Objective To test the level of cell factor interleukin (IL)-21,CXCL13 in the plasma of patients with rheumatoid arthritis (RA),and to analyze the relationship between Follicular helper T cells(Tfh)and clinic features and discuss the possible immunological pathogenesis of RA.Methods The Tfh cells were obtained from patients and healthy controls (NC) and detected by Flow cytometery.While the levels of IL-21,CXCL13 in patients and NC were measured by ELISA tests.Those analysis were performed by student's t-test,one-way ANOVA,SNK-q test,Chi-square test,Spearman's correlation and multiple linear regression.Results The expression of CD4+CXCR5+ICOS+ cells (Tfh) in PBMCs of RA was significantly higher than normal controls (3.0±1.2 vs 1.1±0.4,P＜0.01).Meanwhile,the three RA groups of patients were divided to low,moderate and high disease activity groups,and the results showed that the expression of Tfh were increased accordingly (1.8±0.7,2.5±0.6,4.0±1.2).The expression of Tfh in the three groups were all significantly higher than that of controls (P＜0.01).There was a positive correlation between Tfh and DAS28,ESR,CRP,TJC,and bone erosion,RF and anti-CCP respectively.The expression of Tfh in those patients who had bone destruction was higher than those with no or mild bone destructions (2.7±1.1vs 3.4±1.3).The expression of Tfh in patients with un-treated RA patients,when compared to those RA patients who were treated appropriately and those who were not treated appropriately,was decreased significantly.The expression of Tfh in appropriately treated RA patients was lower than that without appropriately treatment.The level of IL-21,CXCL13 was decreased in patients with RA in the order of high,moderate,low disease activity and NC.Conclusion The expression of Tfh and the levels of IL-21,CXCL13 are increased significantly,and are closely related to disease activity and bone ersions.The expression of Tfh is decreased after relevant treatment.These results indicate that the abnormality of Tfh may play an important role in the pathogenesis of RA.

BACKGROUND: The Htr3a antagonist, ondansetron, has been reported to prolong the QT interval and induce Torsades de pointes in the treatment of postoperative nausea and vomiting. To explore the mechanisms underlying these findings, we examined the effects of ondansetron on the mouse cardiac voltage-gated K⁺ (Kv) channel. METHODS AND RESULTS: Ondansetron increased QT intervals in late pregnant (LP) mice. We measured the Kv channels in freshly isolated left ventricular (LV) myocytes from non-pregnant (NP) and late pregnant (LP) mice, using patch-clamp electrophysiology. Ondansetron blocked Kv current at a dose of 50 µM, and reduced the amplitude of peak current densities in a dose-dependent manner (0, 1, 5, 50 µM), in LP but not in NP mice. In contrast, serotonin and the Htr3 agonist, m-CPBG, increased Kv current densities in NP, but not in LP mice. Interestingly, during pregnancy, serum serotonin levels were markedly increased, suggesting the saturation of the effect of serotonin. Immunostaning data showed that Kv4.3 protein and Htr3a co-localize at the membrane and t-tubule of cardiomyocytes. Moreover, Kv4.3 membrane trafficking was enhanced in response to Htr3a-mediated serotonin stimulation in NP, but not in LP mice. Membrane analysis showed that serotonin enhances Kv4.3 membrane trafficking in NP, but not LP mice. CONCLUSION: Ondansetron reduced Kv current densities, and reduced the Kv4.3 membrane trafficking in LP mouse ventricular cardiomyocytes. This data suggests that QT prolongation by ondansetron is mediated by the reduction of Kv current densities and Kv4.3 membrane trafficking.
Animals ; Electrophysiology ; Membranes ; Mice* ; Muscle Cells* ; Myocytes, Cardiac ; Ondansetron* ; Postoperative Nausea and Vomiting ; Pregnancy ; Serotonin ; Torsades de Pointes

