Ninety-eight miRNAs are involved in the immune response. However, the genetic roles of these miRNAs remain unclear in Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aimed to explore the association and functional roles of copy number variants (CNV) in several miRNAs with BD and VKH syndrome. Genotyping of CNVs was examined by TaqMan PCR. The expression of miR-23a, transfection efficiency and cytokine production were measured by real-time PCR, flow cytometry or ELISA. First, replication and combined studies for miR-23a, miR-146a and miR-301a demonstrated a similar association with VKH syndrome (Combined: P = 5.53 × 10(-8); P = 8.43 × 10(-31); P = 9.23 × 10(-8), respectively). No association of CNVs of the above mentioned miRNAs was observed in BD patients. mRNA expression of miR-23a showed a positive association with its copy numbers. Additionally, individuals with high copy number of miR-23a show an increased production of interleukin-6 (IL-6), but not IL-8 and monocyte chemoattractant protein-1 (MCP-1) by stimulated PBMCs. miR-23a transfected ARPE-19 cells modulated the production of IL-6 and IL-8, but not MCP-1. Our results suggest that CNVs of miR-146a, miR-23a and miR-301a confer susceptibility to VKH syndrome, but not to BD. The contribution of miR-23a to VKH syndrome may be mediated by increasing the production of IL-6.

Diabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM).

Paraoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme that performs multiple physiological activities. Previous studies suggest that PON1 plays an anti-inflammatory role in the cardiovascular system, although its roles in hematopoiesis and adaptive immunity have not been clarified. To investigate the impact of PON1 on the immune system, we generated PON1-knockout (PON1-/-) rats using the CRISPR/Cas9 system. The thymus was smaller in PON1-/- rats than that in wild-type (PON1+/+) rats. Furthermore, analysis of thymocyte development revealed diminished total T cell numbers and a decrease in CD4+, CD8+ and double-positive T cells in peripheral blood and thymus from PON1-/- rats. This may be due to a block in the transition of T cells from the double-negative to the double-positive stage. We also showed that the activation of p38 MAPK phosphorylation contributed to the increased apoptosis and defective T cell development in PON-/- rats. Therefore, our results indicate that PON1 functions as a novel regulator of T cell development.

TRAF5 and TRAF3IP2 have been reported to be associated with several autoimmune diseases. Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two autoimmune uveitis entities whereby both genetic and environmental factors are thought to be involved.

Natural antisense transcripts (NATs), as one type of regulatory RNAs, occur prevalently in plant genomes and play significant roles in physiological and pathological processes. Although their important biological functions have been reported widely, a comprehensive database is lacking up to now. Consequently, we constructed a plant NAT database (PlantNATsDB) involving approximately 2 million NAT pairs in 69 plant species. GO annotation and high-throughput small RNA sequencing data currently available were integrated to investigate the biological function of NATs. PlantNATsDB provides various user-friendly web interfaces to facilitate the presentation of NATs and an integrated, graphical network browser to display the complex networks formed by different NATs. Moreover, a 'Gene Set Analysis' module based on GO annotation was designed to dig out the statistical significantly overrepresented GO categories from the specific NAT network. PlantNATsDB is currently the most comprehensive resource of NATs in the plant kingdom, which can serve as a reference database to investigate the regulatory function of NATs. The PlantNATsDB is freely available at http://bis.zju.edu.cn/pnatdb/.

TNF Receptor-Associated Factor 5 (TRAF5) has been shown to be associated with autoimmune disease. The current study sought to investigate the potential association of TRAF5 with acute anterior uveitis (AAU) and pediatric uveitis in Han Chinese.

