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N 6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer. 18097, a potent (IC 50 values 0.64 μmol/L) and selective inhibitor of fat mass and obesity-associated protein (FTO), can suppress growth, lipogenesis, and in vivo metastasis of breast cancer cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Recently, populations of Chinese spiny frogs (Quasipaa spinosa), an important amphibian species in China, have decreased, mainly due to a disease caused by the gram-negative bacteria Proteus mirabilis. To elucidate the immune response of the frogs, this study aimed to identify novel candidate genes functionally associated with P. mirabilis infection-induced "rotting skin" disease. Chinese spiny frogs were infected with P. mirabilis , and the skin transcriptome was sequenced using the MGISEQ-2000 platform. A total of 233,965 unigenes were obtained by sequencing, of which 27.23 % were known genes. Screening of differentially expressed genes (DEGs) indicated 210 unigenes differentially expressed after P. mirabilis infection, of which 132 unigenes were up-regulated, and 78 unigenes were down-regulated. Using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, DEGs were identified as enriched in signal pathways, such as oxidative phosphorylation, apoptosis, and the Janus kinase-signal transducer and activator of transcription pathway. Of the DEGs, there was a significant upregulation of the colony stimulating factor 2 receptor beta common subunit , interleukin 2 receptor subunit gamma , cathelicidin antimicrobial peptide , interleukin-17 receptor E , receptor-interacting serine/threonine-protein kinase 3 , and pulmonary surfactant-associated protein D immune genes following P. mirabilis infection. Conversely, scavenger receptor cysteine-rich domain-containing group B protein , tumor protein p53 inducible nuclear protein 2 , suppressor of cytokine signaling 2 , and metalloreductase STEAP3 were significantly downregulated. In conclusion, the first skin transcriptome database of Chinese spiny frogs was established, and several immune genes were identified to elucidate the pathogenic mechanism of "skin rot" in Chinese spiny frogs and other cultured frogs. [Display omitted] • Skin transcriptomes were obtained from Chinese spiny frogs with Proteus mirabilis. • 210 genes were differentially expressed between the P. mirabilis infected group and the control group. • Among the DEGs, many immune-related genes were closely associated with P. mirabilis infection. [ABSTRACT FROM AUTHOR]

Short chain fatty acids (SCFAs), the microbial metabolites of fermentable dietary fibers exert multiple beneficial effects on mammals including humans. We examined the effects of fermentable dietary fibers on suppressor of cytokine signaling 1 (SOCS1), a negative regulator of inflammatory signaling, on the intestinal epithelial cells of the mouse colon and human intestinal Caco-2 cells, specifically focusing on the role of SCFAs. Feeding fermentable fibers, guar gum (GG) and partially hydrolyzed GG (PHGG) increased SOCS1 expression in the colon and the cecal pool of some SCFAs including acetate, propionate, and butyrate. The antibiotic administration abolished the GG-mediated SOCS1 expression in the colon. In Caco-2 cells, butyrate, but not other SCFAs, increased SOCS1 expression. Taken together, fermentable fibers such as GG and PHGG upregulate the colonic SOCS1 expression, possibly through the increased production of butyrate in mice and can be a potential tool in the fight against inflammatory diseases. Abbreviations: GG: Guar gum; GPR: G protein-coupled receptor; IL: Interleukin; JAK: Janus kinase; NF- κB: Nuclear factor-kappa B; PHGG: Partially hydrolyzed guar gum; SCFA: Short chain fatty acid; SOCS: Suppressor of cytokine signaling; STAT: Signal transducer and activator of transcription; TLR: Toll-like receptor. Butyrate produced from microbial metabolism of GG increases the SOCS1 protein in the colon. [ABSTRACT FROM AUTHOR]

Arsenic is a common environmental pollutant, typically affecting the skin most severely. Recent studies have shown that arsenic's toxicity may be linked to N6-methyladenosine (m6A), an abundant and dynamic epigenetic RNA modification. However, it is not completely understood how m6A contributes to arsenite-induced skin lesions. Herein, it is shown that methyltransferase-like 3 (METTL3) plays a crucial role in the involvement of arsenite-induced skin lesions in an m6A-dependent manner. Using bioinformatic analysis and experimental approaches, we demonstrate that arsenite induces METTL3 upregulation, represses suppressors of cytokine signaling 3 (SOCS3) expression in an m6A- YTH m6A RNA binding protein 2 (YTHDF2)-dependent manner, and leads to the aberrant activation of the Janus kinase (JAK)2/signal transducer and activator of transcription 3(STAT3) signaling pathway. We further found that the activated transcription factor STAT3 binds to the promoter regions of Krt1 and Krt10, promoting their transcription, which ultimately leads to arsenite-induced skin lesions. In conclusion, our study reveals the role of m6A in arsenite-induced skin lesions through the activation of the JAK2/STAT3/Krt signaling axis. The findings provide new insight into the potential molecular mechanisms underlying arsenic toxicity regulation through m6A modification. [Display omitted] • METTL3-mediated m6A methylation is involved in arsenite-induced HaCaT cell damage. • METTL3 may be involved in arsenicosis by regulating the JAK-STAT signaling pathway. • Arsenite induces METTL3 inhibition of JAK2/STAT3 signaling pathway activation by SOCS3. • Arsenite disrupts SOCS3 protein levels in a METTL3-YTHDF2-dependent manner. • Arsenite participates in skin lesions by inducing METTL3 activation STAT3 with Krt. [ABSTRACT FROM AUTHOR]

