Emodin suppresses mast cell migration via modulating the JAK2/STAT3/JMJD3/CXCR3 signaling to prevent cystitis.

AIMS: This study aimed to determine the preventive effects of emodin on cyclophosphamide (CYP)-induced cystitis and to explore the molecular mechanism. METHODS: In vivo, mice were modeled by CYP. Before a half hour of CYP treatment, Jumonji domain-containing protein-3 (JMJD3) inhibitors (GSK-J4) and emodin were used to treat CYP model mice. Bladder samples were stained for hematoxylin-eosin and toluidine blue. Next, JMJD3 was quantified by immunofluorescence staining, RT-PCR, and Western blot. CXCR3 was quantified by Western blot and ELISA. In vitro, before stimulated by lipopolysaccharide (LPS), human bladder smooth muscle cells (hBSMCs) were transfected with pcDNA3.1-JMJD3 plasmids, shRNA-JMJD3 plasmids or pretreated with emodin. Collected cells to detect JMJD3 and CXCR3 ligands again; collected supernatant of culture for Transwell assay. Finally, as the JAK2 inhibitor, AG490 was used to pretreat LPS-induced hBSMCs. Western blot was performed to quantify proteins. RESULTS: Emodin inhibited mast cell migration and suppressed the expression of JMJD3, CXCR3, and CXCR3 ligands, not only in vivo but also in vitro. The pharmacological effects of emodin were similar to GSK-J4 or JMJD3 inhibition. In addition, emodin significantly downregulated the phosphorylation of JAK2 and STAT3, and inhibited JMJD3/CXCR3 axis transduction like AG490. CONCLUSION: Emodin has a preventive effect on cystitis by inhibiting mast cell migration through inhibition of the JAK2/STAT3/JMJD3/CXCR3 signaling pathway.

Bioinspired Bidirectional Stiffening Soft Actuators Enable Versatile and Robust Grasping.

The bending stiffness modulation mechanism for soft grippers has gained considerable attention to improve grasping versatility, capacity, and stability. However, lateral stability is usually ignored or hard to achieve at the same time with good bending stiffness modulation performance. Therefore, this article presents a bioinspired bidirectional stiffening soft actuator (BISA), enabling compliant and stable performance. BISA combines the air tendon actuation (ATA) and a bone-like structure (BLS). The ATA is the main actuation of the BISA, and the bending stiffness can be modulated with a maximum stiffness of about 0.7 N/mm and a maximum magnification of three times when the bending angle is 45°. Inspired by the morphological structure of the phalanx, the lateral stiffness can be modulated by changing the pulling force of the BLS. The actuator with BLSs can improve the lateral stiffness by about 3.9 times compared to the one without BLSs. The maximum lateral stiffness can reach 0.46 N/mm. And the lateral stiffness can be modulated by decoupling about 1.3 times (e.g., from 0.35 to 0.46 N/mm when the bending angle is 45°). The test results show that the influence of the rigid structures on bending is small with about 1.5 mm maximum position errors of the distal point of the actuator in different pulling forces. The advantages brought by the proposed method enable versatile four-finger grasping. The performance of this gripper is characterized and demonstrated on multiscale, multiweight, and multimodal grasping tasks.

Analyzing and validating the prognostic value and immune microenvironment of clear cell renal cell carcinoma.

Tumor immune microenvironment (TIME) plays an important role in tumor diagnosis, prevention, treatment and prognosis. However, the correlation and potential mechanism between clear cell renal cell carcinoma (ccRCC) and its TIME are not clear. Therefore, we aimed to identify potential prognostic biomarkers related to TIME of ccRCC. Unsupervised consensus clustering analysis was performed to divide patients into different immune subgroups according to their single-sample gene set enrichment analysis (ssGSEA) scores. Then, we validated the differences in immune cell infiltration, prognosis, clinical characteristics and expression levels of HLA and immune checkpoint genes between different immune subgroups. Weighted gene coexpression network analysis (WGCNA) was used to identify the significant modules and hub genes that were related to the immune subgroups. A nomogram was established to predict the overall survival (OS) outcomes after independent prognostic factors were identified by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses. Five clusters (immune subgroups) were identified. There was no significant difference in age, sex or N stage. And there were significant differences in race, T stage, M stage, grade, prognosis and tumor microenvironment. WGCNA revealed that the red module has an important relationship with TIME, and obtained 14 hub genes. In addition, the nomogram containing LAG3 and GZMK accurately predicted OS outcomes of ccRCC patients. LAG3 and GZMK have a certain correlation with the prognosis of ccRCC patients, and play an important role in the TIME. These two hub genes deserve further study as biomarkers of the TIME.