The carcass and meat quality traits of pig breeds living at three different altitudes (Yorkshire pigs, YP: 500m; Qingyu Pigs, QYP: 1500m; Tibetan pigs, TP: 2500m) were compared. It was observed that there are obvious differences in pig breeds with respect to performance parameters. Specifically, YP had the best carcass traits, showing high slaughter rates and leanest meat. Conversely, QYP had the highest back fat thickness and intramuscular fat (IMF) content. For the high-altitude breed TP, the animals exhibited low L* and high a* values. The genotypes contributing to the observed phenotypes were supported by a PCR analysis. The glycolytic genes expression (HK, PFK, PK) were highest in YP, whereas expression of genes related to adipogenesis (C/EBPα, FABP4, SCD1) were highest in QYP. As expected, genes associated with angiogenesis and hypoxia (HIF1a, VEGFA) were expressed at the highest levels in TP. The composition and proportion of amino and fatty acids in pig muscles at the three altitudes examined also varied substantially. Among the breeds, TP had the highest proportion of umami amino acids, whereas QYP had the highest proportion of sweet amino acids. However, TP also exhibited the highest proportion of essential fatty acids and the lowest proportion of n6:n3. This study explains the high-altitude adaptive evolution and the formation of meat quality differences in different altitude pigs from various angles and provides a reference for local pork food processing and genetic improvement of local pigs.

The macrophage-to-myofibroblast transition (MMT) process is an important pathway that contributing to renal interstitial fibrosis (RIF). Fatty acid-binding protein 4 (FABP4) deteriorated RIF via promoting inflammation in obstructive nephropathy. However, the clinical significance of FABP4 in fibrotic kidney disease remains to be determined and little is known of the FABP4 signaling in MMT. Biopsy specimens of chronic kidney disease patients and kidneys subjected to unilateral ureteral obstruction (UUO) of FABP4-deficient mice or FABP4 inhibitor-treated mice were collected for the investigation of FABP4 mediating MMT of RIF. We conducted kidney RNA-seq transcriptomes and TGF-β1-induced bone marrow-derived macrophage (BMDM) assays to determine the mechanisms of FABP4. We found that FABP4 expression correlated with RIF in biopsy specimens and the injured kidneys of UUO mice where FABP4 was co-expressed with MMT cells. In UUO mice, FABP4 deficiency and a highly selective FABP4 inhibitor BMS309403 treatment both suppressed RIF. FABP4 ablation also attenuated the UUO-induced number of MMT cells and serum amyloid A1 (Saa1) expression. The siRNA-mediated Saa1 knockdown decreased the number of MMT cells in vitro. In conclusion, FABP4 is an important factor contributing to RIF by mediating MMT, and genetic/pharmacological inhibition of FABP4 provides a novel approach for the treatment of kidney fibrosis.

Renal ischaemia-reperfusion (RI/R) injury is one major pathological state of acute kidney injury (AKI) with a mortality rate ranking 50% to 80%. MiR-144-5p acts as a molecular trigger in various diseases. We presumed that miR-144-5p might be involved RI/R injury progression. We found that RI/R injury decreased miR-144-5p expression in rat models. MiR-144-5p downregulation promoted cell apoptosis rate and activated Wnt/β-catenin signal in RI/R injury rats. By performing bioinformatic analysis, RIP, RNA pull-down, luciferase reporter experiments, we found that circ-AKT3 sponged to miR-144-5p and decreased its expression in RI/R injury rats. Moreover, we found that circ-AKT3 promoted cell apoptosis rate and activated Wnt/β-catenin signal, and miR-144-5p mimic reversed the promotive effect of circ-AKT3 in rat models. We also found that circ-AKT3 increased the oxidative stress level in rat models. In conclusion, our study suggests that the circAKT3 is involved RI/R injury progression through regulating miR-144-5p/Wnt/β-catenin pathway and oxidative stress.

Hypertension may be influenced by multiple factors, including social and individual determinants. Regional and individual economic disparity in China is closely associated with such factors that may give rise to diverse health outcomes. This study examines the relationship between regional economic development, household income, gender and hypertension prevalence in China.

Alzheimer's disease is a neurodegenerative disorder. Therapeutically, a transplantation of bone marrow mesenchymal stem cells (BMMSCs) can play a beneficial role in animal models of Alzheimer's disease. However, the relevant mechanism remains to be fully elucidated.

