood was collected in a tube of normal saline over 40 minutes and measured. 4A4, 2-76, and 1D4 are all high inhibitory titer, type I Mabs that produced significant bleeding with 180 U/kg fVIII when compared to control. In addition, 2-76 and 4A4 were tested at the higher dose of fVIII and significant bleeding was again seen. In comparison, the high titer type II Mab 2-54 had a similar inhibitory titer but no significant bleeding at either dose of fVIII. B94 is a type II inhibitor with a similar inhibitory profile to 2-54, but maximum inhibition is 45% as compared to 82% for 2-54. B94 also was not pathogenic at either fVIII dose tested. Both 4C7—a non-inhibitory Mab—and B25—a very low titer Mab that would be predicted to have residual fVIII activity at the Mab concentration tested—did not produce significant bleeding. The inhibitory titer alone did not predict bleeding phenotype within a diverse panel of anti-A2 Mabs. This discrepancy combined with similar findings in the C2 domain stress the importance of inhibitor properties not detected in the standard Bethesda assay in predicting response to fVIII therapy. Disclosures: No relevant conflicts of interest to declare.
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Kurisaki, Keiko, Akira Kurisaki, Ulrich Valcourt, Alexei A. Terentiev, Katerina Pardali, Peter ten Dijke, Carl-Henrik Heldin, Johan Ericsson, and Aristidis Moustakas. "Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation." Molecular and Cellular Biology 23, no. 13 (July 1, 2003): 4494–510. http://dx.doi.org/10.1128/mcb.23.13.4494-4510.2003.
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ABSTRACT Smad proteins transduce transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-β and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-β or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-β- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-β or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-β growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-β superfamily pathways.
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Vernallis, Ann B., Keith R. Hudson, and John K. Heath. "An Antagonist for the Leukemia Inhibitory Factor Receptor Inhibits Leukemia Inhibitory Factor, Cardiotrophin-1, Ciliary Neurotrophic Factor, and Oncostatin M." Journal of Biological Chemistry 272, no. 43 (October 24, 1997): 26947–52. http://dx.doi.org/10.1074/jbc.272.43.26947.
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Chow, Tan Wei, Ming Thong Ong, and Shaharum Shamsuddin. "WNT inhibitory factor-1 (WIF-1): A new role in carcinogenesis?" Journal of Clinical Oncology 32, no. 15_suppl (May 20, 2014): 11124. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.11124.
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Camussi, G., C. Tetta, F. Bussolino, and C. Baglioni. "Synthesis and release of platelet-activating factor is inhibited by plasma alpha 1-proteinase inhibitor or alpha 1-antichymotrypsin and is stimulated by proteinases." Journal of Experimental Medicine 168, no. 4 (October 1, 1988): 1293–306. http://dx.doi.org/10.1084/jem.168.4.1293.
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TNF and IL-1 stimulate the synthesis and release of platelet-activating factor (PAF) by neutrophils and vascular endothelial cells. Serum inhibits PAF production even after inactivation of an acetylhydrolase that degrades PAF. Human plasma was fractionated by gel filtration chromatography, and two inhibitory fractions were detected, one containing PAF-acetylhydrolase activity and the other alpha 1-proteinase inhibitor. Low concentrations of this antiproteinase and of human plasma alpha 1-antichymotrypsin inhibited TNF-induced PAF synthesis in neutrophils, macrophages, and vascular endothelial cells. Both antiproteinases also inhibited PAF production stimulated by phagocytosis in macrophages and induced with IL-1 in neutrophils or with TNF in vascular endothelial cells. These results suggest that a proteinase activated on the plasma membrane or secreted by these cells is involved in promoting PAF synthesis. Indeed, addition of elastase to macrophages, neutrophils, and endothelial cells stimulated synthesis and release of PAF much faster than TNF. A similar stimulation was observed in incubations with cathepsin G. To identify a proteinase activated in TNF-treated cells, neutrophils and endothelial cells were incubated with specific chloromethyl ketone inhibitors of elastase and cathepsin G. Synthesis of PAF was significantly inhibited by low concentrations of the cathepsin G inhibitor. The finding that antiproteinases are inhibitory at concentrations 100-fold lower than those present in plasma raises questions as to the ability of TNF and IL-1 to stimulate neutrophils in circulation or endothelial cells to synthesize PAF. We propose that PAF production is limited to zones of close contact between cells, which exclude antiproteinases.
