Surfactant protein-A inhibits thymic stromal lymphopoietin-mediated T follicular helper cell differentiation and IgE production in asthma.

Lung surfactant protein A (SP-A) is critical for immunomodulation. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) drive T follicular helper (Tfh) cells differentiation in allergic asthma. We employed wild-type (WT) and SP-A-/- mice injected with TSLP and ovalbumin (OVA)-activated DCs and challenged with OVA. Compared with WT mice, we showed that allergic inflammation was dramatically increased in SP-A-/- mice. In parallel, both IL-4-producing CD45RA-CXCR5+PD-1+CD4+ cells (Tfh2) and IgE were markedly increased in SP-A-/- mice. Further study showed that SP-A prohibited TSLP activated-DCs from expressing OX40L. When we blocked OX40L-OX40 and IL-4R signaling, the differentiation of Tfh2 and IgE responses in SP-A-/- mice was significantly inhibited. In severe asthma patients, SP-A is dysfunctional in modulating the TSLP-DCs-mediated differentiation of Tfh cells. This study suggests that SP-A acts as a modulator of Tfh differentiation and IgE generation in asthma.

Inflammation accelerates copper-mediated cytotoxicity through induction of six-transmembrane epithelial antigens of prostate 4 expression.

Copper is an essential trace metal, but imbalance in copper homeostasis can induce oxidative damage. Inflammation is a fundamental element of various pulmonary diseases. Although a positive relationship between copper and chronic pulmonary diseases has been reported, the underlying reasons are still not clear. The copper level in the sputum of patients with various pulmonary diseases was measured. An inflammatory model was established to evaluate the impact of inflammation on copper uptake in the lung. We found that the level of sputum copper was increased in patients with various pulmonary diseases, especially chronic obstructive pulmonary disease and asthma. Then, we confirmed that mice with pulmonary inflammation were susceptible to copper-mediated oxidative damage because of copper overload in lung tissue. Further investigation demonstrated that interleukin (IL)-17 and tumor necrosis factor (TNF)-α exerted synergistic effects in airway epithelial cells by upregulating the expression of six-transmembrane epithelial antigens of prostate 4 (STEAP4), a metalloreductase that reduces extracellular copper ions from the cupric state to the cuprous state and facilitates copper uptake. Inhibition of STEAP4 decreased the copper uptake of cells and inhibited copper-mediated oxidative damage. Moreover, we demonstrated that the upregulation of STEAP4 by IL-17 and TNF-α was largely dependent on TNF receptor-associated factor 4 (TRAF4). Traf4-/- mice were resistant to copper-mediated oxidative damage. Our data suggest a novel IL-17/TNF-α-TRAF4-STEAP4 axis that regulates copper homeostasis.

IL-6 alters migration capacity of CD4+Foxp3+ regulatory T cells in systemic lupus erythematosus.

Regulatory T cells (Tregs) are impaired in human systemic lupus erythematosus (SLE) and involved in disease pathogenesis. However, the mechanisms responsible for the Treg dysfunction in SLE remain unclear. In this study, we aimed to investigate the chemotaxis of Treg response to inflammatory stimulation. Sixty two patients were enrolled, and chemokine receptors, including CCR4, CCR5, CCR6, CCR8 and CXCR3 on CD4+Foxp3+Tregs and non-Treg CD4 T cells, were analysed using FACS. The expression of CCR4 and CCR6 on Tregs of SLE patients decreased, while the expression of CCR4 on non-Treg CD4 T cells increased, as compared with those of age- and sex-matched healthy donors. In parallel, in SLE, the chemotactic capacity of non-Treg CD4 T cells response to CCR4 and CCR6 ligands dramatically increased, while that of Tregs significantly decreased. Moreover, we found that cytokines IL-6 and IL-10 positively and negatively modulate the expression of those receptors respectively. IL-6, the significantly increased cytokine in active SLE, dramatically elevated CCR4 and CCR6 expression on non-Treg CD4 T cells. However, as for Tregs, these cells produced more IL-10 than non-Treg CD4 T cells upon IL-6 stimulation, and these IL-10 led to the inhibition of CCR4 and CCR6. In sum, our data provided new evidence suggesting a functional deficiency of Tregs in SLE. It may suggest that those dysfunctional Tregs have less access to the inflammation locus to exert inhibitory capacity.

