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RA is a chronic, autoimmune-mediated inflammatory pathology. Long non-coding RNAs (lncRNAs) are a novel group of non-coding RNAs with a length of >200 nucleotides. There are reports emerging that suggest that lncRNAs participate in establishing and sustaining autoimmune diseases, including RA. In this review article, we highlight the functions of lncRNAs in different cell types in RA. Our review indicates that lncRNAs affect various cellular components and are novel candidates that could constitute promising targets for the diagnosis and treatment of RA. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) are useful for modeling neuron development and related diseases. Cortical interneurons are essential players in neuropsychiatric diseases such as autism. miRNAs are a class of pivotal regulators in neural differentiation. Using a previously established model of cortical interneuron differentiation from human embryonic stem cells, we profiled miRNAs involved in differentiation from human iPSCs. A number of miRNAs were modulated in the differentiation process. This study captured the temporal in vitro neurogenesis from iPSCs to mature cortical interneurons. The specific miRNAs identified at each stage of differentiation are of potential use for drug discovery and prospective clinical applications. [ABSTRACT FROM AUTHOR]

Objectives: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified., Methods: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR., Results: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway., Conclusions: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To uncover the function and underlying mechanism of an essential transcriptional factor, PU.1, in the development of rheumatoid arthritis (RA)., Methods: The expression and localisation of PU.1 and its potential target, FMS-like tyrosine kinase 3 (FLT3), in the synovium of patients with RA were determined by western blot and immunohistochemical (IHC) staining. UREΔ (with PU.1 knockdown) and FLT3-ITD (with FLT3 activation) mice were used to establish collagen antibody-induced arthritis (CAIA). For the in vitro study, the effects of PU.1 and FLT3 on primary macrophages and fibroblast-like synoviocytes (FLS) were investigated using siRNAs. Mechanistically, luciferase reporter assays, western blotting, FACS and IHC were conducted to show the direct regulation of PU.1 on the transcription of FLT3 in macrophages and FLS. Finally, a small molecular inhibitor of PU.1, DB2313, was used to further illustrate the therapeutic effects of DB2313 on arthritis using two in vivo models, CAIA and collagen-induced arthritis (CIA)., Results: The expression of PU.1 was induced in the synovium of patients with RA when compared with that in osteoarthritis patients and normal controls. FLT3 and p-FLT3 showed opposite expression patterns compared with PU.1 in RA. The CAIA model showed that PU.1 was an activator, whereas FLT3 was a repressor, of the development of arthritis in vivo. Moreover, results from in vitro assays were consistent with the in vivo results: PU.1 promoted hyperactivation and inflammatory status of macrophages and FLS, whereas FLT3 had the opposite effects. In addition, PU.1 inhibited the transcription of FLT3 by directly binding to its promoter region. The PU.1 inhibitor DB2313 clearly alleviated the effects on arthritis development in the CAIA and CIA models., Conclusions: These results support the role of PU.1 in RA and may have therapeutic implications by directly repressing FLT3. Therefore, targeting PU.1 might be a potential therapeutic approach for RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rheumatoid arthritis (RA) is an inflammation-involved disorder and features the disruption of CD4 + T lymphocytes. Herein, we describe that microRNA-10b-5p (miR-10b) promotes RA progression by disrupting the balance between subsets of CD4 + T cells. MiR-10b-deficient mice protected against collagen antibody-induced arthritis (CAIA) model. RNA sequencing results indicated that disordered genes in miR-10b -/- CAIA model are closely associated with CD4 + T cells differentiation. Moreover, miR-10b mimics promoted Th1/Th17 and suppressed Th2/Treg cells differentiation, whereas miR-10b inhibitor induced contrary effects. In addition, GATA3 and PTEN was confirmed as two targets of miR-10b, and GATA3 siRNA could increase Th1 and reduce Th2 cells meanwhile PTEN siRNA could increase Th17 and decrease Treg cells. Furthermore, miR-10b inhibitor significantly ameliorated collagen-induced arthritis (CIA) development by attenuating the dysfunctional CD4 + T cell subpopulations. The present findings suggest that miR-10b could disrupt the balance of CD4 + T subsets, while suppressed miR-10b could attenuate the severity of experimental arthritis, which provided us a novel mechanistic and therapeutic insight into the RA., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

During spermatogenesis, a group of undifferentiated spermatogonia undergoes an essential transition to a differentiating stage, which involves gain of Kit receptor. In the current study, we showed that a small non-coding RNA, miRNA-26b could induce transition from Kit - to Kit + and inhibit proliferation of spermatogonia. A key transcriptional factor for undifferentiated spermatogonia, Plzf, was proven as a direct target of miR-26b. When undifferentiated spermatogonia were treated with Retinoic acid (RA), miR-26b was increased, further promoting RA-induced differentiation of spermatogonia. In addition, miR-26b could repress 5-hydroxymethylcytosine (5hmC) via repression of Tet3 in spermatogonia. These findings demonstrate that miR-26b might play a role in promoting the transition from Kit - to Kit + SSCs., (Copyright © 2018. Published by Elsevier Inc.)

Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. Database URL: http://germlncrna.cbiit.cuhk.edu.hk/, (© The Author(s) 2015. Published by Oxford University Press.)

Tanshinone IIA (TSA) is one of the major lipophilic components of Salvia miltiorrhiza Bunge reported to exhibit an antitumor effect. The exact intracellular signaling mechanisms involved remain elusive and were therefore the subject of this study. The process of angiogenesis is related to tumor progression, invasion and metastasis and is generally perceived as an indicator of tumor prognosis. Among the most critical factors that induce angiogenesis, the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway and CD146 (melanoma adhesion molecule) play key roles in this process. This study aimed to demonstrate that TSA has potent anti-angiogenic activity in vitro and ex vivo. Additionally, we evaluated the role of TSA in the VEGF/VEGFR2 pathway. Through a series of in vitro experiments, we found that TSA has a negative effect on cell proliferation, migration and tube formation of human umbilical vascular endothelial cells. We further showed that TSA can inhibit angiogenesis using chorioallantoic membrane (CAM) and rat aortic ring assays. Furthermore, western blotting demonstrated that TSA effectively suppressed the expression of VEGR2 and CD146. These results suggest that TSA inhibits angiogenesis by downregulation of the VEGF/VEGFR2 pathway.