Proteomic study on CUMS-induced senile depression mice's frontal lobe cortex and the regulating effect of KTLD formula.

OBJECTIVE: The aim of this study was to investigate the protein expression of chronic unpredictable mild stress (CUMS)-induced senile depression in SAMP-8 mice's frontal lobe cortex and the regulating effect of the kidney tonifying and liver dispersing (KTLD) formula. MATERIALS AND METHODS: A total of 15 male SAMP-8 mice were randomly divided into control, CUMS, and KTLD groups. CUMS and KTLD mice were subjected to CUMS for 21 days. Control group mice were kept to normal feeding. At the same time as molding, the herbal gavage (KTLD formula, 19.5 g/kg/d) was given from the beginning of the stress stimulation, while the control group and the CUMS group mice were given the same volume of saline for 21 days. Open-field testing (OFT) was used to assess the mice's depression levels. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify differentially expressed proteins (DEPs) in mice's frontal lobe cortex. Bioinformatics analysis including Gene Ontology (GO); Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) networks were utilized to study the DEPs connections. RESULTS: Results revealed that mice with senile depression experienced more anxiety and depression than control mice, whereas KTLD mice had the opposite experience. Biological processes including transport, regulation of transcription, and DNA-templated were identified in both KTLD and CUMS. The KEGG enrichment study of the DEPs in KTLD revealed their involvement in the MAPK signaling pathway, glutamatergic synapse, dopaminergic synapse, axon guidance, and ribosome. KEGG pathway enrichment showed that the mechanism of senile depression and the pathway of KTLD are closely related to axonal conductance and ribosomes. According to the PPI analysis, disease-related proteins regulated by KTLD revealed that some proteins, such as GLOI1 and TRRAP, have potential interactions. This provides fresh insight into how KTLD works to cue senile depression. CONCLUSIONS: KTLD treats senile depression via multiple targets and pathways, which may include regulations of 467 DEPs. Proteomics showed significant changes in protein levels in geriatric depression and after KTLD intervention. Senile depression involves the cross-linking and modulation of signal pathways, presenting a pattern of multiple pathways and multiple targets. According to a protein pathway enrichment and protein interaction model of KTLD in senile depression, KTLD is capable of treating senile depression via multiple pathways and targets.

Matrix metalloproteinase 12 (MMP12) as an adverse prognostic biomarker of vascular invasion in hepatic cell carcinoma.

OBJECTIVE: Vascular invasion is closely associated with tumor recurrence and poor outcomes in hepatocellular carcinoma (HCC). In this study, we evaluated the potential prognostic value of matrix metalloproteinase-12 (MMP12) as a biomarker of vascular invasion in HCC patients. MATERIALS AND METHODS: The Gene Expression Omnibus GSE77509 and TCGA Liver Hepatocellular Carcinoma datasets were analyzed to explore the relationships between genes, vascular invasion, and patient survival. The role of MMP12 in HCC was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival, as well as in silico analysis. RESULTS: Overexpression of MMP12 was associated with poor prognosis in HCC patients with vascular invasion. MMP12 was identified as an independent predictor of overall survival (OS) (HR 2.543; 95% CI 1.224, 5.285; p = 0.012) and disease-free survival (DFS) (HR 2.034; 95% CI 1.160, 3.566; p = 0.013) in multivariate Cox analysis in HCC patients. MMP12 expression, vascular invasion, tumor status, and AJCC T stage were independent predictors of OS with a concordance index (C-index) of 0.713 (95% CI, 0.671, 0.756). MMP12 expression was related to hypomethylation status and positively correlated with tumor immune cell infiltration and the expression of immune cell-related biomarkers. CONCLUSIONS: Upregulation of MMP12 was associated with poor prognosis and vascular invasion in HCC. These data suggest that MMP12 may have potential as a therapeutic target and biomarker in HCC.

NCAPG is a prognostic biomarker associated with vascular invasion in hepatocellular carcinoma.

OBJECTIVE: Vascular invasion is closely associated with tumor recurrence and poor patient outcomes in individuals diagnosed with hepatocellular carcinoma (HCC). In this study, we explored the potential value of NCAPG as a prognostic biomarker of vascular invasion in HCC patients. MATERIALS AND METHODS: Two Gene Expression Omnibus (GEO) datasets (GSE14520 - GPL3721 Subset; GSE67140 - GPL8786) were utilized to explore the relationship between genes and HCC-associated vascular invasion. Hub genes associated with vascular invasion were identified through analyses of Cytoscape using the Cytohubba plugin, and relationships between specific genes and patient survival outcomes were assessed through univariate and multivariate analyses of the TCGA-Liver Hepatocellular Carcinoma (TCGA-LIHC) database. RESULTS: In total, 10 hub genes were associated with vascular invasion in the two analyzed GEO datasets. Importantly, non-SMC condensin I complex subunit G (NCAPG) overexpression was correlated with poor prognosis for patients in the TCGA-LIHC database. NCAPG was identified as an independent predictor of HCC patient overall survival (OS) (HR 2.543; 95% CI 1.224, 5.285; p = 0.012) and disease-free survival (DFS) (HR 2.034; 95% CI 1.160, 3.566; p = 0.013) in a multivariate Cox analysis. NCAPG expression status, vascular invasion status, tumor status, and AJCC T stage were independent predictors of OS, with a concordance index (c-index) value of 0.713 (95% CI, 0.671, 0.756). NCAPG expression levels were related to hypomethylation status and were positively correlated with tumor immune cell infiltration and immune cell-related biomarker expression. CONCLUSIONS: NCAPG upregulation is associated with poor prognosis in hepatocellular carcinoma patients with vascular invasion.

