We report three new porphyrin-based, pillared paddle-wheel homologous series: porphyrin paddle-wheel frameworks PPF-3, -4, and -5. These compounds are assembled from free base or palladium tetrakis(4-carboxyphenyl)porphine, M(NO(3))(2) (M = Co and Zn), and 4,4'-bipyridine via solvothermal reactions. The resulting solids exhibit 3D metal-organic frameworks, where 2D layers are pillared by bipyridine with three different packing arrangements.
Background Previous studies indicate that transcranial direct current stimulation (tDCS) with anode over motor cortex (M1) and cathode over contralateral supraorbital region (SO) may be effective in reducing pain, but these studies are limited in number and have not focused on older adults with osteoarthritis (OA). Objective To evaluate the preliminary efficacy and safety of M1-SO applied tDCS on clinical pain severity and mobility performance in adults with knee OA pain. Methods Forty 50- to 70-year-old community-dwelling participants with knee OA were randomly assigned to receive five daily sessions of 2 mA tDCS for 20 min (n = 20) or sham tDCS (n = 20). We measured clinical pain severity via Numeric Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Short-Form McGill Pain Questionnaire. In addition, we measured mobility performance using the 6-Minute Walk Test and the Short Physical Performance Battery. Moreover, we obtained a sensation/safety questionnaire and measured cognition changes using the PROMIS-Applied Cognition-Abilities-Short Form 8a. Results Active tDCS over M1-SO significantly reduced Numeric Rating Scale of pain compared to sham tDCS after completion of the five daily sessions, and remained up to three weeks. No other measures were significantly different from sham. Participants tolerated tDCS over M1-SO well without serious adverse effects or cognition changes. Conclusion Although not consistent in all pain measurements, our findings demonstrate promising clinical efficacy for reduction in pain perception for older adults with knee OA. Trial registration ClinicalTrials.gov Identifier NCT02512393.
This paper describes the electroactuation of microcantilevers coated on one side with cationic polyelectrolyte brushes. We observed very strong cantilever deflection by alternating the potential on the cantilever between +0.5 and -0.5 V at frequencies up to 0.25 Hz. The actuation resulted from significant increases in the expansive stresses in the polymer brush layer at both negative and positive potentials. However, the deflection at negative bias was significantly larger. We have developed a theoretical framework that correlates conformational changes of the polymer chains in the brush layer with the reorganization of ions due to the potential bias. The model predicts a strong increase in the polymer volume fraction, close to the interface, which results in large expansive stresses that bend the cantilever at negative potentials. The model also predicts that the actuation responds much stronger to negative potentials than positive potentials, as observed in the experiments.
Although a range of biological and pharmacological activities of melatonin have been reported, little is known about its potential anti-inflammatory efficacy in periodontal disease. In this study, we investigated the effects of melatonin on the production of inflammatory mediators by murine macrophages stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a major cause of inflammatory reactions in the periodontium, and sought to determine the underlying mechanisms of action. Melatonin suppressed the production of nitric oxide (NO) and interleukin-6 (IL-6) at both gene transcription and translation levels in P. intermedia LPS-activated RAW264.7 cells. P. intermedia LPS-induced NF-κB-dependent luciferase activity was significantly inhibited by melatonin. Melatonin did not reduce NF-κB transcriptional activity at the level of IκB-α degradation. Melatonin blocked NF-κB signaling through the inhibition of nuclear translocation and DNA-binding activity of NF-κB p50 subunit and suppressed STAT1 signaling. Although further research is required to clarify the detailed mechanism of action, we conclude that melatonin may contribute to blockade of the host-destructive processes mediated by these two proinflammatory mediators and could be a highly efficient modulator of host response in the treatment of inflammatory periodontal disease.
