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Abstract Toll-like receptors (TLRs) play a crucial role in the induction of innate immune response against bacterial and viral infections. TLRs induce downstream signaling via MyD88- and TRIF-dependent pathways. Cardamonin is a naturally occurring chalcone from Alpinia species exhibiting anti-inflammatory effects. However, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of cardamonin in TLR signaling pathways. Cardamonin inhibited NF-κB activation as well as COX-2 expression induced by TLR agonists. Cardamonin inhibited the activation of IRF3 and the expression of interferon-inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Cardamonin also inhibited ligand-independent NF-κB activation overexpressed by MyD88, IKKβ, or p65 and IRF3 activation overexpressed by TRIF, TBK1, or IRF3. However, cardamonin had no effect on TBK1 kinase activity in vitro. These results suggest that cardamonin modulates both the MyD88- and TRIF-dependent pathways of TLRs and represents a potentially new anti-inflammatory candidate. Highlights • Toll-like receptors (TLR) play a significant role in the induction of innate immune responses. • Cardamonin is a naturally occurring chalcone from Alpinia species exhibiting anti-inflammatory effects. • Cardamonin suppressed the activation of IRF3 and the expression of IP-10 induced by TLR3 or TLR4 agonists. • These results demonstrate that cardamonin is a potential therapeutic candidate in the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Toll‐like receptors (TLRs) induce an innate immune system. In general, there are two main pathways in TLRs: the myeloid differentiation primary response protein 88 (MyD88)‐dependent and toll‐interleukin‐1 receptor domain‐containing adapter‐inducing interferon‐β (TRIF)‐dependent pathways. In this study, it has been investigated whether eicosapentaenoic acid (EPA), a polyunsaturated fatty acid (PUFA), and arachidic acid (ACA), a saturated fatty acid (SFA), can modulate the TLR signaling pathways. EPA suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of Interferon gamma‐induced protein (IP‐10) induced by Toll‐like receptor 3 (TLR3) or TLR4 agonists by targeting TANK‐binding kinase 1 (TBK1); however, ACA did not. These results demonstrate that EPA inhibits the TRIF‐dependent signaling in the TLR3 and TLR4 pathways. The results raise the possibility that certain dietary PUFAs can modulate TLR‐derived signaling and inflammatory target gene expression and can alter the susceptibility to microbial infection and chronic inflammatory diseases. Practical application: Eicosapentaenoic acid (EPA) is a bioactive lipid that modulates inflammation and immunity. TLRs play a central role as initiators of the innate immune responses. EPA regulates TRIF‐dependent pathways of TLRs by targeting TBK1. EPA may be a useful strategy to understand the mechanism of antiinflammatory activities. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata , exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF-κB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro . These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play critical roles in the induction of immune and inflammatory responses by recognizing invading microbial pathogens. One of the most important proteins for inflammatory responses is inducible nitric oxide synthase (iNOS). The dysregulated iNOS activation play important roles in the development of certain inflammatory diseases. The present study investigated the effects of arachidic acid (ACA), which is a saturated fatty acid (SFA), and eicosapentanoic acid (EPA), which is polyunsaturated fatty acid (PUFA), on inflammation by modulating NF-κB activation and iNOS expression induced by TLRs agonists in murine macrophages. EPA suppressed NF-κB activation and iNOS expression induced by a lipopolysaccharide, macrophage-activating lipopeptide 2-kDa, and polyriboinosinic polyribocytidylic acid, but ACA did not. These results suggested that EPA can modulate TLR signaling pathways and subsequent chronic inflammatory responses, but ACA did not mediate these effects. All the results suggest that EPA is a promising novel agent for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Rock fragmentation plays a critical role in large-scale quarrying operations because of its direct effects on the costs of drilling, blasting, secondary blasting and crushing. In this aspect, it is essential to consider rock fragmentation in blasting design. The optimum blasting pattern to excavate a quarry efficiently and economically can be determined based on the minimum production cost which is generally estimated according to rock fragmentation. By comparing various prediction models, it can be ascertained that the results obtained from the Kuz–Ram model relatively coincide with the results from field measurements. This model uses the rock factor to signify conditions of rock mass such as block size, rock jointing, strength, and others. The rock factor is estimated from geologic data such as block size of rock mass, rock jointing, strength, and others, and its 3-D spatial distribution was predicted by a sequential indicator simulation (SIS) technique. The entire quarry in question was classified into three types of rock mass and an optimum blasting pattern was proposed for each type based on the 3-D spatial distribution of the rock factor. It can, therefore, be concluded that it is possible to design a blasting pattern to achieve a minimum production cost in large-scale quarrying operations by predicting rock fragmentation based on the 3-D spatial distribution of the rock factor. [Copyright &y& Elsevier]

Inflammation is a pathological process that is known to be involved in numerous diseases. Microbial infection or tissue injury activates inflammatory responses, resulting in the induction of proinflammatory proteins including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).Aster yomenais used in traditional Korean remedies to treat cough, asthma, and insect bites. Here, we investigated the effects ofA. yomenaextract (EAY) on the expression of COX-2 and iNOS induced by LPS. EAY inhibited NF-κB activation and IκBα degradation induced by LPS. EAY suppressed LPS-induced COX-2 and iNOS expression which are the target genes regulated through NF-κB activation in macrophages. EAY also suppressed LPS-induced nitrite production. These results suggest that EAY has the potential to be developed as a potent anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play significant roles in recognizing the pathogen-associated molecular patterns that induce innate immunity, and subsequently, acquired immunity. In general, TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways, which lead to the activation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP) has been previously synthesized in our laboratory. To evaluate the therapeutic potential of MNP, its effect on signal transduction via the TLR signaling pathways was examined. MNP was shown to inhibit the activation of NF-κB and IRF3 induced by TLR agonists, as well as to inhibit the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. MNP also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the MyD88- or TRIF-dependent signaling pathways. These results suggest that MNP can modulate MyD88- and TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression. [ABSTRACT FROM AUTHOR]

We present calculations for histidine–(H 2 O) n ( n = 0–6) to examine the effects of micro-hydrating water molecules on the relative stability of the zwitterionic vs. canonical forms of histidine. We calculate the structures and Gibbs free energies of the conformers at wB97XD/6-311++G(d,p) level of theory. We find that six water molecules are required to produce the thermodynamically stable histidine zwitterion. By calculating the barriers of canonical ↔ zwitterionic transformation, we predict that both the most stable canonical and zwitterionic forms of histidine–(H 2 O) 6 may be observed in low temperature gas phase environment. [ABSTRACT FROM AUTHOR]