Skin cancer is currently the most common type of human cancer in Americans. Myricetin, a naturally occurring phytochemical, has potent anticancer-promoting activity and contributes to the chemopreventive potential of several foods, including red wine. Here, we show that myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-KB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimiidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis. [Cancer Res 2008;68(14):6021-30]
Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), durvalumab (Imfinzi®), and avelumab (Bavencio®), which block the immune checkpoint proteins, have brought about a significant breakthrough in the treatment of a wide range of cancers, as they can induce durable therapeutic responses. In recent years, crystal structures of the antibodies against PD-1, PD-L1, and CTLA-4 have been reported. In this review, we describe the latest structural studies of these monoclonal antibodies and their interactions with the immune checkpoint proteins. A comprehensive analysis of the interactions of these immune checkpoint blockers can provide a better understanding of their therapeutic mechanisms of action. The accumulation of these structural studies would provide a basis that is essential for the rational design of next-generation therapies in immuno-oncology.
Considerable attention has focused on the health-promoting effects of red wine and its nonflavonoid polyphenol compound resveratrol. However, the underlying molecular mechanisms and molecular target(s) of red wine or other potentially active ingredients in red wine remain unknown. Here, we report that red wine extract (RWE) or the red wine flavonoid quercetin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells. The activation of activator protein-1 and nuclear factor-KB induced by TPA was dose dependently inhibited by RWE or quercetin treatment. Western blot and kinase assay data revealed that RWE or quercetin inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) 1 and Raf1 kinase activities and subsequently attenuated TPAinduced phosphorylation of ERK/p90 ribosomal S6 kinase. Although either RWE or quercetin suppressed Raf1 kinase activity, they were more effective in inhibiting MEK1 activity. Importantly, quercetin exerted stronger inhibitory effects than PD098059, a well-known pharmacologic inhibitor of MEK. Resveratrol did not affect either MEK1 or Raf1 kinase activity. Pull-down assays revealed that RWE or quercetin (but not resveratrol) bound with either MEK1 or Raf1. RWE or quercetin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are involved in the activation of MEK/ ERK signaling. Docking data suggested that quercetin, but not resveratrol, formed a hydrogen bond with the backbone amide group of Ser 212 , which is the key interaction for stabilizing the inactive conformation of the activation loop of MEK1. [Cancer Res 2008;68(3):946-55]
Background: Adipogenesis contributes to the increase in adipose tissue mass. Results: Preadipocytes treated with piceatannol showed reduced adipogenesis with impairment of the early cell cycle progress and insulin-signaling pathway. Conclusion:The anti-adipogenic function of piceatannol is through inhibition of mitotic clonal expansion and insulin receptor activity in the early phase of adipogenesis. Significance: Piceatannol is a novel anti-adipogenic compound that could modulate development of adipose tissue.
Rhamnetin (1), a commonly occurring plant O-methylated flavonoid, possesses antioxidant properties. To address the potential therapeutic efficacy of 1, its anti-inflammatory activity and mode of action in mouse macrophage-derived RAW264.7 cells stimulated with lipopolysaccharide (LPS) or interferon (IFN)-γ were investigated. Rhamnetin (1) suppressed mouse tumor necrosis factor (mTNF)-α, mouse macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine production in LPS-stimulated macrophages. A nontoxic dose of 1 suppressed nitric oxide production. It was found that the anti-inflammatory effects of 1 are mediated by actions on the p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and cyclooxygenase (COX)-2 pathways in LPS- or IFN-γ-stimulated RAW264.7 cells. It was determined that 1 binds to human JNK1 (9.7 × 10(8) M(-1)) and p38 MAPK (2.31 × 10(7) M(-1)) with good affinity. The binding model showed interactions with the 3'- and 4'-hydroxy groups of the B-ring and the 5-hydroxy group of the A-ring of 1. Further, 1 exerted an anti-inflammatory effect, reducing the levels of pro-inflammatory cytokines and mediators.
The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα–TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis.
ObjectivesThe purpose of the present study was to identify the association between presenteeism and long working hours, shiftwork, and occupational stress using representative national survey data on Korean workers.MethodsWe analyzed data from the second Korean Working Conditions Survey (KWCS), which was conducted in 2010, in which a total of 6,220 wage workers were analyzed. The study population included the economically active population aged above 15 years, and living in the Republic of Korea. We used the chi-squared test and multivariate logistic regression to test the statistical association between presenteeism and working hours, shiftwork, and occupational stress.ResultsApproximately 19% of the workers experienced presenteeism during the previous 12 months. Women had higher rates of presenteeism than men. We found a statistically significant dose–response relationship between working hours and presenteeism. Shift workers had a slightly higher rate of presenteeism than non-shift workers, but the difference was not statistically significant. Occupational stress, such as high job demand, lack of rewards, and inadequate social support, had a significant association with presenteeism.ConclusionsThe present study suggests that long working hours and occupational stress are significantly related to presenteeism.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.