CircRBMS3 promotes gastric cancer tumorigenesis by regulating miR-153-SNAI1 axis.

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Mounting evidence showed that circular RNAs (circRNAs) play critical roles in human malignancy. However, the knowledge about circRNAs in GC is still unclear. In the current study, high throughput microarray assay showed that circRBMS3 was upregulated in GC tissues, which was further confirmed by quantitative reverse transcription polymerase chain reaction. Correlation analysis revealed that high circRBMS3 expression was associated with advanced TNM stage, depth of invasion, and lymph-node metastasis. Kaplan-Meier analysis indicated that GC patients with high circRBMS3 expression have a poor overall survival (OS). Function assays showed that circRBMS3 silencing reduced GC cells proliferation and invasion in vitro, and inhibited the tumor growth in vivo. Mechanistically, we found that miR-153 could act as a target of circRBMS3. Subsequently, we showed that circRBMS3 promoted snail family zinc finger 1 (SNAI1) expression via inhibiting miR-153 in GC cells. Collectively, these results suggested that circRBMS3 promoted GC cells proliferation and invasion via regulating miR-153/SNAI1 axis.

Reprograming of peripheral Foxp3+ regulatory T cell towards Th17-like cell in patients with active systemic lupus erythematosus.

Treg is essential to limit the extend and duration of the immune response, but its stability is still under debate. Here we demonstrate that IL-17-producing Treg cells (Th17-like cells) increased in peripheral blood of patients with Systemic Lupus Erythematosus (SLE). Notably, the Th17-like cells from patient with active SLE were characterized with some phenotype and function of Th17 cells. Upon stimulation, Helios-Foxp3 + CD4+ T cells decrease Foxp3 expression but increase expression of IL-17 and RORγt. Damage associated molecule pattern and inflammatory cytokines are important for induction of IL-17 expression in Treg cells. The Th17-like cells from patients with active SLE lose suppressive function and have robust response to stimulation of autoantigens. We also observed that the level of Th17-like cells in peripheral blood is closely associated with the clinical index of SLE. These findings suggest that instability of Treg plays a critical role in pathogenesis of autoimmune diseases.

hsa_circ_0081143 promotes cisplatin resistance in gastric cancer by targeting miR-646/CDK6 pathway.

BACKGROUND: Increasing studies indicated that circRNAs play critical roles in tumor progression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain largely unclear. METHODS: Microarray assay was used to screen the abnormally expressed circRNAs in GC. Cell viability assay, transwell assay and in vivo assay were performed to assess the effects of hsa_circ_0081143 on GC cells. Next, interaction between hsa_circ_0081143 and miR-646 was detected by luciferase reporter assay and RNA pull-down assay. RESULTS: High throughput microarray assay showed that hsa_circ_0081143 was upregulated in GC tissues, which was further confirmed by qRT-PCR. Correlation analysis showed that high hsa_circ_0081143 expression was associated with the advanced TNM stage, lymphnode metastases, and poor overall survival of GC patients. Hsa_circ_0081143 inhibition decreased GC cells viability, invasion ability and induced the sensitivity of GC cells to cisplatin (DDP) in vitro. Mechanistically, we showed that hsa_circ_0081143 could act as an endogenous sponge by directly binding to miR-646 and downregulation of miR-646 efficiently reversed the inhibition of CDK6 induced by hsa_circ_008114 knockdown. Additionally, hsa_circ_0081143 silencing suppressed the tumorigenesis and remarkably enhance DDP inhibitory effects of GC cells in vivo. CONCLUSIONS: Our study indicated a novel regulatory loop that hsa_circ_0081143/miR-646/CDK6 axis in GC progression. These data suggested that hsa_circ_0081143 might act as a potential novel therapeutic strategy for GC treatment.

