Bostonia: The Boston University Alumni Magazine. Volume 12

Founded in 1900, Bostonia magazine is Boston University’s main alumni publication

Structures of Ruthenium-modified Pseudomonas aeruginosa Azurin and [Ru(2,2’-bipyridine)_2(imidazole)_2)]SO_4•10H_2O

The crystal structure of Ru(2,2'-bipyridine)_2(imidazole)(His83)azurin (RuAz) has been determined to 2.3 Å ¬resolution by X-ray crystallography. The spectroscopic and thermodynamic properties of both the native protein and [Ru(2,2'-bipyridine)_2(imidazole)_2]^(2+) are maintained in the modified protein. Dark-green RuAz crystals grown from PEG 4000, LiNO_3, CuCl_2 and Tris buffer are monoclinic, belong to the space group C2 and have cell parameters a = 100.6, b = 35.4, c = 74.7 Å and β = 106.5°. In addition, [Ru(2,2'-bipyridine)_2(imidazole)_2]SO_4•10H_2O was synthesized, crystallized and structurally characterized by X-ray crystallography. Red-brown crystals of this complex are monoclinic, space group P2_1/n, unit-cell parameters a = 13.230 (2), b = 18.197 (4), c = 16.126 (4) Å, β = 108.65 (2)°. Stereochemical parameters for the refinement of Ru(2,2'-bipyridine)_2(imidazole)(His83) were taken from the atomic coordinates of [Ru(2,2'-bipyridine)_2(imidazole)_2]^(2+). The structure of RuAz confirms that His83 is the only site of chemical modification and that the native azurin structure is not perturbed significantly by the ruthenium label

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results: We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system

Linear-Chain Structures of Platinum(II) Diimine Complexes

The structures of three linear-chain platinum(II) diimine complexes have been determined [Pt···Pt, Å]:  Pt(bpm)Cl_2·0.5(nmp) (3) [3.411(1), 3.371(1)], Pt(phen)(CN)_2 (6) [3.338(1), 3.332(1)], and Pt(bpy)(NCS)_2 (7) [3.299(2)] (bpm = 2,2‘-bipyrimidine, phen = 1,10-phenanthroline, bpy = 2,2‘-bipyridine, nmp = 1-methyl-2-pyrrolidinone). The Pt···Pt distances in these and in seven related compounds range from 3.24 to 3.49 Å. While we find evidence of interligand interactions influencing these structures, the Pt···Pt bonds are the most important of the stacking forces. The metal−metal distances are generally consistent with an electronic structural model in which σ-donor/π-acceptor ligands strengthen Pt···Pt bonding interactions (for example, the Pt···Pt distances in 3 are 0.04 and 0.08 Å shorter than in the bpy analogue). We have also found that the yellow form of Pt(dmbpy)(NCO)_2 (1b) (4,4‘-dimethyl-2,2‘-bipyridine) has a columnar structure; however, in contrast to the linear-chain form (1), which is orange, the Pt atoms are well separated (>4.9 Å). Interestingly, the yellow form is 7% denser than the orange form; this result is consistent with the concept that directed intermolecular interactions give rise to lower density polymorphs. Crystal data:  (3) monoclinic, C2/m (No. 12), a = 12.668(4) Å, b = 15.618(6) Å, c = 6.704(3) Å, β = 93.43(3)°, Z = 4; (6) orthorhombic, Pbca (No. 61), a = 38.731(13) Å, b = 18.569(3) Å, c = 6.628(1) Å, Z = 16; (7) orthorhombic, Pbcm (No. 57), a = 10.349(3) Å, b = 19.927(5) Å, c = 6.572(3) Å, Z = 4; (1b) monoclinic, C2/c (No. 15), a = 17.313(4) Å, b = 12.263(3) Å, c = 14.291(4) Å, β = 114.00(2)°, Z = 8

A Bis(pyrazolyl)(bipyridyl)platinum Complex

(4,4' -Dimethyl-2,2'-bipyridyl)bis(3,5-dimethylpyrazolium) platinum(II) 0.5-tetrahydrofuran solvate monohydrate, [Pt(C_5H_7N_2MC_(12)H_(12)-N2)].0.5C_4H_80.H_2O, M_r = 623.65, monoclinic, P2_1/n, ɑ = 8.625 (2), b = 20.593 (8), c = 14.451(4) Å, β = 90.32 (2)°, v = 2566.7 (14) Å^3, Z = 4, D_x = 1.61 g cm^(-3), λ(Mo Kɑ)= 0.71073 Å, μ = 55.50 cm^(-1), F(000) = 1232, room temperature, R = 0.0387 for 2874 reflections with F_o^2 > 3σ(F_o^2). The square-planar Pt complex has normal Pt-N(bipyridyl) bonds [2.009 (8) Å] and slightly short Pt-N(pyrazolyl) bonds [1.983 (7) Å]. The ligand molecules have normal distances and angles; the planes of the pyrazolyl ligands are twisted by about 60° to the bipyridyl-Pt plane, with the closest contacts between the pyrazolyls being -3.3 Å (Cl4···N5 and C19···N3)

The red form of [Re(phen)(CO)_3(H_2O)]CF_3SO_3•H_2O

The coordination geometry of the cations in the red form of aquatricarbonyl(1,10-phenanthroline-N, N')rhenium(I) trifluoromethanesulfonate hydrate, [Re(C_(12)H_8N_2)(CO)_3- (H_2O)]CF_3SO_3•H_2O, is approximately octahedral, with a facial arrangement of the linearly coordinated carbonyl ligands. The phenanthroline (phen) ligands interleave to form a columnar r-stacked structure