PURPOSE: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs). MATERIALS AND METHODS: EV solutions (0.4 µg/µL) derived from normoxia-preconditioned MSCs (EVNM) and hypoxia-preconditioned MSCs (EVHM) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats. RESULTS: EVHM significantly reduced infarct size (24±2% vs. 8±1%, p < 0.001), and diminished arrhythmias by recovering electrical conduction, INa current, and Cx43 expression. EVHM also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3β induced after IR injury. miRNA-26a was significantly increased in EVHM, compared with EVNM, in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a. CONCLUSION: EVHM reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.
Animals ; Arrhythmias, Cardiac ; Connexin 43 ; Extracellular Vesicles* ; Heart ; Humans* ; In Vitro Techniques ; Mesenchymal Stromal Cells* ; Rats ; Real-Time Polymerase Chain Reaction ; Reperfusion Injury* ; Wnt Signaling Pathway

Objective: To investigate the distribution of gross α and gross β radioactive levels in drinking raw water from different regions of Guangdong province, and to establish the radioactive level base line value in raw water. Methods: The samples from 191 drinking water sources in use in Guangdong province were collected in rainy season and dry season, respectively, and determined and analyzed under the standard examination method for drinking water-radiological parameters (GB/T 5750.13-2006). The levels of gross α and gross β radioactivity were evaluated under the standard for drinking water quality (GB 5749-2006). Results: A total of 377 raw water samples were taken, including 189 samples in rainy season and 188 samples in dry season, in which 186 samples were matched between rainy season and dry season. In dry season, the gross α levels ranged from 0.008 Bq/L to 0.582 Bq/L, averaged at (0.034±0.060) Bq/L, while the gross β levels ranged from 0.014 Bq/L to 0.637 Bq/L, averaged at (0.108±0.091) Bq/L. In rainy season, the gross α levels ranged from 0.008 Bq/L to 0.402 Bq/L, averaged at (0.045±0.064) Bq/L, while the gross β levels ranged from 0.014 Bq/Lto 0.848 Bq/L, averaged at (0.125±0.128) Bq/L. The gross α and gross β radioactivity levels of other samples were much lower than the guidance values in the national radioactivity standards on drinking water radioactivity, except for a sample from Shanwei area. The gross α and gross β radioactivity levels in the rainy season were higher than in the dry water season, and the gross α radioactivity levels in the rainy season were significantly higher than in the dry water season. There were significant differences in gross α and gross β radioactivity levels in rainy(F_{rainy season}=1.819, 2.709, P<0.05) and dry season (F_{dry season}=1.985, 8.461, P<0.05)in different water systems, and the levels of gross α and gross β radioactivity in the rivers in western Guangdong were the highest. The gross α and gross β radioactivity levels of groundwater in rainy season were higher than in river water and lake water, and the gross α and gross β radioactivity levels in river water were higher than in lake and reservoir water, with the statistically significant differences(F_{total α}=39.323, F_{total β}=25.911, P<0.05), the gross α and gross β radioactivity levels in dry season were higher than in river water and lake water, with the statistically significant difference(F_{total α}=11.520, F_{total β}=28.435, P<0.05). The highest radioactivity levels is in groundwater, followed by river water, and the lowest is in lake and reservoir water. Conclusions The natural radioactivity background levels in drinking raw water in Guangdong province is lower than the limit value on drinking water stipulated by our country. The radioactivity levels in raw water in western Guangdong is significantly higher than in other water systems, and the radioactivity level in river water is also significantly higher than in lake and reservoir water.

PURPOSE: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. MATERIALS AND METHODS: We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(−/−)-NP). RESULTS: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(−/−)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. CONCLUSION: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents.
*Action Potentials/drug effects ; Animals ; Cell Membrane/drug effects/metabolism ; Disease Models, Animal ; Electrocardiography ; Female ; HSC70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Heart Ventricles/drug effects/*metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac/drug effects/metabolism ; Potassium Channels/metabolism ; Pregnancy ; Rabbits ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT3/metabolism ; Serotonin/*metabolism ; Serotonin 5-HT3 Receptor Agonists/pharmacology