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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 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]

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]

Diesel exhaust particles (DEPs) are a major cause of cancer progression as well as a variety of acute and chronic diseases. It is well-known that programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can induce immune escape in tumor cells. However, the function of PD-L1 in bronchial epithelial cells or how PD-L1 relates to cellular oxidation under DEPs-mediated oxidative stress is not well known. In this study, we investigated how PD-L1 affected DEPs-induced oxidative stress and cytotoxicity in human bronchial epithelial (HBE) cells, Beas-2B. DEPs not only induced intracellular reactive oxygen species (ROS) production, but also increased PD-L1 expression in HBE cells. Beas-2B cells overexpressing PD-L1 showed higher levels of ROS production, DNA damage, and apoptosis after DEPs treatment compared to control cells. In particular, the expression of an antioxidant enzyme heme-oxygenase-1 (HO-1) and nuclear translocation and transcriptional activity of Nrf2, a major regulator of HO-1, were lower in Beas-2B overexpressing PD-L1 cells than in control cells. DEPs-induced ROS generation, DNA damage and apoptosis in Beas-2B cells overexpressing PD-L1 were significantly restored by overexpressing HO-1. Collectively, our results suggest that DEPs can increase the expression of PD-L1 in HBE cells and that overexpressing PD-L1 might eventually promote DEPs-induced oxidative DNA damage and apoptosis. [Display omitted] • DEPs increase PD-L1 expression in human bronchial epithelial cells. • Beas-2B-PD-L1 cells show accelerated cytotoxicity after DEPs exposure. • Antioxidant systems regulated by Nrf2 are suppressed in Beas-2B-PD-L1 cells. • DEPs-induced cytotoxicity is restored by HO-1 overexpression in Beas-2B-PD-L1 cells. [ABSTRACT FROM AUTHOR]

Sauchinone, a lignan isolated from Saururus chinenesis, is known to exhibit anti-inflammatory and anti-oxidant effects. Recently, sauchinone has been reported to inhibit the growth of various cancer cells, but its effects on breast cancer cells remain poorly understood. In the present study, we investigated the effects of sauchinone on the growth of breast cancer cells along with the underlying molecular mechanisms. Our results show that sauchinone treatment markedly inhibited the proliferation, migration, and invasion of breast cancer cells. Sauchinone reduced the phosphorylation of Akt, ERK, and CREB increased by transforming growth factor-β (TGF-β). In particular, sauchinone treatment suppressed the expression of matrix metalloproteinase (MMP)-13 (MMP13) by regulating the Akt-CREB signaling pathway. Sauchinone was less effective in inhibiting cell migration in Mmp13-knockdown cells than in control cells, suggesting that MMP13 may be a novel target for sauchinone. Our study suggests that sauchinone inhibits the growth of breast cancer cells by attenuating the Akt-CREB-MMP13 pathway. In addition, the targeted inhibition of MMP13 by sauchinone represents a promising approach for the treatment of breast cancer., (© 2021 The Author(s).)

Toll-like receptors (TLRs) are pattern recognition receptors that recognize molecular structures derived from microbes and initiate innate immunity. TLRs have two downstream signaling pathways, the MyD88- and TRIF-dependent pathways. Dysregulated activation of TLRs is closely linked to increased risk of many chronic diseases. Previously, we synthesized fumaryl pyrrolidinone, (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1- yl)-2-butenoate (IPOP), which contains a fumaric acid isopropyl ester and pyrrolidinone, and demonstrated that it inhibits the activation of nuclear factor kappa B by inhibiting the MyD88-dependent pathway of TLRs. However, the effect of IPOP on the TRIF-dependent pathway remains unknown. Here, we report the effect of IPOP on signal transduction via the TRIF-dependent pathway of TLRs. IPOP inhibited lipopolysaccharide- or polyinosinic-polycytidylic acid-induced interferon regulatory factor 3 activation, as well as interferon- inducible genes such as interferon inducible protein-10. These results suggest that IPOP can modulate the TRIF-dependent signaling pathway of TLRs, leading to decreased inflammatory gene expression.

Toll-like receptors (TLRs) are primary sensors that detect a wide variety of microbial components involving induction of innate immune responses. After recognition of microbial components, TLRs trigger the activation of myeloid differential factor 88 (MyD88) and Toll-interleukin-1 (IL-1) receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream signaling pathways. 6-Shoagol, an active ingredient of ginger, inhibits the MyD88-dependent signaling pathway by inhibiting inhibitor-kappaB kinase activity. Inhibitor-kappaB kinase is a key kinase in nuclear factor kappaB (NF-kappaB) activation. However, it is not known whether 6-shogaol inhibits the TRIF-dependent signaling pathway. Our goal was to identify the molecular target of 6-shogaol in the TRIF-dependent pathway of TLRs. 6-Shogaol inhibited the activation of interferon-regulatory factor 3 (IRF3) induced by lipopolysaccharide (LPS) and by polyriboinosinic polyribocytidylic acid (poly[I:C]), overexpression of TRIF, TANK-binding kinase1 (TBK1), and IRF3. Furthermore, 6-shogaol inhibited TBK1 activity in vitro. Together, these results suggest that 6-shogaol inhibits the TRIF-dependent signaling pathway of TLRs by targeting TBK1, and, they imply that 6-shogaol can modulate TLR-derived immune/inflammatory target gene expression induced by microbial infection.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear factor-kappaB (NF-kappaB) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-kappaB is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing IFNbeta(TRIF)-dependent signaling pathways leading to activation of NF-kappaB and IFN-regulatory factor 3 (IRF3). Acrolein inhibited NF-kappaB and IRF3 activation by LPS, but it did not inhibit NF-kappaB or IRF3 activation by MyD88, inhibitor kappaB kinase (IKK)beta, TRIF, or TNF-receptor-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-kappaB and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.

Garlic has long been used as a folk medicine. Numerous studies have demonstrated that a garlic extract and its sulfur-containing compounds inhibited nuclear factor kappa B (NF-kappaB) activation induced by various receptor agonists including lipopolysaccharide (LPS). Toll-like receptors (TLRs) play a key role in sensing diverse microbial products and inducing innate immune responses. The dimerization of TLR4 is required for the activation of downstream signaling pathways, including NF-kappaB. Therefore, TLR4 dimerization may be one of the first lines of regulation in activating LPS-induced signaling pathways. We report here biochemical evidence that the ethyl acetate fraction of garlic inhibited the LPS-induced dimerization of TLR4, resulting in the inhibition of NF-kappaB activation and the expression of cyclooxygenase 2 and inducible nitric oxide synthase. Our results demonstrate for the first time that a garlic extract can directly inhibit the TLRs-mediated signaling pathway at the receptor level. These results shed a new insight into understanding how garlic modulates the immune responses that could modify the risk of many chronic diseases.