An unexpected all-metal aromatic tetranuclear silver cluster in human copper chaperone Atox1.

Metal clusters, such as iron-sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins. Herein we report the formation and crystal structure of a planar square tetranuclear silver cluster when silver ions were mixed with human copper chaperone Atox1. Quantum chemical studies reveal that two Ag 5s1 electrons in the tetranuclear silver cluster fully occupy the one bonding molecular orbital, with the assumption that this Ag4 cluster is Ag4 2+, leading to extensive electron delocalization over the planar square and significant stabilization. This bonding pattern of the tetranuclear silver cluster represents an aromatic all-metal structure that follows a 4n + 2 electron counting rule (n = 0). This is the first time an all-metal aromatic silver cluster was observed in a protein.

Icariin Ameliorates Lower Back Pain in Rats via Suppressing the Secretion of Cytokine-Induced Neutrophil Chemoatractant-1.

PURPOSE: To investigate whether icariin (ICA), a well-known medicine extracted from the stem and leaf of Epimedium brevicornum Maxim, had analgesic effect on lower back pain (LBP) in rats. METHODS: In a puncture-induced LBP rat model, the severity of LBP was quantified using the paw/foot withdrawal threshold method after intragastric administration of ICA at a dosage of 50 mg/kg/d or 100 mg/kg/d. The pain-related peptides of substance P (SP) and calcitonin gene-related peptide (CGRP) were also measured in intervertebral disc (IVD) tissue using RT-PCR after ICA treatment. In addition, the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) in IVD was quantified using RT-PCR and ELISA examination. RESULTS: ICA treatment resulted in a significant amelioration of mechanical allodynia in a dose-response manner, and the analgesic effect could last for two weeks even during the washout period. More importantly, the mechanism of analgesic pharmacological effect in ICA was to suppress the upregulated CINC-1, the homolog of IL-8 in rats, which is a crucial proalgesic factor contributing to LBP, in IVDs. CONCLUSION: ICA is a novel herbal extract to relieve LBP, and it may be a promising alternative pain killer in the future.

Computation Revealed Mechanistic Complexity of Low-Valent Cobalt-Catalyzed Markovnikov Hydrosilylation.

We explored the mechanism of Markovnikov-selective hydrosilylation of phenylacetylene catalyzed by N-N-N Pincer-cobalt complex with density functional theory (DFT) calculations. In contrast to the previously proposed Co(I) mechanism, computational results suggest a Co(0) pathway, which is further supported by experimental studies. At the same time, our study reveals unexpected complexity in terms of the origin of regioselectivity. First, different orientations between the phenyl group in the substrate and the ligand plane lead to two possible transition states responsible for the branched product. However, the favored one varies according to ligand substitution pattern. Second, both entropy and solvation effects (rather than the conventional approach that considers electronic energies) have to be considered to explain regioselectivity, where the dominant factor also varies from case to case. Despite this complexity, computations predict a general overall ligand structure-regioselectivity relationship. In addition to increasing steric hindrance, introduction of an electron-withdrawing group to the ligands will also increase regioselectivity, which unveils a new dimension of ligand design.

Dose reduction of recombinant human tumor necrosis factor inhibitors (etanercept) can be effective in ankylosing spondylitis patients with synovitis of the hip in a Chinese population.

Ankylosing spondylitis (AS) is an immune-mediated inflammatory arthritis and enthesitis involving the spine and peripheral joints. In recent years, specific antagonist of tumor necrosis factor (anti-TNFα, etanercept) 50 mg weekly therapy has rapidly gained popularity for the treatment of AS. However, the dose of etanercept has not been determined in Asian, particularly Chinese populations. The purpose of the study was to evaluate the efficacy and safety of dose reduction of etanercept (50 mg/week in 4 weeks followed by 25 mg/week in 8 weeks) in the treatment of AS with synovitis of the hip, as against the conventional dose (50 mg/week in 12 weeks) in a Chinese population. Forty-three Chinese AS patients with synovitis of the hip were involved in this study. Seventeen of them were randomized to receive conventional dose of etanercept treatment and 26 were given a dose reduction regimen for 12 weeks. The primary efficacy endpoint was disease activity of response for AS at week 12, including Bath AS Disease Activity Index (BASDAI), the serum erythrocyte sediment rate (ESR), C-reactive protein (CRP), and assessment of synovitis of the hip by ultrasonography. At 12 weeks, all of the patients had responses to some extent and the efficacy variables improved significantly over time, but not between treatment groups. Nine patients experienced at least one adverse event (generally, infections and injection site reactions), most of them mild or moderate. In sum, the dose reduction of etanercept regimen in the 12-week AS treatment was confirmed as a safe and effective therapy as the conventional dose was given.