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Osanai, Tomohiro, Makoto Tanaka, Kasumi Mikami, Maiko Kitajima, Koji Magota, Hirofumi Tomita, and Ken Okumura. "Mitochondrial inhibitory factor protein 1 attenuates coupling factor 6‐induced aging signal." Journal of Cellular Biochemistry 119, no. 7 (March 25, 2018): 6194–203. http://dx.doi.org/10.1002/jcb.26828.
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Zaichuk, Tetiana A., Emelyn H. Shroff, Rebekah Emmanuel, Stephanie Filleur, Thomas Nelius, and Olga V. Volpert. "Nuclear Factor of Activated T Cells Balances Angiogenesis Activation and Inhibition." Journal of Experimental Medicine 199, no. 11 (June 7, 2004): 1513–22. http://dx.doi.org/10.1084/jem.20040474.
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It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial–derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain–like interleukin 1β–converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.
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Lee, Min-Jung, Eun-Jung Kim, Liwen Li, and Han-Sung Jung. "Roles of Wnt inhibitory factor 1 during tooth morphogenesis." Cell and Tissue Research 362, no. 1 (April 18, 2015): 61–68. http://dx.doi.org/10.1007/s00441-015-2170-3.
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NAKAMARU, Y. "Macrophage migration inhibitory factor (MIF) in allergic rhinitis*1." Journal of Allergy and Clinical Immunology 113, no. 2 (February 2004): S245. http://dx.doi.org/10.1016/j.jaci.2004.01.346.
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Chimeo, Cindy, Analia Veronica Fernandez-Gimenez, Michelangelo Campanella, Ofelia Mendez-Romero, and Adriana Muhlia-Almazan. "The shrimp mitochondrial FoF1-ATPase inhibitory factor 1 (IF1)." Journal of Bioenergetics and Biomembranes 47, no. 5 (August 25, 2015): 383–93. http://dx.doi.org/10.1007/s10863-015-9621-0.
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Thung, E. G., J. Chou, L. You, Z. Xu, and D. M. Jablons. "Hypermethylation Silences Wnt Inhibitory Factor 1 in Nasopharyngeal Carcinoma." Journal of Investigative Medicine 54, no. 1_suppl (January 2006): 104–5. http://dx.doi.org/10.1177/108155890605401s28.
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Kazama, Yoshiaki. "The Importance of the Binding of Factor Xa to Phospholipids in the Inhibitory Mechanism of Tissue Factor Pathway Inhibitor: The Transmembrane and Cytoplasmic Domains of Tissue Factor Are not Essential for the Inhibitory Action of Tissue Factor Pathway Inhibitor." Thrombosis and Haemostasis 77, no. 03 (1997): 492–97. http://dx.doi.org/10.1055/s-0038-1655995.
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SummaryTo investigate the inhibitory mechanism of tissue factor pathway inhibitor (TFPI), an attempt was made to examine the inhibitory activity of TFPI toward the factor Vila-truncated tissue factor (TF1-219) complex, which lacks its transmembrane and cytoplasmic domains. Factor VIIa-TF1-219 activity was significantly inhibited by TFPI-factor Xa complex in the presence of phospholipids, but was not in the absence of phospholipids. In addition, TFPI did not inhibit factor VIIa-TF1-219activity in the presence of γ-carboxyglutamic acid-domainless factor Xa. The ability of TFPI-factor Xa complex to inhibit factor VIIa-TF1-219 activity was totally dependent on the presence of phospholipids and was neutralized by prothrombin fragment 1 in a dose-dependent manner. These results indicate that the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory mechanism of TFPI and confirm that the binding of factor Xa to phospholipids through its γ-carboxyglutamic acid domain is essential for this reaction.
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Fedorczyk, Bartlomiej, Piotr F. J. Lipiński, Anna K. Puszko, Dagmara Tymecka, Beata Wilenska, Wioleta Dudka, Gerard Y. Perret, Rafal Wieczorek, and Aleksandra Misicka. "Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165." Molecules 24, no. 9 (May 6, 2019): 1756. http://dx.doi.org/10.3390/molecules24091756.
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Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2% to 58.1% at 10 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, 3, IC50 = 8.39 μM). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound 3 and discuss the observed structure–activity relationships.
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Seckinger, P., K. Williamson, J. F. Balavoine, B. Mach, G. Mazzei, A. Shaw, and J. M. Dayer. "A urine inhibitor of interleukin 1 activity affects both interleukin 1 alpha and 1 beta but not tumor necrosis factor alpha." Journal of Immunology 139, no. 5 (September 1, 1987): 1541–45. http://dx.doi.org/10.4049/jimmunol.139.5.1541.
