An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype.

Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are still unknown. The current study showed that the antitumor immune microenvironment was activated in glioma in Nfat1-/- mice, suggesting induction of the immune-suppressive microenvironment by nuclear factor of activated T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate the transcriptional activity of complement 3 (C3) and increase the secretion of C3a, which could then bind to C3aR and promote M2-like macrophage polarization by activating TIM-3. Simultaneously, C3a/C3aR activated the Ca2+-NFAT1 pathway, forming a positive feedback loop for the M2-like polarization of TAMs, which further promoted the MES transition of GSCs. Finally, disruption of this feedback loop using a C3aR inhibitor significantly inhibited glioma growth both in vitro and in vivo. The current study demonstrated that a NFAT1-C3a-C3aR positive feedback loop induces M2-like TAMs and further promotes the malignant phenotype of GSCs, which might be the potential therapeutic target for glioma.

Identification of common genetic characteristics of rheumatoid arthritis and major depressive disorder by bioinformatics analysis and machine learning.

Introduction: Depression is the most common comorbidity of rheumatoid arthritis (RA). In particular, major depressive disorder (MDD) and rheumatoid arthritis share highly overlapping mental and physical manifestations, such as depressed mood, sleep disturbance, fatigue, pain, and worthlessness. This overlap and indistinguishability often lead to the misattribution of physical and mental symptoms of RA patients to depression, and even, the depressive symptoms of MDD patients are ignored when receiving RA treatment. This has serious consequences, since the development of objective diagnostic tools to distinguish psychiatric symptoms from similar symptoms caused by physical diseases is urgent. Methods: Bioinformatics analysis and machine learning. Results: The common genetic characteristics of rheumatoid arthritis and major depressive disorder are EAF1, SDCBP and RNF19B. Discussion: We discovered a connection between RA and MDD through immune infiltration studies: monocyte infiltration. Futhermore, we explored the correlation between the expression of the 3 marker genes and immune cell infiltration using the TIMER 2.0 database. This may help to explain the potential molecular mechanism by which RA and MDD increase the morbidity of each other.

NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma.

BACKGROUND: Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. METHODS: The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. RESULTS: High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB-dependent transcriptional activity. CONCLUSION: Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.

Bumetanide: A review of its neuroplasticity and behavioral effects after stroke.

Stroke often leads to neuronal injury and neurological functional deficits. Whilst spontaneous neurogenesis and axon regeneration are induced by ischemic stroke, effective pharmacological treatments are also essential for the improvement of neuroplasticity and functional recovery after stroke. However, no pharmacological therapy has been demonstrated to be able to effectively improve the functional recovery after stroke. Bumetanide is a specific Na+-K+-Cl- co-transporter inhibitor which can maintain chloride homeostasis in neurons. Therefore, many studies have focused on this drug's effect in stroke recovery in recent years. Here, we first review the function of Na+-K+-Cl- co-transporter in neurons, then how bumetanide's role in reducing brain damage, promoting neuroplasticity, leading to functional recovery after stroke, is elucidated. Finally, we discuss current limitations of bumetanide's efficiency and their potential solutions. These results may provide new avenues for further exploring mechanisms of post-stroke functional recovery as well as promising therapeutic targets for functional disability rehabilitation after ischemic stroke.