Variability in disease development due to differences in strains and breeders constitutes a substantial challenge in preclinical research. However, the impact of the breeder on non-alcoholic steatohepatitis (NASH) is not yet fully elucidated. This retrospective study investigates NASH development in guinea pigs from Charles River or Envigo fed a high fat diet (20% fat, 15% sucrose, 0.35% cholesterol) for 16 or 24/25 weeks. Charles River animals displayed more severe NASH, with higher steatosis (p < 0.05 at week 16), inflammation (p < 0.05 at both week), fibrosis (p < 0.05 at week 16) and disease activity (p < 0.05 at both weeks). Accordingly, alanine and aspartate aminotransferase were increased at week 24/25 (p < 0.01). Hepatic expression of inflammatory (Ccl2, Cxcl8) and fibrotic (Pdgf, Serpine1, Col1a1) genes was also increased (p < 0.05). Differences were observed in healthy chow (4% fat, 0% sucrose, 0% cholesterol) fed animals: Envigo animals displayed higher relative liver weights (p < 0.01 at both weeks), liver cholesterol (p < 0.0001 at week 24/25) and aspartate aminotransferase (p < 0.05 at week 16), but lower levels of alkaline phosphatase (p < 0.0001 at week 24/25). These findings accentuates the importance of the breeder and its effect on NASH development and severity. Consequently, this may affect reproducibility, study comparison and limit the potential of developing novel therapies.

Background: The traditional Chinese medicine Huangqi decoction (HQD) consists of Radix Astragali and Radix Glycyrrhizae in a ratio of 6: 1, which has been used for the treatment of liver fibrosis. In this study, we tried to elucidate its action of mechanism (MoA) via a combination of metabolomics data, network pharmacology and molecular docking methods.

Methods: Firstly, we collected prototype components and metabolic products after administration of HQD from a publication. With known and predicted targets, compound-target interactions were obtained. Then, the global compound-liver fibrosis target bipartite network and the HQD-liver fibrosis protein-protein interaction network were constructed, separately. KEGG pathway analysis was applied to further understand the mechanisms related to the target proteins of HQD. Additionally, molecular docking simulation was performed to determine the binding efficiency of compounds with targets. Finally, considering the concentrations of prototype compounds and metabolites of HQD, the critical compound-liver fibrosis target bipartite network was constructed.

Results: 68 compounds including 17 prototype components and 51 metabolic products were collected. 540 compound-target interactions were obtained between the 68 compounds and 95 targets. Combining network analysis, molecular docking and concentration of compounds, our final results demonstrated that eight compounds (three prototype compounds and five metabolites) and eight targets (CDK1, MMP9, PPARD, PPARG, PTGS2, SERPINE1, TP53, and HIF1A) might contribute to the effects of HQD on liver fibrosis. These interactions would maintain the balance of ECM, reduce liver damage, inhibit hepatocyte apoptosis, and alleviate liver inflammation through five signaling pathways including p53, PPAR, HIF-1, IL-17, and TNF signaling pathway.

Conclusions: This study provides a new way to understand the MoA of HQD on liver fibrosis by considering the concentrations of components and metabolites, which might be a model for investigation of MoA of other Chinese herbs.

Keywords: Huangqi decoction; Liver fibrosis; Mechanism of action; Metabolomics; Molecular docking; Network pharmacology.

Background/aim: Increased expression of inflammatory cytokine genes through cell interactions in tissues may cause chronic inflammation, leading to the development of lifestyle-related diseases. Since the activation of inflammatory cytokine genes in monocytes/macrophages by co-culturing with cancer cells or adipocytes was suppressed by pre-treatment with low-dose lipopolysaccharide (LPS), we hypothesized that low-dose LPS-activated macrophages may regulate the expression of immune response-related genes in other cells.

Materials and methods: Phorbol myristate acetate-treated human monocytes (THP-1) were activated by LPS. The conditioned medium of LPS-activated THP-1 cells was added to human adipocytes. After 5 days, the expression of genes encoding interleukin (IL)-6 (IL6), IL-8 (IL8), monocyte chemotactic protein (MCP)-1 (CCL2), adiponectin (ADIPOQ), and plasminogen activator inhibitor (PAI)-1 (SERPINE1) was analyzed using quantitative real-time PCR.