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Abstract Urine from monocytic leukemia and other febrile patients contains an inhibitor of interleukin 1 (IL-1), as measured by prostaglandin E2 and collagenase production by human fibroblasts and synovial cells. With the use of recombinant IL-1, the IL-1 inhibitor was partially purified by using ammonium sulfate precipitation, anion-exchange, and gel filtration chromatographies. IL-1 inhibitory activity elutes with an 18,000 to 25,000 apparent molecular size. The same fractions also inhibit IL-1 assayed by the proliferation of murine thymocytes and human fibroblasts. Both forms of human recombinant IL-1, IL-1 alpha and IL-1 beta, which show only 26% homology, but nevertheless bind to the same receptor, are affected by this natural inhibitor to the same extent. In contrast, human recombinant tumor necrosis factor, which shares some of the biologic activities of IL-1, is not inhibited by the urinary IL-1 inhibitor. This study shows that the various biologic activities of both forms of human recombinant IL-1 are inhibited by a partially purified natural urine-derived factor.
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Plantier, Jean-Luc, Didier Saboulard, Marc Delcourt, Nathalie Enjolras, and Claude Negrier. "Substitution of Four Residues Revealed by High-Throughput Screening of Human Factor VIII A2 Domain Generated a Recombinant Molecule That Escapes to Anti-Factor VIII Antibodies." Blood 112, no. 11 (November 16, 2008): 3067. http://dx.doi.org/10.1182/blood.v112.11.3067.3067.
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Abstract Using Massive Mutagenesis technique® we performed a high-throughput alanine substitution of 206 residues between aminoacids 376 to 649 from factor VIII (FVIII) A2 domain. The pattern of activity and the levels of production of FVIII mutants were assessed following transient expression in COS-1 cells. FVIII mutants that kept at least 50% of wild-type activity were then screened in an inhibitor assay against total immunoglobulin G (IgG) fractions from patients with severe hemophilia A who had developed inhibitory antibodies (n=4; range 6–15 BU/mL) or a non immune IgG as control. In this assay, the cell culture supernatants containing FVIII were incubated in a volume of FVIII-depleted plasma for 1h30 in the presence of IgG. The residual activity was then measured in a chronometric assay. No single mutations were able to significantly allow FVIII to escape inhibitors. Four mutations (S409A, L462A, E507A, L629A) having a tendency to resist to inhibitors were selected and recombined two by two leading to a significant but insufficient resistance to anti-FVIII antibodies. The effect of the mutations was additive since a molecule (FVIII-4A2) combining the 4 substitutions significantly resisted to the inhibitory antibodies. Residual activity of FVIII-4A2 ranged from 8% to up to 82% of the initial activity depending on the inhibitor plasma whereas this residual activity never exceeded 30% for control wild-type FVIII. Following production by CHO cells, purified FVIII-4A2 demonstrated a similar pattern of resistance to the four IgG fractions already assayed. FVIII-4A2 was then assayed against 11 additional unrelated inhibitors (range 3–2662 BU/mL) and displayed also a resistance against 10 out of the 11 IgG fractions. The resistance was in all case only partial in relation with the likely presence of anti-C2 and/or anti-A3-C1 inhibitors within the IgG fractions. As detected in a solid-phase assay, the decrease in inhibitory effect was for some of the IgG fractions partly related to a decrease in their binding capacity. As a control experiment, FVIII-4A2 was poorly recognized by the monoclonal antibody GMA012 directed against the A2 domain. In contrast, the binding to ESH4, an anti-C2 monoclonal antibody was not affected. Such combination of mutations opened the perspective for the generation of a recombinant FVIII molecule that can be used as an effective substitutive FVIII therapy in patients with inhibitors.
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Metcalf, D. "The Unsolved Enigmas of Leukemia Inhibitory Factor." Stem Cells 21, no. 1 (January 1, 2003): 5–14. http://dx.doi.org/10.1634/stemcells.21-1-5.
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Al-Salem, Huda S., Md Arifuzzaman, Iman S. Issa, and A. F. M. Motiur Rahman. "Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism." Applied Sciences 11, no. 9 (April 21, 2021): 3746. http://dx.doi.org/10.3390/app11093746.
