Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Enzymatic mechanisms of biological magnetic sensitivity.

Primary biological magnetoreceptors in living organisms is one of the main research problems in magnetobiology. Intracellular enzymatic reactions accompanied by electron transfer have been shown to be receptors of magnetic fields, and spin-dependent ion-radical processes can be a universal mechanism of biological magnetosensitivity. Magnetic interactions in intermediate ion-radical pairs, such as Zeeman and hyperfine (HFI) interactions, in accordance with proposed strict quantum mechanical theory, can determine magnetic-field dependencies of reactions that produce biologically important molecules needed for cell growth. Hyperfine interactions of electrons with nuclear magnetic moments of magnetic isotopes can explain the most important part of biomagnetic sensitivities in a weak magnetic field comparable to the Earth's magnetic field. The theoretical results mean that magnetic-field dependencies of enzymatic reaction rates in a weak magnetic field that can be independent of HFI constant a, if H << a, and are determined by the rate constant of chemical transformations in the enzyme active site. Both Zeeman and HFI interactions predict strong magnetic-field dependence in weak magnetic fields and magnetic-field independence of enzymatic reaction rate constants in strong magnetic fields. The theoretical results can explain the magnetic sensitivity of E. coli cell and demonstrate that intracellular enzymatic reactions are primary magnetoreceptors in living organisms. Bioelectromagnetics. 38:511-521, 2017. © 2017 Wiley Periodicals, Inc.

Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis.

OBJECTIVES: To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death. METHODS: The effects of geldanamycin on TNFα-induced proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated. RESULTS: Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. CONCLUSIONS: GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor. Key Points • Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A. • GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. • Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.

Magnetic field effects on copper metal deposition from copper sulfate aqueous solution.

Effects of a magnetic field (≤0.5 T) on electroless copper metal deposition from the reaction of a copper sulfate aqueous solution and a zinc thin plate were examined in this study. In a zero field, a smooth copper thin film grew steadily on the plate. In a 0.38 T field, a smooth copper thin film deposited on a zinc plate within about 1 min. Then, it peeled off repeatedly from the plate. The yield of consumed copper ions increased about 2.1 times compared with that in a zero field. Mechanism of this magnetic field effect was discussed in terms of Lorentz force- and magnetic force-induced convection and local volta cell formation.