High HBXIP expression is related to poor prognosis in HCC by extensive database interrogation.

OBJECTIVE: The involvement of HBXIP in cancer development and cancer cell survival is well known. This work probed the potential of HBXIP as a prognostic biomarker in hepatic cell cancer (HCC). MATERIALS AND METHODS: First, pan-cancer analysis of HBXIP expression was conducted using The Cancer Genome Atlas (TCGA) database to validate the expression of HBXIP in different cancers. The GSE14520 (GPL3721 Subset) database was used to validate HBXIP in HCC. The association between survival outcomes and prognostic factors was assessed employing univariate and multivariate survival analyses for TCGA Liver Hepatocellular Carcinoma. The biological function of the HBXIP Gene was annotated by gene set enrichment analysis. The relationship between HBXIP expression and immune cells and immune markers was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) database. RESULTS: Malignant tissues demonstrated evident upregulation of HBXIP at transcriptional and protein levels over normal tissues (p < 0.05) with this elevated expression linked to an advanced tumor stage in HCC cohorts. Univariate analysis revealed an evident correlation emerged between prognosis and HBXIP for GSE14520 databases (p < 0.05). The disease-free survival (DFS) and overall survival (OS) (five-year values) were lower in samples demonstrating elevated HBXIP (HR: 2.413; 95% CI 1.601, 3.638; p < 0.001) and (HR: 1.613; 95% CI 1.446, 1.844; p = 0.003), respectively vs. lower HBXIP expression. HBXIP emerged as an independent factor in OS prognosis (HR 2.184; 95% CI 1.495, 3.196; p < 0.001) and DFS (HR 1.764; 95% CI 1.261, 2.466; p < 0.001), respectively according to multivariate analysis. Further, multiple Cox analyses in the validation cohort revealed that independent factors for OS were HBXIP, AJCC T stage, vascular invasion, and tumor status with the C-index score of 0.727 (95% CI, 0.704 to 0.750). HBXIP level showed a significantly positive association with tumor immune cell infiltration, and biomarkers of immune cells; besides, the rectum Rho GTPase effectors signaling pathway was also identified. CONCLUSIONS: HCC advancement and survival involves HBXIP, which also emerged as a functional biomarker for HCC survival prediction.

Increased long non-coding RNA ARAP1-AS1 expression and its prognostic significance in human gastric cancer: a preliminary study.

OBJECTIVE: Multiple studies have unveiled that long non-coding RNAs (lncRNAs) contribute to oncogenesis. LncRNA ARAP1 antisense RNA 1 (ARAP1-AS1) has been demonstrated to serve as an oncogene in bladder tumor and colorectal cancer. This study attempted to explore the correlation of ARAP1-AS1 expressions with clinical progress and prognosis in gastric cancer (GC) patients. PATIENTS AND METHODS: RT-PCR was carried out to examine the levels of ARAP1-AS1 in 157 GC patients. The associations between ARAP1-AS1 expression and clinicopathologic features in GC patients were analyzed using the Chi-square test. The prognostic value of abnormally expressed ARAP1-AS1 in GC patients was further analyzed via Kaplan-Meier assays and multivariate survival assays. RESULTS: The levels of ARAP1-AS1 were dramatically increased in GC samples compared with paired adjacent non-tumor specimens (p=0.01). The upregulation of ARAP1-AS1 was distinctly associated with TNM stage (p=0.010) and lymphatic metastasis (p=0.007). Further survival study revealed that patients with higher levels of ARAP1-AS1 had shorter overall survival (p=0.0020) and disease-free survival than those with lower levels of ARAP1-AS1. Finally, multivariate survival assay identified ARAP1-AS1 upregulation as an independent unfavorable prognostic factor in GC patients. CONCLUSIONS: Our preliminary results identified a novel GC-related factor, ARAP1-AS1 which may be a potential prognostic biomarker for GC patients.

FHL2 participates in renal interstitial fibrosis by altering the phenotype of renal tubular epithelial cells via regulating the ß-catenin pathway.

