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C3G is a GEF (guanine nucleotide exchange factor) for Rap GTPases, among which the isoform Rap1b is an essential protein in platelet biology. Using transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat, we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKC-Rap1b pathway. C3G also plays important roles in angiogenesis, tumor growth, and metastasis through its regulation of the platelet secretome. In addition, C3G contributes to megakaryopoiesis and thrombopoiesis. Here, we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis. C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1, which resulted in decreased thrombus formation in vivo. Additionally, we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin, PMA or ADP, in the referenced transgenic mouse model, through the use of a battery of specific inhibitors. We found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving PKC-Src. This phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase Shp2. Moreover, C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 activities. However, it inhibits the synthesis of TXA2 through cPLA2 regulation. Taken together, our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine pathway (KP), leading to the transformation of L-tryptophan (Trp) into L-kynurenine (Kyn) and other downstream metabolites. Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by using clinical samples, we found that the expression and activity of IDO1 and/or TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival. The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4 (AQP4), implying the potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we found that IDO1/TDO accounted for the release of Kyn, which activated AhR to promote cell motility via the Kyn-AhR-AQP4 signaling pathway in U87MG glioma cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. Together, our results showed that the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK-STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK-STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.Genome stability relies on proper coordination of mitosis and cytokinesis, where dynamic microtubules capture and faithfully segregate chromosomes into daughter cells. With a high-content RNAi imaging screen targeting more than 2,000 human lncRNAs, we identify numerous lncRNAs involved in key steps of cell division such as chromosome segregation, mitotic duration and cytokinesis. Here, we provide evidence that the chromatin-associated lncRNA, linc00899, leads to robust mitotic delay upon its depletion in multiple cell types. We perform transcriptome analysis of linc00899-depleted cells and identify the neuronal microtubule-binding protein, TPPP/p25, as a target of linc00899. [https://www.selleckchem.com/products/chir-98014.html GSK-3 inhibitor] We further show that linc00899 binds TPPP/p25 and suppresses its transcription. In cells depleted of linc00899, upregulation of TPPP/p25 alters microtubule dynamics and delays mitosis. Overall, our comprehensive screen uncovers several lncRNAs involved in genome stability and reveals a lncRNA that controls microtubule behaviour with functional implications beyond cell division.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Dyslipidemia exhibits a high incidence after liver transplantation, in which tacrolimus, a widely used immunosuppressant, plays a fundamental role. MicroRNAs and related circRNAs represent a class of noncoding RNAs that have been recognized as important regulators of genes associated with lipid metabolism. However, their transcriptional activities and functional mechanisms in tacrolimus-related dyslipidemia remain unclear. In this study, we observed that tacrolimus could induce triglyceride accumulation in hepatocytes by stimulating sterol response element-binding proteins (SREBPs) and miR-33a. Our in silico and experimental analyses identified miR-33a as a direct target of circFASN. Tacrolimus could downregulate circFASN and result in elevated miR-33a in vivo and in vitro. Overexpression of circFASN or silencing of miR-33a decreased the promoting effects of tacrolimus on triglyceride accumulation. Clinically, the incidence of dyslipidemia in liver transplant recipients with elevated serum miR-33a after liver transplantation was higher than that in patients without elevated serum miR-33a (46.