Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling.

Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3-dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction-elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast-like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription.

[Natural regeneration of Larix principis-rupprechtii plantations with different densities and its influencing factors]. / ä¸åŒå¯†åº¦åŽåŒ—è½å¶æ¾æž—å¤©ç„¶æ›´æ–°åŠå ¶å½±å“å› å­.

In this study, we analyzed the natural regeneration of Larix principis-rupprechtii pure plantations with stand densities of 128, 240, 320, 400, 480, 560, 640 and 720 trees·hm-2 in the Guandi Mountains and its influencing factors. The results showed that the regeneration index first increased and then decreased with the increases of stand density, and that the regeneration performance of stand with medium density (400-560 trees·hm-2) was significantly better than other stands. Light conditions, herbaceous plants and litter of the understory had a dual effect on the regeneration of L. principis-rupprechtii. Excessive light, herbaceous plant cover or over-thick litter was not instrumental to the regeneration. Soil organic matter promoted stand regeneration by providing soft soil texture, adequate water content, low phosphorus but high nitrogen. The effects of the examined factors on the regeneration index were as follows: soil water content (0.798) > total nitrogen (0.621) > litter thickness (-0.597) > soil porosity (0.504) > soil organic matter (0.493) > total phosphorus (-0.404) > transmitted total light (-0.274) > herbaceous plants cover (-0.021). In the plantation management, stand density could be controlled at about 480 trees·hm-2 by thinning or replanting, while litter could be cleared properly to improve soil condition and to promote natural regeneration of L. principis-rupprechtii.

Sphingosine-1-phosphate induces human endothelial VEGF and MMP-2 production via transcription factor ZNF580: novel insights into angiogenesis.

Sphingosine-1-phosphate (S1P)-induced migration and proliferation of endothelial cells are critical for angiogenesis. C2H2-zinc finger (ZNF) proteins usually play an essential role in altering gene expression and regulating the angiogenesis. The aim of this study is to investigate whether a novel human C2H2-zinc finger gene ZNF580 (Gene ID: 51157) is involved in the migration and proliferation of endothelial cells stimulated by S1P. Our study shows that EAhy926 endothelial cells express S1P1, S1P3 and S1P5 receptors. Furthermore, S1P upregulates both ZNF580 mRNA and protein levels in a concentration- and time-dependent manner. SB203580, the specific inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, blocks the S1P-induced upregulation of ZNF580. Moreover, overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) expression as well as the migration and proliferation of EAhy926 endothelial cells. These results elucidate the important role that ZNF580 plays in the process of migration and proliferation of endothelial cells, which provides a foundation for a novel approach to regulate angiogenesis.

[The role of ZFP580 in the regulation of rat VSMCs migration by ATRA and its mechanism].

OBJECTIVE: To investigate the probable roles of the novel C2H2 zinc finger transcription factor ZFP580 on all-transretinoic acid (ATRA)-regulated VSMCs migration and underlying mechanisms. METHODS: Rat aortic VSMCs were isolated, cultured and identified. VSMCs were treated with ATRA at the concentrations of 0, 5, 10 or 20 µmol/L for 24 hours. The migration ability of VSMCs was observed in each group and compared with control group which was treated by 0 µmol/L ATRA. The mRNA and protein expression levels of ZFP580 were detected by QPCR and Western blot. ZFP580 protein expression in VSMCs was detected under ATRA stimulation when ERK inhibitor PD98059 was used to inhibit the protein expression of ERK. Adenovirus transfection technology was used to obtain VSMCs with overexpression or low expression of ZFP580, and QPCR and Western blot were used to detect the mRNA and protein levels of MMP-2, MMP-9 and ZFP580. RESULTS: On the 10th day of VSMCs culture, immunofluorescence showed that SM22 alpha antibody, as a specific marker of smooth muscle cells, was positive. Compared to the control group, VSMCs migration was reduced by 32%, 43%, and 59% in the group of 5, 10, and 20 µmol/L ATRA pretreatment. Compared with the control group, VSMCs treated by 20 µmol/L ATRA reduced the cell migration by 49%, 36% and 22% at 24, 48 and 72 h. The mRNA and protein expression levels of ZFP580 were increased with the increase of ATRA stimulation solubility and the extension of stimulation time. ERK was increased significantly after 15 min of ATRA stimulation. Pretreatment with ERK inhibitor PD98059 (20 µmol/L) inhibited the expression of ERK protein and reduced the expression of ATRA-induced ZFP580 protein. Overexpression of ZFP580 inhibited the expressions of MMP-2 and MMP-9, whereas down-expression of ZFP580 promoted the expressions of MMP-2 and MMP-9. CONCLUSION: ATRA increased the expression of ZFP580 through the ERK signaling pathway, while ZFP580 was involved in ATRA's inhibition of VSMCs migration by affecting the expression of downstream MMP-2 and MMP-9.