Catalytic hydrogenation of olefins by a multifunctional molybdenum-sulfur complex.

Exploration of molybdenum complexes as homogeneous hydrogenation catalysts has garnered significant attention, but hydrogenation of unactivated olefins under mild conditions are scarce. Here, we report the synthesis of a molybdenum complex, [Cp*Mo(Ph2PC6H4S-CH = CH2)(Py)]+ (2), which exhibits intriguing reactivity toward C2H2 and H2 under ambient pressure. This vinylthioether complex showcases efficient catalytic activity in the hydrogenation of various aromatic and aliphatic alkenes, demonstrating a broad substrate scope without the need for any additives. The catalytic pathway involves an uncommon oxidative addition of H2 to the cationic Mo(II) center, resulting in a Mo(IV) dihydride intermediate. Moreover, complex 2 also shows catalytic activity toward C2H2, leading to the production of polyacetylene and the extension of the vinylthioether ligand into a pendant triene chain.

Glutathione S-transferase P1 Ile105Val polymorphism contributes to increased risk of gastric cancer in East Asians.

Glutathione S-transferase P1 (GSTP1) is an important enzyme playing critical roles in the phase II detoxification pathway. There were many studies investigating the association between GSTP1 gene Ile105Val polymorphism and gastric cancer risk, but studies from East Asians reported inconsistent findings. We performed a meta-analysis to investigate the association in East Asians. Published literature from PubMed and Chinese Biomedical Literature databases were searched for eligible publications. Pooled odds ratios (ORs) with 95 % confidence intervals (95 %CIs) were calculated using random or fixed-effect model according the between-study heterogeneity. A total of 12 studies with 2,552 cases and 5,474 controls were finally included into the meta-analysis. Meta-analysis of those 12 studies showed that there was an obvious association between GSTP1 Ile105Val polymorphism and gastric cancer risk in East Asians under three genetic models (for valine vs. isoleucine, OR=1.32, 95 %CI 1.05-1.66, P=0.015; for ValVal vs. IleIle, OR=2.00, 95 %CI 1.34-2.98, P=0.001; for the recessive model, OR=1.96, 95 %CI 1.35-2.83, P<0.001). Sensitivity analysis by removing one study at a time suggested the pooled results were stable under the three genetic models above. There was no risk of publication bias. In conclusion, the meta-analysis suggests that there is a strong evidence for the association between GSTP1 Ile105Val polymorphism and increased risk of gastric cancer in East Asians and contributes to increased risk of gastric cancer in East Asians.

Association analysis between MDR1 gene polymorphisms and risk of hepatocellular carcinoma in Chinese population.

The objective of this study was to evaluate the association between MDR1 gene polymorphisms and hepatocellular carcinoma (HCC) risk. Genomic DNA of 1431 subjects was extracted from peripheral blood and genotyping was performed using the created restriction site-polymerase chain reaction (CRS-PCR). We found that the c.1465C > T single nucleotide polymorphisms (SNP) increased HCC risk in all genetic models (p < 0.05) and the allele-T of c.1465C > T may contribute to the risk of HCC. No significantly increased HCC risk was detected in c.159G > T SNP. Our data indicated that the genetic variants of MDR1 gene may be a valuable molecular marker for HCC.

[Retracted] MicroRNA­145 inhibits the malignant phenotypes of gastric carcinoma cells via downregulation of fascin 1 expression.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell apoptotic assay data shown in Figs. 3D and 4D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 13: 1033­1039, 2016; DOI: 10.3892/mmr.2015.4609].