A number of a disintegrin and metalloprotease (ADAM) family members are expressed in mammalian male reproductive organs such as testis and epididymis. These reproductive ADAMs are divided phylogenically into three major groups: ADAMs 1, 4, 6, 20, 21, 24, 25, 26, 29, 30, and 34 (the first group); ADAMs 2, 3, 5, 27, and 32 (the second group); and ADAMs 7 and 28 (the third group). Previous mouse knockout studies indicate that ADAM1, ADAM2, and ADAM3 have intricate expressional relationships, playing critical roles in fertilization. In the present study, we analyzed processing, biochemical characteristics, localization, and expressional relationship of the previously-unexplored, second-group ADAMs (ADAM5, ADAM27, and ADAM32). We found that all of the three ADAMs are made as precursors in the testis and processed during epididymal maturation, and that ADAM5 and ADAM32, but not ADAM27, are located on the sperm surface. Using sperm from Adam2(-/-) and Adam3(-/-) mice, we found that, among the three ADAMs, the level of ADAM5 is modestly and severely reduced in Adam3 and Adam2 knockout sperm, respectively. Further, we analyzed ADAM7, an epididymis-derived sperm surface ADAM from the separate phylogenetic group, in the knockout sperm. We found that the level of ADAM7 is also significantly reduced in both Adam2 and Adam3-null sperm. Taken together, our results suggest a novel expressional relationship of ADAM5 and ADAM7 with ADAM2 and ADAM3, which play critical roles in fertilization.
Xanthine oxidase is a molybdenum-containing enzyme that catalyzes the hydroxylation of xanthine and a wide variety of other aromatic heterocycles. In the course of the reaction with xanthine and substrates such as 2-hydroxy-6-methylpurine (HMP), the enzyme gives rise to a Mo(V) EPR signal, denoted "very rapid", that arises from an authentic catalytic intermediate. The two alternative catalytic mechanisms proposed for this enzyme differ critically in whether the distance between Mo and C8 of the purine nucleus in this intermediate is short enough to admit a direct bonding interaction. To examine this distance, we have performed 13C ENDOR measurements of the "very rapid" EPR signal generated by xanthine oxidase during reaction with 13C8-HMP. The resulting (13)C8 hyperfine tensor, A = [10.2(1), 7.0(1), 6.5(1)] MHz, is discussed in the framework of a detailed consideration of factors involved in extracting metrical parameters from an anisotropic hyperfine interaction composed of contributions from multiple sources, in particular, the effect of the local contributions from spin density on (13)C8. The analysis presented here gives a Mo...C distance whose value is expected to be ca. 2.7-2.9 A in the "very rapid" intermediates formed with both xanthine and HMP, consistent with plausible bond lengths for a Mo-O-C8 fragment where C8 is a trigonal-planar aromatic carbon. The difference from earlier conclusions is explained. The data thus do not support the existence of a direct Mo-C bond in the signal-giving species. This conclusion supports a mechanism that does not involve such an interaction and which begins with base-assisted nucleophilic attack of the Mo(VI)-OH group on the C-8 of substrate, with concomitant hydride transfer to the Mo=S group to give Mo(IV)-SH; the EPR-active "very rapid" species then forms by one-electron oxidation and deprotonation to yield the EPR-detectable Mo(V)OS(OR) species. We further discuss the complexities and limitations of the semiempirical method used to arrive at these conclusions.
Competition for cellular iron (Fe) is a vital component of the interaction between host and pathogen. Most bacteria have an obligate requirement for Fe to sustain infection, growth, and survival in host. To obtain iron required for growth, many bacteria secrete iron chelators (siderophores). This study was undertaken to test whether a bacterial siderophore, deferoxamine (DFO), could trigger inflammatory signals in human intestinal epithelial cells as a single stimulus. Incubation of human intestinal epithelial HT-29 cells with DFO increased the expression of IL-8 mRNA, as well as the release of IL-8 protein. The signal transduction study revealed that both p38 and extracellular signal-regulated kinase-1/2 were significantly activated in response to DFO. Accordingly, the selective inhibitors for both kinases, either alone or in combination, completely abolished DFO-induced IL-8 secretion, indicating an importance of mitogen-activated protein kinases pathway. These proinflammatory effects of DFO were, in large part, mediated by activation of Na+/H+ exchangers, because selective blockade of Na+/H+ exchangers prevented the DFO-induced IL-8 production. Interestingly, however, DFO neither induced NF-κB activation by itself nor affected IL-1β- or TNF-α-mediated NF-κB activation, suggesting a NF-κB-independent mechanism in DFO-induced IL-8 production. Global gene expression profiling revealed that DFO significantly up-regulates inflammation-related genes including proinflammatory genes, and that many of those genes are down-modulated by the selective mitogen-activated protein kinase inhibitors. Collectively, these results demonstrate that, in addition to bacterial products or cell wall components, direct chelation of host Fe by infected bacteria may also contribute to the evocation of host inflammatory responses.
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