Metal–organic frameworks featuring ligands with open chelating groups are versatile platforms for the preparation of a diverse set of heterogeneous catalysts through postsynthetic metalation. The ...crystalline nature of these materials allows them to be characterized via X-ray diffraction, which provides valuable insight into the structure of the metal sites that facilitate catalysis. A highly porous and thermally robust zirconium-based metal–organic framework, Zr6O4(OH)4(bpydc)6 (bpydc2– = 2,2′-bipyridne-5,5′-dicarboxylate), bears open bipyridine sites that readily react with a variety of solution- and gas-phase metal sources to form the corresponding metalated frameworks. Remarkably, Zr6O4(OH)4(bpydc)6 undergoes a single-crystal-to-single-crystal transformation upon metalation that involves a change in space group from Fm3̅m to Pa3̅. This structural transformation leads to an ordering of the metalated linkers within the framework, allowing structural characterization of the resulting metal complexes. Furthermore, Zr6O4(OH)4(bpydc)6 yields an active heterogeneous catalyst for arene C–H borylation when metalated with Ir(COD)2BF4 (COD = 1,5-cyclooctadiene). These results highlight the unique potential of metal–organic frameworks as a class of heterogeneous catalysts that allow unparalleled structural characterization and control over their active sites.
Although gas adsorption properties of extended three-dimensional metal–organic materials have been widely studied, they remain relatively unexplored in porous molecular systems. This is particularly ...the case for porous coordination cages for which surface areas are typically not reported. Herein, we report the synthesis, characterization, activation, and gas adsorption properties of a family of carbazole-based cages. The chromium analog displays a coordination cage record BET (Brunauer−Emmett−Teller) surface area of 1235 m2/g. With precise synthesis and activation procedures, two previously reported cages similarly display high surface areas. The materials exhibit high methane adsorption capacities at 65 bar with the chromium(II) cage displaying CH4 capacities of 194 cm3/g and 148 cm3/cm3. This high uptake is a result of optimal pore design, which was confirmed via powder neutron diffraction experiments.
Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A ...relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3- than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepcidin expression. Both Alk2 and Alk3 were required for induction of hepcidin gene expression by BMP2 in cultured hepatocytes or by iron challenge in vivo. These observations demonstrate that one type I BMP receptor, Alk3, is critically responsible for basal hepcidin expression, whereas 2 type I BMP receptors, Alk2 and Alk3, are required for regulation of hepcidin gene expression in response to iron and BMP signaling.
Zirconium-based coordination cages have received considerable recent attention as a result of their structural tunability and amenability to postsynthetic modification. Although these structures have ...adopted tetrahedral (4-vertex) or cigar (2-vertex) geometries depending on the shape and nuclearity of the ligand used in their assembly, their structures have not previously been shown to be either tunable or dynamic. Here, we examine the speciation of a series of zirconium-based cages where the geometry and nuclearity of the product cage can be tuned via judicious functionalization of dicarboxylate ligands. We further show that many of these materials exist as both cage structures in solution or the solid state. With appropriate solvent exchange and activation conditions, the cigar structures can display Brunauer–Emmett–Teller (BET) surface areas as high as 123 m2/g. As a result of their expanded pore structures, the tetrahedra display significantly increased BET surface areas approaching 700 m2/g. These results show that by appropriate ligand functionalization the structures of zirconium-based cages can be modified to tune their phase and surface area. Finally, the isolation of phase-pure cages allows for the utilization of anion metathesis reactions to tune their solubility.
The adoption of pulmonary vaccines to advantageously provide superior local mucosal protection against aerosolized pathogens has been faced with numerous logistical and practical challenges. One of ...these persistent challenges is the lack of effective vaccine adjuvants that could be well tolerated through the inhaled route of administration. Despite its widespread use as a vaccine adjuvant, aluminum salts (alum) are not well tolerated in the lung. To address this issue, we evaluated the use of porous aluminum (Al)-based metal-organic framework (MOF) nanoparticles (NPs) as inhalable adjuvants. We evaluate a suite of Al-based MOF NPs alongside alum including DUT-4, DUT-5, MIL-53 (Al), and MIL-101-NH
(Al). As synthesized, MOF NPs ranged between ~ 200 nm and 1 µm in diameter, with the larger diameter MOFs matching those of commercial alum. In vitro examination of co-stimulatory markers revealed that the Al-based MOF NPs activated antigen presenting cells more effectively than alum. Similar results were found during in vivo immunizations utilizing ovalbumin (OVA) as a model antigen, resulting in robust mucosal humoral responses for all Al MOFs tested. In particular, DUT-5 was able to elicit mucosal OVA-specific IgA antibodies that were significantly higher than the other MOFs or alum dosed at the same NP mass. DUT-5 also was uniquely able to generate detectable IgG2a titers, indicative of a cellular immune response and also had superior performance relative to alum at equivalent Al dosed in a reduced dosage vaccination study. All MOF NPs tested were generally well-tolerated in the lung, with only acute levels of cellular infiltrates detected and no Al accumulation; Al content was largely cleared from the lung and other organs at 28 days despite the two-dose regime. Furthermore, all MOF NPs exhibited mass median aerodynamic diameters (MMADs) of ~ 1.5-2.5 µm when dispersed from a generic dry powder inhaler, ideal for efficient lung deposition. While further work is needed, these results demonstrate the great potential for use of Al-based MOFs for pulmonary vaccination as novel inhalable adjuvants.
Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that ...involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice.
MGP-deficient mice (MGP(-/-)) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP(-/-) mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP(-/-) mice survived longer than vehicle-treated MGP(-/-) mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP(-/-) and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP(-/-) aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189.
Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP(-/-) mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE—The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain- and loss-of-function experiments in mice have ...supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.
METHODS AND RESULTS—We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR) mice. LDLR mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.
CONCLUSION—These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' ...untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
The mRNA processing body (P-body) is a cellular structure that regulates gene expression by degrading cytoplasmic mRNA. The objective of this study was to identify and characterize novel components ...of the mammalian P-body. Approximately 5% of patients with the autoimmune disease primary biliary cirrhosis have antibodies directed against this structure. Serum from one of these patients was used to identify a cDNA encoding Ge-1, a 1,401-amino-acid protein. Ge-1 contains an N-terminal WD 40 motif and C-terminal domains characterized by a repeating psi(X(2-3)) motif. Ge-1 co-localized with previously identified P-body components, including proteins involved in mRNA decapping (DCP1a and DCP2) and the autoantigen GW 182. The Ge-1 C-terminal domain was necessary and sufficient to target the protein to P-bodies. Following exposure of cells to oxidative stress, Ge-1-containing P-bodies were found adjacent to TIA-containing stress granules. During the recovery period, TIA returned to the nucleus while Ge-1-containing P-bodies localized to the perinuclear region. siRNA-mediated knock-down of Ge-1 resulted in loss of P-bodies containing Ge-1, DCP1a, and DCP2. In contrast, Ge-1-containing P-bodies persisted despite knock-down of DCP2. Taken together, the results of this study show that Ge-1 is a central component of P-bodies and suggest that Ge-1 may act prior to the 5(')-decapping step in mRNA degradation.
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