Impact of Corticosteroids on the Proportions of Circulating Tfh Cell Subsets in Patients With Systemic Lupus Erythematous.

Objectives: This study aimed to analyze the distribution of T follicular helper (Tfh) cells in lupus patients, and the effects of steroids on circulating Tfh cells. Methods: Circulating Tfh cell subsets were defined by multicolor flow cytometry as Tfh17, Tfh2 or Tfh1 subpopulations of CXCR5+CD45RA-CD4+ T cells in the peripheral blood of SLE patients and healthy controls. To test the effects of corticosteroid on Tfh cells, PBMC harvested from both SLE and healthy controls were cocultured with dexamethasone, and then analyzed by Flow cytometry. Results: The proportion of Tfh17 cells in SLE patients was increased significantly compared with healthy controls. Additionally, patients with an active disease had reduced Tfh1 subsets than those with an inactive disease and healthy controls. The frequency of Tfh2 cells was associated with the proportion of circulating plasmablasts and the amount of anti-dsDNA. Dexamethasone reduced the percentage of Tfh2 cells while increased the proportion of Tfh17 subset in gated CXCR5+CD45RA-CD4+ T cells. Conclusion: Our study investigated the distribution of circulating Tfh subsets in lupus patients. Corticosteroids treatment not only down-regulated the proportion of circulating Tfh cells, but also altered the distribution of Tfh subsets in vivo and in vitro.

[Retracted] MicroRNA­101 induces apoptosis in cisplatin­resistant gastric cancer cells by targeting VEGF­C.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the cell apoptotic assay data shown in Figs. 3C and 5B were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 13: 572­578, 2016; DOI: 10.3892/mmr.2015.4560].

Safety of the Xuesaitong injection in China: results from a large-scale multicentre post-marketing surveillance study in a real-world setting.

OBJECTIVE: The safety profile of traditional Chinese medicine injections has emerged as the greatest challenge to their clinical application. The authors aimed to perform a post-marketing surveillance study in a real-world setting to evaluate the safety of the Xuesaitong (XST) injection in China. METHODS: This multi-centre, post-marketing, observational study enrolled patients who received XST injections in 42 centres in China between March 2015 and November 2017. Adverse drug reactions (ADRs) and adverse drug events (ADEs) were collected and evaluated in a post-marketing database. Logistic regression analysis was performed to analyse the risk factors for ADRs. RESULTS: A total of 30,008 consecutive patients with a mean age of 62.29 ± 14.58 years were included in this post-marketing study. The incidences of ADEs and ADRs were 0.5% and 0.33%, respectively. The most common clinical manifestations were damage to skin and appendages (47.66%). There were four new kinds of ADEs found in the present monitoring study. The majority of ADRs were type B (62.62%) and occurred within 24 h after XST injection treatment. No severe ADRs were reported in this analysis. Multivariate logistic regression analysis showed that the hospital level (OR = 0.607; 95% CI = 0.407-0.906; p = .0144), hypertension (OR = 1.979; 95% CI, 1.323-2.959; p = .0009) and solvent type (OR = 2.951; 95% CI, 1.608-5.417; p = .0005) were risk factors for ADR occurrence. CONCLUSION: XST injection is well tolerated and has a favourable safety profile for patients in a real-world setting. This post-marketing study provided further evidence of the safety of XST injections for clinical applications.

MicroRNA-613 induces the sensitivity of gastric cancer cells to cisplatin through targeting SOX9 expression.