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients' kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell's C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II-IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.

Tanshinone IIA (TSA), a major lipophilic component extracted from the roots of Salvia miltiorrhiza Bunge, has been widely used in China for its various biological activities. However, its effect on ovarian reserve in aged mice was not studied elsewhere.

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.

The current view is that eukaryotic replisomes are independent. Here we show that Ctf4 tightly dimerizes CMG helicase, with an extensive interface involving Psf2, Cdc45, and Sld5. Interestingly, Ctf4 binds only one Pol α-primase. Thus, Ctf4 may have evolved as a trimer to organize two helicases and one Pol α-primase into a replication factory. In the 2CMG-Ctf43-1Pol α-primase factory model, the two CMGs nearly face each other, placing the two lagging strands toward the center and two leading strands out the sides. The single Pol α-primase is centrally located and may prime both sister replisomes. The Ctf4-coupled-sister replisome model is consistent with cellular microscopy studies revealing two sister forks of an origin remain attached and are pushed forward from a protein platform. The replication factory model may facilitate parental nucleosome transfer during replication.

Early and accurate diagnosis of prostate cancer (PCa) is extremely important, as metastatic PCa remains hard to treat. EWI-2, a member of the Ig protein subfamily, is known to inhibit PCa cell migration. In this study, we found that EWI-2 localized on both the cell membrane and exosomes regulates the distribution of miR-3934-5p between cells and exosomes. Interestingly, we observed that EWI-2 is localized not only on the plasma membrane but also on the nuclear envelope (nuclear membrane), where it regulates the nuclear translocation of signaling molecules and miRNA. Collectively, these functions of EWI-2 found in lipid bilayers appear to regulate PCa cell metastasis through the epidermal growth factor receptor-mitogen-activated protein kinase-extracellular-signal-regulated kinase (EGFR-MAPK-ERK) pathway. Our research provides new insights into the molecular function of EWI-2 on PCa metastasis, and highlights EWI-2 as a potential PCa biomarker.

Renal fibrosis is a pathologic change in chronic kidney disease (CKD). MicroRNAs (miRNAs) have been shown to play an important role in the development of renal fibrosis. However, the biological role of miR-27b-3p in renal fibrosis remains unclear. Thus, this study aimed to investigate the role of miR-27b-3p in the progression of renal fibrosis. In this study, HK-2 cells were stimulated with transforming growth factor (TGF)-β1 for mimicking fibrosis progression in vitro. The unilateral ureteric obstruction (UUO)-induced mice renal fibrosis in vivo was established as well. The results indicated that the overexpression of miR-27b-3p significantly inhibited epithelial-to-mesenchymal transition (EMT) in TGF-β1-stimulated HK-2 cells, as shown by the decreased expressions of α-SMA, collagen III, Fibronectin and Vimentin. In addition, overexpression of miR-27b-3p markedly decreased TGF-β1-induced apoptosis in HK-2 cells, as evidenced by the decreased levels of Fas, active caspase 8 and active caspase 3. Meanwhile, dual-luciferase assay showed that miR-27b-3p downregulated signal transducers and activators of transcription 1 (STAT1) expression through direct binding with the 3'-UTR of STAT1. Furthermore, overexpression of miR-27b-3p attenuated UUO-induced renal fibrosis via downregulation of STAT1, α-SMA and collagen III. In conclusion, miR-27b-3p overexpression could alleviate renal fibrosis via suppressing STAT1 in vivo and in vitro. Therefore, miR-27b-3p might be a promising therapeutic target for the treatment of renal fibrosis.