OBJECTIVE: To investigate the potential role of FHL2 (four and a half LIM domains protein 2) in the renal interstitial fibrosis and its underlying mechanism. MATERIALS AND METHODS: NRK-52E, the rat tubular epithelial cell line, was selected for the in vitro experiments. The unilateral ureteral obstruction (UUO) mouse model and phenotype changes of NRK-52E cells were induced by TGF-ß (transforming growth factor-ß) treatment. Protein and mRNA expressions of biomarkers of tubular cells and renal fibrosis in NRK-52E cells were detected. Meanwhile, phenotype changes of NRK-52E cells were detected after FHL2 overexpression. Furthermore, CD1 mice were selected for constructing the UUO mouse model. Protein and mRNA expressions of biomarkers of tubular cells and renal fibrosis in kidney tissues were detected. CD1 mice with FHL2 overexpression were constructed by tail vein injection of FHL2 plasmid for further observation of renal interstitial fibrosis. Expressions of ß-catenin pathway-related genes were detected by Western blot and polymerase chain reaction (PCR), respectively. RESULTS: The FHL2 expression was increased during the phenotype change of NRK-52E cells induced by TGF-ß treatment. Overexpression of FHL2 led to a significant phenotype change. Similarly, the FHL2 expression was elevated in the UUO mouse model. Renal interstitial fibrosis was exaggerated and expression levels of genes related to the ß-catenin pathway were increased after injection of FHL2 plasmid. CONCLUSIONS: FHL2 is involved in renal interstitial fibrosis by altering the phenotype of renal tubular epithelial cells via regulating the ß-catenin pathway.

Silencing of LncRNA TCONS_00088786 reduces renal fibrosis through miR-132.

OBJECTIVE: To examine the role of long non-coding ribonucleic acid (LncRNA) TCONS_00088786 in the development of renal interstitial fibrosis and its potential mechanism in this process. MATERIALS AND METHODS: Unilateral ureteral obstruction (UUO) was used to induce tubulointerstitial fibrosis. Masson staining showed the degree of renal fibrosis in UUO mice. Immunohistochemistry and immunofluorescence were performed to detect the fibrosis-related proteins, the 24-h urine volume and protein content. The renal functions were reflected via serum creatinine (Scr) and blood urea nitrogen (BUN). Changes in lncRNATCONS_00088786, miR-132 and collagen I and III in the development process of renal fibrosis were detected through reverse transcription-polymerase chain reaction (RT-PCR). Small interfering RNA (siRNA) was transfected into NRK52E cells to mimic the knockdown. Western blot was adopted to detect the changes in miR-132, collagen I and III after the siRNA was transfected by transforming growth factor-ß (TGF-ß) for 24 h. RESULTS: With the development of renal fibrosis, lncRNA TCONS_00088786 and miR-132 were increased gradually. After the knockdown of lncRNA TCONS_00088786, miR-132 was decreased and fibrosis-related protein was also decreased. CONCLUSIONS: Decreased lncRNA TCONS _00088786 inhibits renal interstitial fibrosis by reducing miR-132 and it may be a potential novel molecular target for the treatment of renal interstitial fibrosis.

Meta-analysis of the association between PADI4 -92C/G polymorphism and rheumatoid arthritis in the Chinese population

Many studies have evaluated the correlation between peptidylarginine deiminase 4 (PADI4) -92C/G polymorphism and rheumatoid arthritis (RA), but the results remain inconclusive. Therefore, we performed a meta-analysis in the Chinese population to provide comprehensive data on the association between PADI4 -92C/G polymorphism and RA. Eligible studies published before May 2016 were identified in PubMed and Chinese databases. The strengths of these associations were assessed by pooled odds ratios (OR) and 95% confidence interval (CI). Eight studies documenting a total of 1351 RA cases and 1585 controls were included in this meta-analysis. In the overall analysis, a significant association between the PADI4 -92C/G polymorphism and RA was found in the Chinese population (G vs C: OR=1.32, 95%CI=1.02-1.71; GG+CG vs CC: OR=1.75, 95%CI=1.20-2.53). The subgroup analyses stratified by geographic area(s) and source of controls revealed significant results in South China, in hospital-based studies and population-based studies. In summary, this meta-analysis suggested that PADI4 -92C/G polymorphism may be associated with the RA incidence in the Chinese population, especially for South China. Further studies conducted on other ethnic groups are required for definite conclusions.

Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway.

STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-α on tumors, and its defects in expression is associated with IFN-α resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-α on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-α-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-α alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-α-induced phosphorylation of STAT1. Further study revealed that aspirin-prompted phosphorylation of STAT1 was activated through phosphorylation of JAK1. Furthermore, aspirin-activated STAT1 upregulated the transcription of proapoptotic IFN-stimulated gene (ISG) of X-linked inhibitor of apoptosis-associated factor-1 and downregulated the transcription of antiapoptotic ISG of G1P3, which in turn promoted the expression of Bax and activation of caspase-9 and caspase-3, thereby sensitizing HCC cells to IFN-α-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-α in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-α protein and gene therapy.

Exchange bias dependence on interface spin alignment in a Ni80Fe20/(Ni,Fe)O thin film.

A Ni80Fe20/(Ni,Fe)O thin film exhibits a positive exchange bias when cooled in a zero field and a negative exchange bias when field cooled. With transmission electron microscopy and electron energy loss spectrometry, the composition and magnetic structure has been ascertained and a distribution of magnetization easy axes about the interface extrapolated. The results indicate that the positive exchange bias is from antiferromagnetic interface moments perpendicular to their ferromagnetic counterparts. With field cooling the alignment is put into a parallel configuration resulting in a negative exchange bias.