Increasing evidences have suggested that deregulated miRNAs may involve in drug chemoresistance in a lot of human cancers. However, the role of miR-613 in drug chemoresistance of GC cell is still unknown. The expression of miR-613 and Sex-determining region Y (SRY)-box 9 (SOX9) in GC tissues and cell lines was detected by using qRT-PCR. Cell migration and viability were measured by the wound healing assay and CCK-8 assays. Western blot and dual-luciferase reporter were done to identify the target gene of miR-613. We showed that miR-613 expression was downregulated in GC tissues and cell lines. Ectopic expression of miR-613 increased the sensitivity of GC cells to cisplatin. Overexpression of miR-613 suppressed GC cell proliferation, cycle and migration. In addition, we identified SOX9 was a direct target gene of miR-613 in GC cell. We showed that SOX9 expression was upregulated in gastric cancer samples. Moreover, the expression of SOX9 was negatively correlated with miR-613 expression in GC tissues. Furthermore, elevated expression of miR-613 increased the sensitivity of GC cells to cisplatin and suppressed GC cell proliferation and migration by targeting SOX9. These data suggested that miR-613 might function as a chemoresistant suppressor in GC.

MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C.

Deregulation of microRNAs (miRNAs) is known to be associated with drug resistance in human cancers. However, the precise role of miR­101 in the cisplatin (DPP) resistance of human gastric cancer cells has not been elucidated, yet. The present study revealed that miR­101 was markedly downregulated in gastric cancer cell lines compared to that in the normal gastric mucosa epithelial cell line GES1. Furthermore, a significant decrease in miR­101 levels, accompanied with an increased expression of vascular endothelial growth factor (VEGF)­C in DDP­resistant SGC7901 gastric cancer cells (SGC7901/DDP) compared with those in native SGC7901 cells was observed. In addition, forced overexpression of miR­101 significantly inhibited cell proliferation, while enhancing cisplatin­induced apoptosis of SGC7901/DDP cells. A luciferase reporter assay confirmed that VEGF­C was a direct target of miR­101 in SGC7901/DDP cells. Forced overexpression of miR­101 in SGC7901/DDP cells reduced the expression of VEGF­C, while knockdown of miR­101 expression significantly enhanced VEGF­C expression in SGC7901/DDP cells. Finally, overexpression of VEGF­C inhibited DDP­induced apoptosis in SGC7901 cells. In conclusion, the results of the present study suggested that miR­101 inhibited the proliferation and promoted DDP­induced apoptosis of DDP­resistant gastric cancer cells, at least in part via targeting VEGF-C.

MicroRNA­145 inhibits the malignant phenotypes of gastric carcinoma cells via downregulation of fascin 1 expression.

MicroRNA (miR)­145 has been demonstrated to act as a tumor suppressor, and deregulation of fascin 1 (FSCN1) has been observed in several types of human malignancy, including gastric carcinoma. However, the molecular mechanism underlying the function of miR­145, specifically its targets in gastric carcinoma have yet to be fully elucidated. In the present study, downregulation of miR­145 and upregulation of FSCN1 was identified in gastric carcinoma cell lines, compared with normal gastric mucosal epithelial cells. A luciferase reporter assay demonstrated that miR­145 was able to bind to the 3'­untranslated region of FSCN1 mRNA. Overexpression of miR­145 led to a significant decrease in FSCN1 expression levels, whereas knockdown of miR­145 resulted in increased FSCN1 expression levels in gastric carcinoma cells. Furthermore, overexpression of miR­145 inhibited proliferation, migration and invasion in gastric carcinoma cells. Similar effects were also observed in gastric carcinoma cells transfected with FSCN1 small interfering RNA. In addition, overexpression of FSCN1 reversed the suppressive effects of miR­145 upregulation on proliferation, migration and invasion in gastric carcinoma cells, suggesting that FSCN1 is indeed involved in the miR­145­mediated malignant phenotype of gastric carcinoma cells. The present study revealed an anti­oncogenic role of miR­145 in gastric carcinoma via inhibition of FSCN1, and suggested that miR­145 may be used for the treatment of gastric carcinoma.

Genetic variability of genes in NER pathway influences the treatment outcome of gastric cancer.