• PRL activity was regulated by the circadian rhythm. • PRL-induced signaling was significantly decreased in CLOCK−/− mice. • SOCS was up-regulated in CLOCK−/− mice. The circadian molecular Clock is an internal time-keeping system, which regulates various physiological processes. The circadian Clock may be involved in all biological processes. The circadian Clock is closely related to prolactin's activities. However, until now, the effect of circadian Clock dysregulation on PRL's bioactivities remains unclear. Clock protein is an essential component in circadian Clock and necessary for Clock function. Therefore, Clock gene knockout mice (CLOCK −/− mice) was used to explore the effect of circadian Clock dysfunction on PRL's activities. The in vitro and in vivo experimental results showed that PRLR-mediated signaling was significantly down-regulated. PRL-induced JAK2-STAT5 signaling in Clock-/- mice was significantly decreased compared to control mice in vivo. In vitro , PRL/PRLR-mediated signaling in mammary epithelial cell that Clock was knocked down by siRNA was significantly down-regulated compared to control cells. Mechanistically, the expression levels of negative regulatory molecule (the suppressor of cytokine signaling (SOCS) was upregulated in vitro and in vivo , which may be one of the factors that causes the PRL-signaling downregulation. Taken together, the current work indicates that the circadian Clock affects the PRL's activities. This finding lays the foundation for studying the relationship between the circadian Clock and PRL's biological activities. [ABSTRACT FROM AUTHOR]

Abstract: Inflammatory cytokines contribute to periapical tissue destruction. Their activity is potentially regulated by suppressors of cytokine signaling (SOCS), which downregulate signal transduction as part of an inhibitory feedback loop. We investigated the expression of the cytokines tumor necrosis factor α (TNF-α); interleukin (IL)-10 and RANKL; and SOCS-1, -2, and -3 by real-time polymerase chain reaction in 57 periapical granulomas and 38 healthy periapical tissues. Periapical granulomas exhibited significantly higher SOCS-1, -2, and -3, TNF-α, IL-10, and RANKL messenger RNA levels when compared with healthy controls. Significant positive correlations were found between SOCS1 and IL-10 and between SOCS3 and IL-10. Significant inverse correlations were observed between SOCS1 and TNF-α, SOCS1 and RANKL, and SOCS3 and TNF-α. Increased SOCS-1, -2, and -3 messenger RNA levels in periapical granulomas may be related to the downregulation of inflammatory cytokines in these lesions; therefore, SOCS molecules may play a role in the dynamics of periapical granulomas development. [Copyright &y& Elsevier]

BaP and DBP are ubiquitously and contemporaneously present in the environment. However, Current studies largely concentrate on the effects of a single pollutant (BaP or DBP). The liver is vital for biogenic activities. The effects of BaP and DBP co-exposure on liver remain unclear. Thus, we treated human normal liver cell (L02 cell) with BaP or/and DBP. We found that compared to individual exposure, co-exposure to BaP and DBP induced further increased levels of AST and ALT. BaP and DBP co-exposure caused further increased levels of IL-2, IL-6, and TNF-α, decreased IL-10 level, and a higher percentage of apoptotic cells and S-phase arrest cells. BaP and DBP co-exposure worsen the decrease of miR-122–5p level and chaos of SOCS1/STAT3 signaling. Dual-luciferase reporter gene assays showed that SOCS1 was a validated target of miR-122–5p. miR-122–5p overexpression alleviated the increased SOCS1 expression, decreased phospho-STAT3 expression, decreased IL-10 level, increased TNF-α levels, increased percentage of apoptosis and S-phase arrest, and cytotoxicity induced by BaP and DBP co-exposure in hepatocytes. These results suggested that miR-122–5p negatively regulated the synergistic effects on apoptosis and disorder of inflammatory factor secretion involved in hepatocyte injury caused by BaP and DBP co-exposure through targeting SOCS1/STAT3 signaling. [Display omitted] • BaP or/and DBP caused excessive apoptosis and disorder of inflammatory cytokines secretion in hepatocytes. • Co-exposure to BaP and DBP exacerbated hepatocyte injury than individual exposure. • SOCS1/STAT3 signaling participated hepatocyte injury by BaP or/and DBP exposure. • miR-122–5p played an important role in the hepatocytes damage caused by BaP or/and DBP exposure. [ABSTRACT FROM AUTHOR]