The high mortality rate of non-small-cell lung cancer (NSCLC) is mostly due to the high risk of recurrence. A comprehensive understanding of proliferation mechanisms of NSCLC would remarkably contribute to blocking up the invasion and metastasis of tumor cells. In our previous study, the remarkable decreased activity of Thiamine-dependent enzymes (TDEs), involving in intermediary metabolism responsible for energy production of tumor, was found under conditions of thiamine deficiency in vivo. To explore the effect of Oxythiamine (OT), a TDEs antimetabolite, on cell growth, we co-cultured A549 cells with OT in vitro at various doses (0.1, 1, 10 and 100 μM) and time periods (6, 12, 24 and 48 h) and subsequent cell proliferation and apoptosis assays were performed respectively. Our findings demonstrated that A549 cells proliferation was significantly downregulated by OT treatment in a progressively dose as well as time dependent manner. Inhibition of TDEs resulted in antagonism of lung cancer growth by inducing cells to cease the cycle as well as apoptotic cell death. We concluded a critical role of OT, a TDEs antagonistic compound, indicating the potential target of its practical use.

Obesity has become a worldwide epidemic, caused by many factors such as genetic regulatory elements, unhealthy diet, and lack of exercise. MicroRNAs (miRNAs) are non-coding single-stranded RNA classes, which are about 22 nucleotides in length and highly conserved among species. In the last decade, a series of miRNAs were identified as therapeutic targets for obesity. In the present study, we found that miR-126b-5p was associated with adipogenesis. miR-126b-5p overexpression promoted the proliferation of 3T3-L1 preadipocytes by upregulating the expression of proliferation-related genes and downregulating the expression of apoptosis-related genes; the inhibition of miR-126b-5p gave rise to opposite results. Similarly, miR-126b-5p overexpression could promote the differentiation of 3T3-L1 preadipocytes by increasing the expression of lipid deposition genes and triglyceride (TG) and total cholesterol (TC) levels. Moreover, luciferase reporter assay demonstrated that adiponectin receptor 2 (Adipor2) and acyl-CoA dehydrogenase, long chain (ACADL) were the direct target genes of miR-126b-5p. Moreover, overexpression of miR-126b-5p could exacerbate the clinical symptoms of obesity when mice were induced by a high-fat diet, including increased adipose tissue weight, adipocyte volume, and insulin resistance. Interestingly, overexpression of miR-126b-5p in preadipocytes and mice could significantly increase total fatty acid content and change the fatty acid composition of adipose tissue. Taken together, the present study showed that miR-126b-5p promotes lipid deposition in vivo and in vitro, indicating that miR-126b-5p is a potential target for treating obesity.

Senescence of bone marrow-derived mesenchymal stem cells (BMSCs) has been widely reported to be closely correlated with aging-related diseases, including osteoporosis (OP). Moreover, the beneficial functions of BMSCs decline with age, limiting their therapeutic efficacy in OP. In the present study, using RNA sequencing (RNA-Seq), we found that leucine-rich repeat containing 17 (LRRc17) expression in BMSCs was highly positively correlated with age. Therefore, we investigated whether LRRc17 knockdown could rejuvenate aged MSCs and increase their therapeutic efficacy in OP. Consistent with the RNA-Seq results, the protein expression of LRRc17 in senescent BMSCs was significantly increased, whereas LRRc17 knockdown inhibited cell apoptosis and reduced the expression of age-related proteins and G2 and S phase quiescence. Furthermore, LRRc17 knockdown shifted BMSCs from adipogenic to osteogenic differentiation, indicating the critical role of LRRc17 in BMSC senescence and differentiation. Additionally, similar to rapamycin (RAPA) treatment, LRRc17 knockdown activated mitophagy via inhibition of the mTOR/PI3K pathway, which consequently reduced mitochondrial dysfunction and inhibited BMSC senescence. However, the effects of LRRc17 knockdown were significantly blocked by the autophagy inhibitor hydroxychloroquine (HCQ), demonstrating that LRRc17 knockdown prevented BMSC senescence by activating mitophagy. In vivo, compared with untransfected aged mouse-derived BMSCs (O-BMSCs), O-BMSCs transfected with sh-LRRc17 showed effective amelioration of ovariectomy (OVX)-induced bone loss. Collectively, these results indicated that LRRc17 knockdown rejuvenated senescent BMSCs and thus enhanced their therapeutic efficacy in OP by activating autophagy.