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5 results on '"Mizwicki, M. T."'

2. Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord: inhibition of inflammation by resolvin D1

Author

Liu, G., Fiala, M., Mizwicki, M. T., Sayre, J., Magpantay, L., Siani, A., Mahanian, M., Chattopadhyay, M., Antonio La Cava, Wiedau-Pazos, M., Liu, Guanghao, Fiala, Milan, Mizwicki, Mathew T, Sayre, Jame, Magpantay, Larry, Siani, Avi, Mahanian, Michelle, Chattopadhyay, Madhuri, La Cava, Antonio, and Wiedau-Pazos, Martina

Subjects
Original Article
Abstract

Although the cause of neuronal degeneration in amyotrophic lateral sclerosis (ALS) remains hypothetical, there is evidence of spinal cord infiltration by macrophages and T cells. In post-mortem ALS spinal cords, 19.8 ± 4.8 % motor neurons, including caspase-negative and caspase-positive neurons, were ingested by IL-6- and TNF-α-positive macrophages. In ALS macrophages, in vitro aggregated superoxide dismutase-1 (SOD-1) stimulated in ALS macrophages expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, through activation of cyclooxygenase-2 (COX-2) and caspase-1. The lipid mediator resolvin D1 (RvD1) inhibited IL-6 and TNF-α production in ALS macrophages with 1,100 times greater potency than its parent molecule docosahexaenoic acid. ALS peripheral blood mononuclear cells (PBMCs) showed increased transcription of inflammatory cytokines and chemokines at baseline and after stimulation by aggregated wild-type SOD-1, and these cytokines were down regulated by RvD1. Thus the neurons are impacted by macrophages expressing inflammatory cytokines. RvD1 strongly inhibits in macrophages and PBMCs cytokine transcription but does not inhibit their production in PBMCs. Resolvins offer a new approach to ALS inflammation suppressing.

Published
2012

3. Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling

Author

Mizwicki, M. T., Fiala, M., Magpantay, L., Aziz, N., Sayre, J., Liu, G., Siani, A., Chan, D., Martinez-Maza, O., Chattopadhyay, M., Antonio La Cava, Mizwicki, Mathew T, Fiala, Milan, Magpantay, Larry, Aziz, Najib, Sayre, Jame, Liu, Guanghao, Siani, Avi, Chan, Derrick, Martinez-Maza, Otoniel, Chattopadhyay, Madhuri, and La Cava, Antonio

Subjects
chronic inflammation, amyotrophic lateral sclerosis (ALS), Tocilizumab, IL6 receptor signaling
Abstract

Patients with amyotrophic lateral sclerosis (ALS) have evidence of chronic inflammation demonstrated by infiltration of the gray matter by inflammatory macrophages, IL17A-positive T cells, and mast cells. Increased serum levels of IL6 and IL17A have been detected in sporadic ALS (sALS) patients when compared to healthy controls. Herein we investigate, in peripheral blood mononuclear cells (PBMCs), the baseline transcription of genes associated with inflammation in sALS and control subjects and the impact of the IL6 receptor (IL6R) antibody (tocilizumab) on the transcription and/or secretion of inflammation factors (e.g. cytokines) stimulated by the apo-G37R superoxide dismutase (SOD1) mutant. At baseline, PBMCs of four sALS patients (Group 1) showed significantly increased expression of TLR2 and CD14; ALOX5, PTGS2 and MMP1; IL1α, IL1β, IL6, IL36G, IL8 and TNF; CCL3, CCL20, CXCL2, CXCL3 and CXCL5. In four other sALS patients (Group 2), most of the genes just mentioned were expressed at near control levels and a significant decrease in the expression of PPARG, PPARA, RARG, HDAC4 and KAT2B; IL6R, IL6ST and ADAM17; TNFRSF11A; MGAT2 and MGAT3; PLCG1; CXCL3 were detected. Apo-G37R SOD1 up regulated the transcription of cytokines (e.g. IL1α/β, IL6, IL8, IL36G), chemokines (e.g. CCL20; CXCL3, CXCL5), and enzymes (e.g. PTGS2 and MMP1). In vitro, tocilizumab down regulated the transcription of many inflammatory cytokines, chemokines, enzymes, and receptors, which were up regulated by pathogenic forms of SOD1. Tocilizumab also reduced the secretion of the pro-inflammatory cytokines IL1β, IL6, TNFα, GM-CSF, IFNγ, and IL17A by Group 1 PBMCs. Finally, sALS patients had significantly higher concentrations of IL6, sIL6R and C-reactive protein in the cerebrospinal fluid when compared to AD patients. This pilot study demonstrates that in vitro tocilizumab suppresses many factors that drive inflammation in sALS patients, with possible increased efficacy in Group 1 ALS patients.