Results: The increased expression of inflammation-related genes and SERPINE1 in adipocytes was suppressed by the conditioned medium of THP-1 cells activated by low-dose LPS, whereas the expression of ADIPOQ was significantly increased.

Conclusion: Low-dose LPS-activated macrophages convert adipocytes to anti-inflammatory phenotypes.

Keywords: Macrophage; adipocyte; inflammatory cytokine genes; lipopolysaccharide; plasminogen activator inhibitor-1.

The in vitro antifibrotic activity of Tinospora cordifolia (Thunb.) Miers (giloy) was assessed to explore its potential for the management of oral submucous fibrosis. Epithelial cells dissociated from the tissue obtained from histopathologically normal oral mucosa during surgical extraction of third molars were cultured and fibrosis was induced by TGF-β1 in the oral keratinocytes. Cell viability was assessed by MTT and comparative gene expression analysis was carried out in the fibrosis-induced oral keratinocytes treated with various concentrations of Tinospora cordifolia extract (TcE) for matricellular protein-related gene expression. Concentrations of 0.5 µg/mL and 1 µg/mL TcE demonstrated a significant reduction in the expression of CTGF, SERPINE1, COL1A1, FN1, MMP1, MMP2, MMP3, and TIMP2 and an increase in the expression of PLAU, COL3A1, TIMP1, and TIMP3. Although TcE was found to reduce the expression of several fibrotic genes and increase the expression of antifibrotic genes, a varied effect was found, causing increased expression of COL3A1 and decreased expression of TIMP2 on TGF-β1-induced human buccal epithelial cells. However, further studies are warranted to assess the exact mechanism of antifibrotic activity and its clinical applications.

Keywords: Tinospora cordifolia (Thunb.) Miers; antifibrotic activity; giloy; oral submucous fibrosis.

Purpose: Glioblastoma (GBM) remains one of the most fatal malignancy with limited available treatment. Serpin peptidase inhibitor, clade E nexin group 1 (SERPINE1) was found up-regulated in multiple cancers and play crucial roles in facilitating tumor progression and metastasis respectively. However, the role of SERPINE1 in glioblastoma was poorly understood.

Methods: We tested the hypothesis that SERPINE1 mediated malignant behaviors in GBM via regulating hairy and enhancer of split-1 (HES1).

Results: First, SERPINE1 is confirmed to be up-regulated in GBM, while further functional analysis demonstrated that SERPINE1 promoted cell proliferation, migration and invasion in GBM by performing the CCK-8 assay, colony formation assay, wound healing assay and transwell assay. Finally, it was proved that SERPINE1 achieved its pro-tumor functions in GBM via regulating the expression of HES1.

Conclusions: Collectively, our results highlight the critical contribution of SERPINE1 in a series of malignant characteristics of GBM via regulating the expression of HES1, which shed new light on a new direction to develop a more effective therapeutic management of malignant tumors like GBM.

Collagen XII is a regulator of corneal stroma structure and function. The current study examined the roles of collagen XII in regulating corneal stromal transforming growth factor (TGF)-β activation and latency. Specifically, with the use of conventional collagen XII null mouse model, the roles of collagen XII in the regulation of TGF-β latency and activity in vivo were investigated. Functional quantification of latent TGF-β in stromal matrix was performed by using transformed mink lung reporter cells that produce luciferase as a function of active TGF-β. Col12a1 knock-down with short hairpin RNA (shRNA) was used to test the role of collagen XII in TGF-β activation. We found Col12a1^-/- hypertrophic stromas with keratocyte hyperplasia. Increased collagen fibril forward signal was found by second harmonic generation (SHG) microscopy in the absence of collagen XII. Collagen XII regulated mRNA synthesis of Serpine1, Col1a1, and Col5a1 and deposition of collagens in the extracellular matrix. A functional plasminogen activator inhibitor (PAI-1) luciferase assay showed that collagen XII is necessary for latent TGF-β storage in the extracellular matrix and that collagen XII downregulates active TGF-β. Collagen XII dictates stromal structure and function by regulating TGF-β activity. A hypertrophic phenotype in Col12a1^-/- corneal tissue can be explained by abnormal upregulation of TGF-β activation and decreased latent storage.

