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Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM‐induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE‐promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP‐1, these effects were reduced by cotreatment with oleic acid. UPM‐dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP‐1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM‐induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro‐inflammatory cytokine and recovery of cell proliferation. [ABSTRACT FROM AUTHOR]

This study implements a highly uniform 3D vertically stack resistive random‐access memory (VRRAM) with a four‐layer contact hole structure. The fabrication process of a four‐layer VRRAM is demonstrated, and its physical and electrical properties are thoroughly examined. X‐ray photoelectron spectroscopy and transmission electron microscopy are employed to analyze the chemical distribution and physical structure of the VRRAM device. Multilevel capability, reliable endurance (>104 cycles), and retention (104 s) are successfully obtained. Synaptic memory plasticity, such as spike time‐dependent plasticity, spike rate‐dependent plasticity, excitatory post‐synaptic current, paired‐pulse facilitation, and long‐term potentiation and depression is presented. Finally, the vector‐matrix multiplication (VMM) operation is conducted on a 4 × 12 VRRAM array, according to the low resistance state ratio. It is ascertained that the accuracy drop, which can occur due to VMM error, can be limited to a decrease of less than 0.44% point. Utilizing the high‐density, multilevel, and biological characteristics of VRRAM, it is possible to implement high‐performance neuromorphic systems that require densely integrated synaptic devices. [ABSTRACT FROM AUTHOR]

Tomentosin, one of natural sesquiterpene lactones sourced from Inula viscosa L., exerts therapeutic effects in various cell types. Here, we investigated the antioxidant activities and the underlying action mechanisms of tomentosin in HaCaT cells (a human keratinocyte cell line). Specifically, we examined the involvement of tomentosin in aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Treatment with tomentosin for up to 60 min triggered the production of reactive oxygen species (ROS), whereas treatment for 4 h or longer decreased ROS production. Tomentosin treatment also induced the nuclear translocation of Nrf2 and upregulated the expression of Nrf2 and its target genes. These data indicate that tomentosin induces ROS production at an early stage which activates the Nrf2 pathway by disrupting the Nrf2–Keap1 complex. However, at a later stage, ROS levels were reduced by tomentosin-induced upregulation of antioxidant genes. In addition, tomentosin induced the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38 MAPK and c-Jun N-terminal kinase (JNK). SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) attenuated the tomentosin-induced phosphorylation of Nrf2, suggesting that JNK and p38 MAPK signaling pathways can contribute to the tomentosin-induced Nrf2 activation through phosphorylation of Nrf2. Furthermore, N-acetyl-L-cysteine (NAC) treatment blocked both tomentosin-induced production of ROS and the nuclear translocation of Nrf2. These data suggest that tomentosin-induced Nrf2 signaling is mediated both by tomentosin-induced ROS production and the activation of p38 MAPK and JNK. Moreover, tomentosin inhibited the AhR signaling pathway, as evidenced by the suppression of xenobiotic-response element (XRE) reporter activity and the translocation of AhR into nucleus induced by urban pollutants, especially benzo[a]pyrene. These findings suggest that tomentosin can ameliorate skin damage induced by environmental pollutants. [ABSTRACT FROM AUTHOR]

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspase-mediated apoptosis via STAT3 inactivation. To investigate the possible teratological effects of the two enantiomers of a racemic KCP-10043F, therefore chiral resolution of (±)-KCP-10043F was performed and subsequently followed by a series of chemical processes to afford the corresponding chiral diastereomers. By using 1H NMR anisotropy method, the absolute configuration (+)-KCP-10043F and (−)-KCP-10043F could be assigned as S and R configuration, respectively. The bacterial reverse mutation test (Ames test) for racemate (±)-KCP-10043F and its two enantiomers exhibited that all three stereoisomers were found to be nongenotoxic against five bacterial strains with/without metabolic activation. In addition, (R)-(−)-KCP-10043F displayed almost equal anticancer activity to (S)-(+)-KCP-10043F against three cancer cell lines. Based on these overall results, racemate KCP-10043F (OZ-001) could be used for our ongoing preclinical and clinical studies without the expensive asymmetric process and/or chiral separation. [ABSTRACT FROM AUTHOR]

[Display omitted] • The genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 production and dopaminergic neurodegeneration. • Compound 7s, a mPGES-1 inhibitor, exhibited potent neuroprotective activity against 6-OHDA-induced toxicity in PC12 cells. • Compound 7s (MPO-0144) as a small molecule could be a promising therapeutic agent for PD. • Compound 7s ameliorated motor impairments and dopaminergic neuronal damage in animal model of PD. mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE 2 IC 50 = 41.77 nM; mPGES-1 IC 50 = 1.16 nM) exhibited a potent neuroprotection (ED 50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC 50 = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients. [ABSTRACT FROM AUTHOR]

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants. [ABSTRACT FROM AUTHOR]