Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

Background and Objectives: Mesenchymal stem cells (MSCs) have the multipotent capacity to differentiate into multiple tissue lineages as well as to self-renew, which is the main origin of adipocytes. IL6/IL6R pathway exerts a significant role in tissue regeneration and cell differentiation. Whereas, the underlying mechanism between IL6/IL6R pathway and MSCs adipogenesis differentiation remains elusive. Methods: MSCs from healthy donors were cultured in adipogenesis differentiation medium for 0∼14 days, during which their adipogenesis differentiation degree was evaluated by Oil Red O staining. The expression of IL6R was detected in MSCs during adipogenesis differentiation. Knockdown and overexpression of IL6R were respectively performed using siRNA and lentivirus to investigate its effect on MSCs adipogenesis differentiation. The adipogenesis marker genes expression and MAPK pathway activation were detected by Western blotting. The role of P38 pathway in the adipogenesis differentiation of MSCs was determined using the specific inhibitor SB203580. Results: The expression of IL6 and IL6R increased during adipogenesis differentiation in MSCs, which were positively correlated with Oil Red O quantification result. Knockdown and overexpression experiments demonstrated a positive correlation between the expressions of IL6R and MSCs adipogenesis differentiation, accompanied by same trend of P38 phosphorylation. Besides, the specific P38 inhibitor SB203580 markedly inhibited the adipogenesis differentiation potential of MSCs. Conclusions This study reveals IL6R facilitates the adiogenesis differentiation of MSCs via activating P38 pathway.

Objective: To investigate the role of microRNA-96-5p in the proliferation and invasion of gastric cancer cells and its molecular mechanism. Methods: From June 2015 to January 2017, 53 resected specimens were collected. The transcriptional levels of microRNA-96-5p and forkhead box Q1 (FoxQ1) in gastric cancer tissues and the matched para-cancerous tissues were quantified by quantitative real-time PCR (qRT-PCR). The expression of FoxQ1 protein was also detected by immunohistochemistry (IHC). The relationship between microRNA-96-5p expression and the clinicopathological features of gastric cancer and its correlation with FoxQ1 expression were analyzed. The expressions of miRNA-96-5p in gastric cancer tissue and adjacent normal tissue were detected by qRT-PCR. miRNA-96-5p mimics was transfected to BGC-823 gastric cancer cells. The effects of miRNA-96-5p on cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and Transwell assay, respectively. The protein expressions of FoxQ1, E-cadherin and vimentin were determined by western blot. The relationship between FoxQ1 and miRNA-96-5p expressed in BGC-823 cells was detected by dual-luciferase reporter assay. Results: The median expression of miRNA-96-5p in gastric cancer tissue was 1.05, significantly lower than 3.23 of para-cancerous tissues (P<0.05). The positive rate of FoxQ1 expression in gastric cancer tissue was 71.7%, significantly higher than 28.3% of para-cancerous tissues (P<0.05). The expression of FoxQ1 was negatively corelated with the level of miRNA-96-5p (r=-0.613, P=0.006). The expression of miRNA-96-5p in gastric cancer cell BGC-823 was significantly decreased compared with normal gastric epithelial cell (0.96±0.08 vs 2.84±0.15, P<0.05). The results of CCK-8 assay and Transwell assay showed that overexpression of miRNA-96-5p significantly reduced the proliferation and invasion abilities of gastric cancer cells (P<0.05). Overexpression of miRNA-96-5p decreased the protein level of FoxQ1. Moreover, it upregulated the expression of E-cadherin and downregulated the expression of vimentin. The result of dual-luciferase-3′-UTR reporter assay confirmed that miRNA-96-5p binds to the 3′UTR of FoxQ1. Conclusion miRNA-96-5p may suppress the proliferation, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cell by down-regulation of FoxQ1.