Long non-coding RNA LINC00675 is associated with bladder cancer metastasis and patient survival.

BACKGROUND: Muscle-invasive bladder cancer (MIBC), a bladder cancer that spreads into the detrusor muscle of the bladder, leads to a poor outcome. Long noncoding RNA LINC00675 has been reported to play import roles in several cancer types, although its biological function and underlying mechanism in MIBC remain largely unclear. METHODS: Eighty-nine patients with MIBC were enrolled in the present study. RNA expression was measured using a quantitative reverse transcription-polymerase chain reaction. Protein expression was detected using western blotting. Transwell assays were performed to analyze the abilities of bladder cancer cells to migrate and invade. An RNA microarray was carried out to analyze LINC00675-regulated mRNAs in bladder cancer cells. RESULTS: We found that LINC00675 expression was decreased in MIBC tissues compared to matched normal tissues, and was correlated with lymph node-metastatic MIBC. MIBC patients with low expression of LINC00675 had worse survival rates than those with high expression. Functional investigation showed that ectopic expression of LINC00675 inhibited bladder cancer cell migration, invasion and proliferation, whereas LINC00675 knockdown presented an opposite effect. Mechanistically, we found that LINC00675 inhibited ß-catenin and its downstream gene expression. CONCLUSIONS: The findings of the present study suggest that LINC00675 regulates ß-catenin expression, and is associated with bladder cancer metastasis and patient survival.

Bone marrow mesenchymal stem cell derived exosomes miR-21-5p promotes proliferation, migration and invasion of prostate cancer PC-3 cell by downregulating PHLPP2 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effects of exosome originated from bone marrow mesenchymal stem cell (BMSCs) on proliferation, migration and invasion of prostate cancer PC-3 cell and its mechanism. Methods: qPCR was used to detect the expression level of miR-21-5p in prostate cancer cell lines. The morphology of exosomes isolated from BMSCs was observed with an electron microscope. Western blotting was used to detect the expressions of exosome surface markers and the epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Vimentin). Dual luciferase reporter gene experiment was used to detect the targeted regulation relationship between miR-21-5p and PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2). PC-3 cells were co-cultured with 10 μl BMSCs exosomes suspension (Exo group), transfected with sh-PHLPP2 or antagomiR, then CCK-8 and Transwell experiments were used to detect changesinproliferation,migrationandinvasionofPC-3cell.Results: miR-21-5p was highly expressed in prostate cancer PC-3 cell line. The exosomes in the supernatant of BMSCs culture fluid were successfully isolated, and the typical vesicle-like structures of exosomes were observed under transmission electron microscope. Exosomes expressed specific proteins such as CD9, CD63 and CD81. In the Exo group, the proliferation, invasion, migration, as well as the expressions of N-cadherin, Vimentin and miR-21-5p in PC-3 cells were significantly higher than those in the control group (all P<0.05). PHLPP2 is a target gene of miR-21-5p. Compared with the control group, the expression of PHLPP2 in PC-3 cells of Exo group and sh-PHLPP2 group was significantly reduced (0.66±0.09, 0.42±0.05 vs 1.09±0.08, all P<0.01); cell viability, invasion and migration were significantly improved (all P<0.01); and E-cadherin expression level was significantly reduced while N-cadherin and Vimentin expressions were significantly increased (both P<0.05). Conclusion: miR-21-5p is highly expressed in prostate cancer PC-3 cell line. BMSC exosome miR-21-5p can increase the proliferation, migration and invasion ability of PC-3 cells through targeted down-regulation of PHLPP2.