Published
2012

4. Synthesis and Study of Triphenylphosphines Functionalized at the 4-Positions through the Nitrogen Atoms in 1,4,7,10-Tetraoxa-13-azacyclopentadecane and the X-ray Structure of the Oxide of the Molecule Substituted at All Three Positions

Author

Mizwicki, M. T., Haddadian, F., Kimmerling, T. S., Muehl, B. S., Sheu, B.-J., Storhoff, B. N., and Huffman, J. C.

Abstract

Hybrid phosphine crown ether ligands have been obtained from PhP(OMe)2 and P(OPh)3 and carbanions generated by low-temperature Li/Br exchange reactions involving 4‘-bromo-N-phenylaza-15-crown-5 and n-butyllithium. The A1 ν(CO) values for the Ni(CO)3L complexes of these phosphines have been found to be 2063.7 and 2060.8 cm-1, for the bis (1b) and tris (1c) crown species, respectively, indicating the significant electron-donating abilities of the nitrogen atoms. Addition of NaSCN salts in dichloromethane causes these frequencies to increase by 2.40 (1b) and 3.70 cm-1 (1c), indicating that the P(III) centers detect the presence of crown-coordinated ions. The oxide of 1c has been prepared and the X-ray structure obtained. A prominent feature of that structure, R&thremacr; symmetry, is that the nitrogen atoms are nearly planar and the ring carbon-to-nitrogen distances are 1.375 Å, features that are also consistent with a significant amount of sp2 C−N double-bond character. The phenyl rings are arranged in a typical propeller shape with torsion angles of 132.4°.

Published
2001

5. Photoprotection by 1alpha,25-dihydroxyvitamin D and analogs: further studies on mechanisms and implications for UV-damage.

Author

Mason RS, Sequeira VB, Dixon KM, Gordon-Thomson C, Pobre K, Dilley A, Mizwicki MT, Norman AW, Feldman D, Halliday GM, and Reeve VE

Subjects
Animals, Cells, Cultured, DNA Damage, DNA Repair, Ergosterol analogs & derivatives, Ergosterol pharmacology, Guanidines pharmacology, Humans, Interleukin-6 metabolism, Keratinocytes cytology, Keratinocytes radiation effects, Mice, Models, Biological, Nitric Oxide Synthase metabolism, Reactive Nitrogen Species, Ultraviolet Rays, Calcitriol analogs & derivatives, Calcitriol pharmacology
Abstract

Ultraviolet (UV) irradiation causes DNA damage in skin cells, immunosuppression and photocarcinogenesis. 1alpha,25-dihydroxyvitamin D3 (1,25D) reduces UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) in human keratinocytes in culture and in mouse and human skin. UV-induced immunosuppression is also reduced in mice by 1,25D, in part due to the reduction in CPD and a reduction in interleukin (IL-6. The cis-locked analog, 1alpha,25-dihydroxylumisterol3 (JN), which has almost no transactivating activity, reduces UV-induced DNA damage, apoptosis and immunosuppression with similar potency to 1,25D, consistent with a non-genomic signalling mechanism. The mechanism of the reduction in DNA damage in the form of CPD is unclear. 1,25D doubles nuclear expression of p53 compared to UV alone, which suggests that 1,25D facilitates DNA repair. Yet expression of a key DNA repair gene, XPG is not affected by 1,25D. Chemical production of CPD has been described. Incubation of keratinocytes with a nitric oxide donor, SNP, induces CPD in the dark. We previously reported that 1,25D reduced UV-induced nitrite in keratinocytes, similar to aminoguanidine, an inhibitor of nitric oxide synthase. A reduction in reactive nitrogen species has been shown to facilitate DNA repair, but in view of these findings may also reduce CPD formation via a novel mechanism., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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