Objective To investigate the role of microRNA?96?5p in the proliferation and invasion of gastric cancer cells and its molecular mechanism. Methods From June 2015 to January 2017, 53 resected specimens were collected. The transcriptional levels of microRNA?96?5p and forkhead box Q1 (FoxQ1) in gastric cancer tissues and the matched para?cancerous tissues were quantified by quantitative real?time PCR (qRT?PCR). The expression of FoxQ1 protein was also detected by immunohistochemistry (IHC). The relationship between microRNA?96?5p expression and the clinicopathological features of gastric cancer and its correlation with FoxQ1 expression were analyzed. The expressions of miRNA?96?5p in gastric cancer tissue and adjacent normal tissue were detected by qRT?PCR. miRNA?96?5p mimics was transfected to BGC?823 gastric cancer cells. The effects of miRNA?96?5p on cell proliferation and invasion were detected by cell counting kit?8 (CCK?8) assay and Transwell assay, respectively. The protein expressions of FoxQ1, E?cadherin and vimentin were determined by western blot. The relationship between FoxQ1 and miRNA?96?5p expressed in BGC?823 cells was detected by dual?luciferase reporter assay. Results The median expression of miRNA?96?5p in gastric cancer tissue was 1.05, significantly lower than 3.23 of para?cancerous tissues (P＜0.05).The positive rate of FoxQ1 expression in gastric cancer tissue was 71.7%, significantly higher than 28.3% of para?cancerous tissues ( P＜0.05). The expression of FoxQ1 was negatively corelated with the level of miRNA?96?5p (r＝－0.613, P＝0.006). The expression of miRNA?96?5p in gastric cancer cell BGC?823 was significantly decreased compared with normal gastric epithelial cell (0.96±0.08 vs 2.84± 0.15, P＜0.05). The results of CCK?8 assay and Transwell assay showed that overexpression of miRNA?96?5p significantly reduced the proliferation and invasion abilities of gastric cancer cells ( P＜ 0.05 ). Overexpression of miRNA?96?5p decreased the protein level of FoxQ1. Moreover, it upregulated the expression of E?cadherin and downregulated the expression of vimentin. The result of dual?luciferase?3′?UTR reporter assay confirmed that miRNA?96?5p binds to the 3′UTR of FoxQ1. Conclusion miRNA?96?5p may suppress the proliferation, migration and epithelial?mesenchymal transition (EMT) of gastric cancer cell by down?regulation of FoxQ1.

Objective To investigate the role of microRNA?96?5p in the proliferation and invasion of gastric cancer cells and its molecular mechanism. Methods From June 2015 to January 2017, 53 resected specimens were collected. The transcriptional levels of microRNA?96?5p and forkhead box Q1 (FoxQ1) in gastric cancer tissues and the matched para?cancerous tissues were quantified by quantitative real?time PCR (qRT?PCR). The expression of FoxQ1 protein was also detected by immunohistochemistry (IHC). The relationship between microRNA?96?5p expression and the clinicopathological features of gastric cancer and its correlation with FoxQ1 expression were analyzed. The expressions of miRNA?96?5p in gastric cancer tissue and adjacent normal tissue were detected by qRT?PCR. miRNA?96?5p mimics was transfected to BGC?823 gastric cancer cells. The effects of miRNA?96?5p on cell proliferation and invasion were detected by cell counting kit?8 (CCK?8) assay and Transwell assay, respectively. The protein expressions of FoxQ1, E?cadherin and vimentin were determined by western blot. The relationship between FoxQ1 and miRNA?96?5p expressed in BGC?823 cells was detected by dual?luciferase reporter assay. Results The median expression of miRNA?96?5p in gastric cancer tissue was 1.05, significantly lower than 3.23 of para?cancerous tissues (P＜0.05).The positive rate of FoxQ1 expression in gastric cancer tissue was 71.7%, significantly higher than 28.3% of para?cancerous tissues ( P＜0.05). The expression of FoxQ1 was negatively corelated with the level of miRNA?96?5p (r＝－0.613, P＝0.006). The expression of miRNA?96?5p in gastric cancer cell BGC?823 was significantly decreased compared with normal gastric epithelial cell (0.96±0.08 vs 2.84± 0.15, P＜0.05). The results of CCK?8 assay and Transwell assay showed that overexpression of miRNA?96?5p significantly reduced the proliferation and invasion abilities of gastric cancer cells ( P＜ 0.05 ). Overexpression of miRNA?96?5p decreased the protein level of FoxQ1. Moreover, it upregulated the expression of E?cadherin and downregulated the expression of vimentin. The result of dual?luciferase?3′?UTR reporter assay confirmed that miRNA?96?5p binds to the 3′UTR of FoxQ1. Conclusion miRNA?96?5p may suppress the proliferation, migration and epithelial?mesenchymal transition (EMT) of gastric cancer cell by down?regulation of FoxQ1.

Ankylosing spondylitis (AS) is a type of autoimmune disease that predominantly affects the spine and sacroiliac joints. However, the pathogenesis of AS remains unclear. Some evidence indicates that infection with bacteria, especially Gram-negative bacteria, may have an important role in the onset and progression of AS. Recently, many studies have demonstrated that mesenchymal stem cells (MSCs) dysfunction may contribute to the pathogenesis of many rheumatic diseases. We previously demonstrated that MSCs from AS patients exhibited markedly enhanced osteogenic differentiation capacity in vitro under non-inflammatory conditions. However, the properties of MSCs from AS patients in an inflammatory environment have never been explored. Lipopolysaccharide (LPS), a proinflammatory substance derived from the outer membrane of Gram-negative bacteria, can alter the status and function of MSCs. However, whether MSCs from AS patients exhibit abnormal responses to LPS stimulation has not been reported. Autophagy is a lysosome-mediated catabolic process that participates in many physiological and pathological processes. The link between autophagy and AS remains largely unknown. The level of autophagy in ASMSCs after LPS stimulation remains to be addressed. In this study, we demonstrated that although the basal level of autophagy did not differ between MSCs from healthy donors (HDMSCs) and ASMSCs, LPS-induced autophagy was weaker in ASMSCs than in HDMSCs. Specifically, increased TRAF4 expression in ASMSCs impaired LPS-induced autophagy, potentially by inhibiting the phosphorylation of Beclin-1. These data may provide further insight into ASMSC dysfunction and the precise mechanism underlying the pathogenesis of AS.
Autoimmune Diseases ; Autophagy* ; Bacteria ; Gram-Negative Bacteria ; Humans ; In Vitro Techniques ; Membranes ; Mesenchymal Stromal Cells* ; Pathologic Processes ; Phosphorylation ; Rheumatic Diseases ; Sacroiliac Joint ; Spine ; Spondylitis, Ankylosing* ; Tissue Donors ; TNF Receptor-Associated Factor 4*