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Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC50 = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC50 = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC50 = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC50 = 0.369 µM), VEGFR-2 (IC50 = 0.266 µM) and FLT-3 (IC50 = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.
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Chen, Cheng-Yu, Guo-Yuan Zhu, Jing-Rong Wang, and Zhi-Hong Jiang. "Phenanthroindolizidine alkaloids from Tylophora atrofolliculata with hypoxia-inducible factor-1 (HIF-1) inhibitory activity." RSC Advances 6, no. 83 (2016): 79958–67. http://dx.doi.org/10.1039/c6ra16455b.
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Shi, Jialan, and Gary E. Gilbert. "Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites." Blood 101, no. 7 (April 1, 2003): 2628–36. http://dx.doi.org/10.1182/blood-2002-07-1951.
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Lactadherin, a glycoprotein of the milk-fat globule membrane, contains tandem C domains with homology to discoidin-type lectins and to membrane-binding domains of blood-clotting factors V and VIII. We asked whether the structural homology confers the capacity to compete for the membrane-binding sites of factor VIII and factor V and to function as an anticoagulant. Our results indicate that lactadherin competes efficiently with factor VIII and factor V for binding sites on synthetic phosphatidylserine-containing membranes with half-maximal displacement at lactadherin concentrations of 1 to 4 nM. Binding competition correlated to functional inhibition of factor VIIIa–factor IXa (factor Xase) enzyme complex. In contrast to annexin V, lactadherin was an efficient inhibitor of the prothrombinase and the factor Xase complexes regardless of the degree of membrane curvature and the phosphatidylserine content. Lactadherin also inhibited the factor VIIa–tissue factor complex efficiently whereas annexin V was less effective. Because the inhibitory concentration of lactadherin was proportional to the phospholipid concentration, and because lactadherin was not an efficient inhibitor in the absence of phospholipid, the major inhibitory effect of lactadherin relates to blocking phospholipid sites rather than forming inhibitory protein-protein complexes. Lactadherin was also an effective inhibitor of a modified whole blood prothrombin time assay in which clotting was initiated by dilute tissue factor; 60 nM lactadherin prolonged the prothrombin time 150% versus 20% for 60 nM annexin V. These results indicate that lactadherin can function as a potent phospholipid-blocking anticoagulant.
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Morishita, Hideaki, Toru Yamakawa, Tomokazu Matsusue, Takeshi Kusuyama, Rie Sameshima-Aruga, Jiro Hirose, Atsushi Nii, et al. "Novel factor Xa and plasma kallikrein inhibitory-activities of the second Kunitz-type inhibitory domain of urinary trypsin inhibitor." Thrombosis Research 73, no. 3-4 (February 1994): 193–204. http://dx.doi.org/10.1016/0049-3848(94)90098-1.
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Licchesi, J. D. F., L. Van Neste, V. K. Tiwari, L. Cope, X. Lin, S. B. Baylin, and J. G. Herman. "Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1/c-Myc." Oncogene 29, no. 44 (August 9, 2010): 5923–34. http://dx.doi.org/10.1038/onc.2010.322.
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Chim, C. S., T. K. Fung, K. F. Wong, J. S. Lau, and R. Liang. "Infrequent Wnt inhibitory factor-1 (Wif-1) methylation in chronic lymphocytic leukemia." Leukemia Research 30, no. 9 (September 2006): 1135–39. http://dx.doi.org/10.1016/j.leukres.2005.12.005.
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Cornish, J., K. E. Callon, S. G. E. Edgar, and I. R. Reid. "Leukaemia inhibitory factor is mitogenic to osteoblasts." Bone 17, no. 6 (December 1995): 561. http://dx.doi.org/10.1016/8756-3282(96)87802-1.
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Olsson, Lina, Gudrun Lindmark, Marie-Louise Hammarström, Sten Hammarström, and Basel Sitohy. "Evaluating macrophage migration inhibitory factor 1 expression as a prognostic biomarker in colon cancer." Tumor Biology 42, no. 6 (June 2020): 101042832092452. http://dx.doi.org/10.1177/1010428320924524.
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Objective: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker. Methods: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I–IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase–polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry. Results: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan–Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up. Conclusion: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.
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Huang, Jing, Rui Tian, Yongqiang Yang, Rong Jiang, Jie Dai, Li Tang, and Li Zhang. "The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia." Innate Immunity 23, no. 8 (September 27, 2017): 678–86. http://dx.doi.org/10.1177/1753425917733531.
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It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-α and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.