Keywords: FACIT; TGF-β activation; collagen XII; stroma; total collagen.

Background: Circ_0046600 was reported to promote hepatocellular carcinoma (HCC) cell migratory ability. However, the functional roles and mechanism of circ_0046600 in HCC remain largely unknown.

Methods: Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. In vitro experiments were performed using cell counting kit-8 (CCK-8), colony formation, transwell, flow cytometry and Western blot assays, respectively. The direct interactions between miR-1258 and circ_0046600 or SERPINE1 mRNA-binding protein 1 (SERBP1) was verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft tumor model was established to perform in vivo assay. Exosomes were obtained from culture media by using the commercial kit.

Results: Circ_0046600 was highly expressed in HCC tissues and cells. Silencing of circ_0046600 impaired HCC cell growth and metastasis in vitro, as well as impeded HCC tumor growth in vivo. Mechanistically, circ_0046600 could competitively target miR-1258 to prevent the degradation of its target gene SERBP1. Rescue assay showed that miR-1258 inhibition reversed the inhibitory effects of circ_0046600 silencing on HCC cell. Moreover, ectopic overexpression of miR-1258 suppressed cell growth and metastasis in HCC, which was abolished by SERBP1 up-regulation. Furthermore, circ_0046600 was packaged into exosomes and could be derived from HCC cells.

Conclusion: Circ_0046600 promoted HCC progression via up-regulating SERBP1 through sequestering miR-1258; besides that, circ_0046600 was packaged into exosomes and could be released from HCC cells.

Keywords: Circ_0046600; Exosomes; Hepatocellular carcinoma; MiR-1258; SERBP1.

Laryngeal squamous cell carcinoma (LSCC) arises from the squamous epithelium of the larynx and is associated with a high incidence of cervical lymph node metastasis. MicroRNAs (miRNAs) play a crucial role in the epigenetic regulation of cellular biological processes, including cancer metastasis. However, the molecular mechanisms of specific miRNAs responsible for LSCC metastasis and their clinical significance have yet to be fully elucidated. In this study, LSCC cohort datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were downloaded and examined by comprehensive bioinformatics analysis, which revealed that upregulation of mRNA SERPINE1 and downregulation of miR-181c-5p were associated with unfavorable overall survival. Our analysis showed that SERPINE1 expression negatively correlated with the expression level of miR-181c-5p in our LSCC patient samples. Silencing of miR-181c-5p expression promoted cell migration and invasion in cell lines, whereas the overexpression of miR-181c-5p suppressed cell migration and epithelial-to-mesenchymal transition (EMT) through the downregulation of SERPINE1. Further analysis showed that the enhancement effect on EMT and metastasis induced by silencing miR-181c-5p could be rescued through knockdown of SERPINE1 expression in vitro. Collectively, our findings indicated that miR-181c-5p acted as an EMT suppressor miRNA by downregulation of SERPINE1 in LSCC and offers novel strategies for the prevention of metastasis in LSCC.

Keywords: biomarker; epithelial-to-mesenchymal transition; laryngeal squamous cell carcinoma; mRNA; miRNA.

Purpose: To investigate potential target genes associated with the diabetic condition in mouse cavernous endothelial cells (MCECs) for the treatment of diabetes-induced erectile dysfunction (ED).

Materials and methods: Mouse cavernous tissue was embedded into Matrigel, and sprouted cells were subcultivated for other studies. To mimic diabetic conditions, MCECs were exposed to normal-glucose (NG, 5 mmoL) or high-glucose (HG, 30 mmoL) conditions for 72 hours. An RNA-sequencing assay was performed to evaluate gene expression profiling, and RT-PCR was used to validate the sequencing data.