OBJECTIVE: To explore the effect of job burnout of medical staffs on their mental health and the regulating effect of social support and mediating effect of coping style. METHODS: A total of 758 medical staffs in a city of Shandong Province were selected as study subjects by stratified random sampling method and investigated using the Maslach Burnout Questionnaire,General Health Questionnaire,Social Support Rating Scale and Trait Coping Style Questionnaire. RESULTS: Job burnout was negatively associated with social support and positive coping( P < 0. 01),and positively associated with mental health and negative coping( P < 0. 01). Both social support and positive coping style showed a negative correlation with mental health( P < 0. 01). A positive correlation was found between negative coping styles and mental health( P <0. 01). Job burnout showed a direct positive prediction function to mental health [standardized regression coefficients( β) = 0. 28,P < 0. 01]. The subjective support dimensions of social support played a role of negative prediction in regulating job burnout and mental health( β =-0. 10,P < 0. 01). Coping styles played a mediating role in job burnout and mental health. Job burnout affected mental health problems by reducing the positive coping and increasing the partial intermediary role of negative coping,the mediation effect was 10. 9%. CONCLUSION: The medical staffs in Shandong Province have low incidence of job burnout. Job burnout shows negative effect on mental health. Subjective support feelings from social support and positive coping style are important protective factors.

BACKGROUND:Ankylosing spondylitis is an autoimmune disease at high inflammatory state, and its pathogenesis is stil unclear. Besides, there is a lack of entirely satisfactory curative strategies. OBJECTIVE: To explore the immunoregulation capability of bone marrow mesenchymal stem cels from ankylosing spondylitis patients on macrophages and the potential therapeutic use of bone marrow mesenchymal stem cels from healthy donors on ankylosing spondylitis. METHODS: Bone marrow mesenchymal stem cels were extracted from 21 healthy donors and 25 ankylosing spondylitis patients respectively, and passage 4 cels were used in subsequent experiments. A human monocytic cel line was induced to differentiate into macrophages. The phenotypic markers of bone marrow mesenchymal stem cels and macrophages were detected by flow cytometry. Expressions of tumor necrosis factor-α and tumor necrosis factor-α-stimulated gene 6 (TSG-6) proteins in the supernatant of co-culture system were detected by ELISA. Quantitative real-time PCR was applied to detect the mRNA level of cytokines secreted by bone marrow mesenchymal stem cels and macrophages. RESULTS AND CONCLUSION:The typical mesenchymal stem cel surface markers were expressed in both bone marrow mesenchymal stem cels from healthy donors and patients with ankylosing spondylitis, and CD68 was detected positively in induced macrophages. The protein and mRNA levels of tumor necrosis factor-α secreted by macrophages co-cultured with bone marrow mesenchymal stem cels from patients with ankylosing spondylitis were obviously higher than those from healthy donors (P < 0.05). TSG-6 secreted by bone marrow mesenchymal stem cels from patients with ankylosing spondylitis was lower than that by bone marrow mesenchymal stem cels from healthy donors in both RNA transcriptional and protein levels (P < 0.05). Our study demonstrates that bone marrow mesenchymal stem cels from patients with ankylosing spondylitis shows abnormal immunoregulatory function on inhibiting the tumor necrosis factor-α secretion from macrophages, which reveals a mechanism of immune disorder in ankylosing spondylitis. The therapeutic mechanism of bone marrow mesenchymal stem cels from healthy donors may work by secreting enough TSG-6 to inhibit the activation of macrophages in patients with ankylosing spondylitis, and thereby to decrease the secretion of tumor necrosis factor-α. Cite this article:Sun SH, Wang P, Su CY, Xie ZY, Li YX, Li D, Wang S, Su HJ, Wu XH, Deng W, Wu YF, Shen HY. Bone marrow mesenchymal stem cels derived from patients with ankylosing spondylitis show abnormal immunoregulation capability on macrophages. Zhongguo Zuzhi Gongcheng Yanjiu. 2016;20(1):13-19.

Antiviral Agents ; chemistry ; metabolism ; Crystallography, X-Ray ; Ligands ; Protein Binding ; Protein Structure, Tertiary ; RNA Helicases ; chemistry ; classification ; metabolism ; Static Electricity ; Viral Proteins ; chemistry ; classification ; metabolism ; Zika Virus ; enzymology