We performed a study to investigate the role of ERCC1, ERCC2, ERCC5, XPA and XPC polymorphisms from perspective of the whole NER pathway in the prognosis of gastric cancer. A total of 410 gastric cancer patients were recruited between January 2010 and December 2011. Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was used to analyze genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs13181 and s1799793, ERCC5 rs17655, XPA rs1800975 and XPC rs2228001. Our study found that carriers of ERCC1 rs3212986 TT genotype showed significantly favorable survival than wide-type GG genotype in multivariate analysis (OR=6.38, 95% CI=2.54-19.03), and patients with variant CC genotype of ERCC2 rs13181 exhibited better response to chemotherapy than those with AA genotype (OR=2.21, 95% CI=1.17-4.25). By Cox proportional hazards model, patients with variant TT genotype of ERCC1 rs3212986 exhibited longer PFS and OS than those who had GG genotype (for PFS, HR=0.37, 95% CI=0.17-0.75; for OS, HR=0.36, 95% CI=0.13-0.87). For ERCC2 rs13181 polymorphism, carriers with CC genotype demonstrated significantly increased hazards of progression of disease and death in multivariate model (for PFS, HR=0.48, 95% CI=0.26-0.88; for OS, HR=0.44, 95% CI=0.20-0.91). In conclusion, our finding suggests that ERCC1 rs3212986 and ERCC2 rs13181 gene polymorphism could influence the response to chemotherapy and clinical outcome of gastric cancer.

miR-27a as an oncogenic microRNA of hepatitis B virus- related hepatocellular carcinoma.

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcriptional interactions with mRNA. miRNAs have recently emerged as key regulators of various cancers. Although miR- 27a has been implicated in several other cancers, its role in hepatitis B virus-related hepatocellular carcinoma (HCC) is unknown. In this study, we showed miR-27a to be frequently up-regulated in HCC tissues and HCC cell lines (HepG2 and Huh7). Overexpression of miR-27a enhanced cell proliferation, promoted migration and invasion, and activated cell cycling in HepG2 and Huh7 cells. In summary, our results suggest that up-regulation of miR-27a may play an oncogenic role in the development of HCC and might thus be a new therapeutic target in HCC patients.

[Inhibitory effect of telomerase inhibitors combined with X-irradiation on bone marrow hematopoiesis in mice].

The purpose of this study was to evaluate the effect of telomerase inhibitors combined with X-irradiation on bone marrow hematopoiesis in tumor-carrying mice. With an orthogonal experiment design, the telomerase inhibitors [azidothymidine, AZT 300 mg/(kg.day) and lamivudine 150 mg/(kg x day), per os, bid, x 2 weeks] and X-irradiation [total dose 10 Gy (2 Gy x 5) in 1 week] were used to treat BALB/c mice carrying breast cancer MA(782) for evaluating the influence on peripheral blood cells, bone marrow nucleated cells and telomerase activity. Telomerase activity was detected by a PCR-based telomeric repeat amplification protocol (TRAP) coupled with ELISA. The results showed that the number of marrow nucleated cells (x 10(7)/femur) was 2.1875 in untreated group, and 1.7375, 1.7500 and 1.3475 in irradiated, lamivudine and AZT groups, respectively, these suggested that AZT and irradiation could obviously decrease the number of marrow nucleated cells (P< 0.01 or P < 0.05). The peripheral WBC increased 3.7% in untreated mice, and irradiation, lamivudine and AZT reduced 18.09%, 16.19% and 41.00% of WBC, respectively (P < 0.05). Irradiation, lamivudine and AZT showed no obvious effect on RBC and platelet counts (P > 0.05). The telomerase activity (A(450) nm) of marrow cells was 1.498, 1.483, 0.816 and 0.727 in untreated, irradiation, lamivudine and AZT groups, respectively. It is concluded that AZT and lamivudine combined with X-irradiation inhibit bone marrow nucleate cells and the peripheral WBC, manifest inhibitory effect on telomerase activity in murine bone marrow, but have no effect on the peripheral RBC and platelet.