查看更多>>摘要：Circadian rhythm proteins participate in regulating multiple physiological activities, including immune responses. The day-night shift rotation (DNSR) affects the circadian rhythm. The influence of circadian rhythm disturbance associated with DNSR on the regulatory functions of B cells remains to be studied. In this study, Blood samples were collected from 30 nurses engaging DNSR. The B cells were isolated from blood samples through magnetic cell separation. The regulatory function of IL-10 B cells (B10 cells) was evaluated using immunological assays. The results showed that the IL-10 expression was significantly reduced in B10 cells in nurses after DNSR. The capacity of inducing type 1 regulatory T cells (Tr1 cells) in B10 cells was down regulated. The circadian locomotor output cycles kaput (CLOCK) was increased in B10 cells, which was negatively correlated with the reduction of IL-10 expression in B10 cells. CLOCK formed a complex with c-Maf inducing protein (CMIP) to induce CMIP degradation; this restricted the IL10 gene transcription in B10 cells. B10 cells collected from nurses after DNSR were ineffective in suppressing T-cell proliferation and inducing Tr1 cells. In summary, DNSR affects the immune regulating function of B10 cells by disturbing the circadian rhythm.
查看更多>>摘要：Aquaporin-4 (AQP4) is the water regulating channel found in the terminal processes of astrocytes in the brain and is implicated in regulating the astrocyte functions, whereas in neuropathologies, AQP4 performs an important role in astrocytosis and release of proinflammatory cytokines. However, several findings have revealed the modulation of the AQP4 water channel in the etiopathogenesis of various neuropsychiatric diseases. In the current article, we have summarized the recent studies and highlighted the implication of astrocytic dysfunction and AQP4 in the etiopathogenesis of depressive disorder. Most of the studies have measured the AQP4 gene or protein expression in the brain regions, particularly the locus coeruleus, choroid plexus, prefrontal cortex, and hippocampus, and found that in these brain regions, AQP4 gene expression decreased on exposure to chronic mild stress. Few studies also measured the peripheral AQP4 mRNA expression in the blood and AQP4 autoantibodies in the blood serum and revealed no change in the depressed patients in comparison with normal individuals.
查看更多>>摘要：Background: Prostate cancer is one of the most common malignancies in men. Members of the elongation of the very-long-chain fatty acid (ELOVL) gene family have been reported to participate in the occurrence and development of various cancers. However, the function of ELOVL gene family members (ELOVLs) in prostate cancer has not been fully elucidated.Methods: The mRNA expression and prognostic value of ELOVLs in prostate cancer were analyzed using the GEPIA database. The Oncomine database and PrognoScan database were used to further verify the mRNA expression level and prognostic value of ELOVL2 in prostate cancer. RT-qPCR and Western blotting were used to validate the expression levels of ELOVL2 in four prostate cancer cell lines. Immunohistochemistry was performed to detect the ELOVL2 protein expression levels in prostate cancer tissues. Coexpression analysis in the cBioPortal database and enrichment analysis in Kyoto Encyclopedia of Genes and Genomes (KEGG), CCK8, colony formation, and transwell assays were used to identify the functions and mechanisms of ELOVL2.Results: ELOVL2 expression was upregulated in prostate cancer tissues compared with normal tissues. High expression of ELOVL2 indicated a better prognosis in prostate cancer patients. ELOVL2 expression was negatively correlated with Gleason score. Knockdown of ELOVL2 promoted cell proliferation, colony formation, migration, invasion, and the growth of subcutaneous xenografts and activated the PI3K/Akt signaling pathway by down regulating INPP4B, while overexpression of ELOVL2 reversed these effects. In addition, overexpression of INPP4B blocked the promoting effect of sh-ELOVL2 on cell proliferation, colony formation, migration, invasion, and the PI3K/Akt signaling pathway.Conclusions: Our findings suggest that ELOVL2 might be a prognostic biomarker and therapeutic target for prostate cancer.
Arthur, RachaelWathen, AlexanderLemm, A. ElizabethStevenson, K. Freda...
11页
查看更多>>摘要：BTK inhibitors (BTKi) have dramatically improved outcomes for patients with chronic lymphocytic leukaemia (CLL) and some forms of B-cell lymphoma. However, new strategies are needed to enhance responses. Here we have performed a detailed analysis of the effects of BTKi on B-cell receptor (BCR)-induced signalling using primary malignant cells from CLL patients and B-lymphoma cell lines. Although BTK is considered as a key activator of PLC gamma 2, BTKi (ibrutinib and acalabrutinib) failed to fully inhibit calcium responses in CLL samples with strong BCR signalling capacity. This BTKi-resistant calcium signalling was sufficient to engage downstream calcium-dependent transcription and suppress CLL cell apoptosis and was entirely independent of BTK and not just its kinase activity as similar results were obtained using a BTK-degrading PROTAC. BTK-independent calcium signalling was also observed in two B-lymphoma cell lines where BTKi had little effect on the initial phase of the calcium response but did accelerate the subsequent decline in intracellular calcium. In contrast to BTKi, calcium responses were completely blocked by inhibition of SYK in CLL and lymphoma cells. Engagement of BTK-independent calcium responses was associated with BTK-independent phosphorylation of PLC gamma 2 on Y753 and Y759 in both CLL and lymphoma cells. Moreover, in CLL samples, inhibition of RAC, which can mediate BTKindependent activation of PLC gamma 2, cooperated with ibrutinib to suppress calcium responses. BTK-independent calcium signalling may limit the effectiveness of BTKi to suppress BCR signalling responses and our results suggest inhibition of SYK or dual inhibition of BTK and RAC as alternative strategies to strengthen pathway blockade.
NSTL
Elsevier