Effects of constrained dynamic loading, CKIP­1 gene knockout and combination stimulations on bone loss caused by mechanical unloading.

Mechanical stimulation plays an important role in maintaining the growth and normal function of the skeletal system. Mechanical unloading occurs, for example, in astronauts spending long periods of time in space or in patients on prolonged bed rest, and causes a rapid loss of bone mass. Casein kinase 2­interacting protein­1 (CKIP­1) is a novel negative bone regulation factor that has been demonstrated to reduce bone loss and enhance bone formation. The aim of this study was to investigate the effect of constrained dynamic loading (Loading) in combination with CKIP­1 gene knockout (KO) on unloading­induced bone loss in tail­suspension mice. The blood serum metabolism index [alkaline phosphatase (ALP) activity and osteocalcin (OCN) levels], tibia mechanical behavior (including bone trabecular microstructure parameters and tibia biomechanical properties), osteoblast­related gene expression [ALP, OCN, collagen I and bone morphogenetic protein­2 and osteoprotegerin (OPG)] and osteoclast­related gene expression [receptor activators of NF­kB ligand (RANKL)] were measured. The results demonstrated that mice experienced a loss of bone mass after four weeks of tail suspension compared with a wild type group. The mechanical properties, microarchitecture and mRNA expression were significantly increased in mice after Loading + KO treatment (P<0.05). Furthermore, compared with loading or KO alone, the ratio of OPG/RANKL was increased in the combined treatment group. The combined effect of Loading + KO was greater than that observed with loading or KO alone (P<0.05). The present study demonstrates that Loading + KO can counter unloading­induced bone loss, and combining the two treatments has an additive effect. These results indicate that combined therapy could be a novel strategy for the clinical treatment of disuse osteoporosis associated with space travel or bed rest.

Contrast-enhanced ultrasound for differentiating benign from malignant solid small renal masses: comparison with contrast-enhanced CT.

PURPOSE: The study aimed to compare the diagnostic efficiency of contrast-enhanced ultrasound (CEUS) with that of contrast-enhanced computed tomography (CECT) in the evaluation of benign and malignant small renal masses (SRMs) (<4 cm) confirmed by pathology. METHODS: A total of 118 patients with 118 renal masses smaller than 4 cm diagnosed by both CEUS and CECT were enrolled in this study, including 25 benign lesions and 93 malignant lesions. All lesions were confirmed by histopathologic diagnosis after surgical resection. The diagnostic imaging studies of the patients were retrospectively reviewed by two independent ultrasonologists and two independent radiologists blinded to the CT or ultrasound findings and final histological results. All lesions on both CEUS and CECT were independently scored on a 3-point scale (1: benign, 2: equivocal, and 3: malignant). The concordance between interobserver agreement was interpreted using a weighted kappa statistic. The diagnostic efficiency of the evaluation of benign and malignant lesions was compared between CEUS and CECT. RESULTS: All the 118 included lesions were detected by both CEUS and CECT. In CEUS and CECT imaging evaluation of the 118 lesions, the weighted kappa value interpreting the concordance between interobserver agreement was 0.89 (95% CI 0.79-0.98) and 0.93 (95% CI 0.87-0.99), respectively. Both CEUS and CECT demonstrated good diagnostic performance in differential diagnosis of benign and malignant SRMs with sensitivity of 93.5% and 89.2%, specificity of 68% and 76%, PPV of 91.6% and 93.3%, NPV of 73.9% and 65.5%, and AUC of 0.808 and 0.826, respectively. There was no statistically significant difference in any of the diagnostic performance indices between these two methods (P > 0.05). However, the qualitative diagnosis of small papillary renal cell carcinoma (RCC) by CEUS was significantly better than that by CECT (P < 0.05), while there was no significant difference in qualitative diagnostic accuracy on other histotypes of SRMs between CEUS and CECT (P > 0.05). CONCLUSIONS: Both CEUS and CECT imaging modalities are effective for the differential diagnosis of benign and malignant SRMs. Furthermore, CEUS may be more effective than CECT for the qualitative diagnosis of small papillary RCC.