Results: We isolated MCECs exposed to the two glucose conditions. MCECs showed well-organized tubes and dynamic migration in the NG condition, whereas tube formation and migration were significantly decreased in the HG condition. RNA-sequencing analysis showed that MCECs had different gene profiles in the NG and HG conditions. Among the significantly changed genes, which we classified into 14 major gene categories, we identified that aging-related (9.22%) and angiogenesis-related (9.06%) genes were changed the most. Thirteen genes from the two gene categories showed consistent changes on the RNA-sequencing assay, and these findings were validated by RT-PCR.

Conclusions: Our gene expression profiling studies showed that Cyp1a1, Gclm, Igfbp5, Nqo1, Il6, Cxcl5, Olr1, Ctgf, Hbegf, Serpine1, Cyr61, Angptl4, and Loxl2 may play a critical role in diabetes-induced ED through aging and angiogenesis signaling. Additional research is necessary to help us understand the potential mechanisms by which these genes influence diabetes-induced ED.

Keywords: Diabetes mellitus; Erectile dysfunction; Gene expression; Penis; RNA sequencing.

Mechanical ventilation is extensively adopted in general anesthesia and respiratory failure management, but it can also induce ventilator-induced lung injury (VILI). Therefore, it is of great urgency to explore the mechanisms involved in the VILI pathogenesis, which might contribute to its future prevention and treatment. Four microarray datasets from the GEO database were selected in our investigation, and were subjected to the Weighted Gene Co-Expression Network Analysis (WGCNA) to identify the VILI-correlated gene modules. The limma package in R software was used to identify the differentially expressed genes (DEGs) between the VILI and control groups. WGCNA was constructed by merging the GSE9314, GSE9368, GSE11434 and GSE11662 datasets. A total of 49 co-expression network modules were determined as associated with VILI. The intersected genes between hub genes screened from DEGs for VILI and those identified using WGCNA were as follows: Tlr2, Hmox1, Serpine1, Mmp9, Il6, Il1b, Ptgs2, Fos and Atf3, which were determined to be key genes for VILI. Those key genes were validated by GSE86229 and qPCR experiment to have significantly statistical difference in their expression between the VILI and control groups. In a nutshell, nine key genes with expression differences in VILI were screened by WGCNA by integrating multiple data sets.

Keywords: Bioinformatics; VILI; WGCNA.

Tocotrienols (T3), a family of vitamin E, are reported to possess potent anti-cancer effects but the molecular mechanisms behind these effects still remain unclear. The aim of this study was to investigate how T3 exert anti-cancer effects on MDA-MB-231 human breast cancer cells. The MDA-MB-231 cells were chosen for this study as they are triple-negative and highly metastatic cells, which form aggressive tumors in experimental models. The MDA-MB-231 cells were treated with varying concentrations (0-20 µg mL^-1) of gamma (γ) or delta (δ) T3 and the secretome profiles of these cells treated with half maximal inhibitory concentration (IC₅₀) of γT3 (5.8 µg mL^-1) or δT3 (4.0 µg mL^-1) were determined using label-free quantitative proteomic strategy. A total of 103, 174 and 141 proteins were identified with ProteinLynx Global Server (PLGS) score of more than 200 and above 25% sequence coverage in the untreated control and T3-treated cell culture supernatant respectively. A total of 18 proteins were dysregulated between untreated control and T3 (δT3 or γT3) treated conditions. The results showed that T3 treatment downregulated the exogenous Cathepsin D and Serpine1 proteins but upregulated Profilin-1 protein, which play a key role in breast cancer in the MDA-MB-231 cells. These findings strongly suggest that T3 may induce differential expression of secreted proteins involved in the cytoskeletal regulation of RHO GTPase signaling pathway.

Background: Serpin family E member 1 (SERPINE1) is a serine proteinase inhibitor (serpin) upregulated in diverse types of cancer, including Oral squamous cell carcinoma (OSCC) and functions as an oncogenic role. Hence, exploring pathological mechanism underlying SERPINE1 high expression is crucial to the targeted therapy of OSCC.Methods: Bioinformatics analysis was performed to identify the miRNA and the candidate gene contributing to OSCC progression. The viability, proliferation and apoptosis of the OSCC cell were evaluated using CCK-8 assay, BrdU assay, and cell apoptosis assay, respectively. The RNA pull-down assay and luciferase reporter assay were conducted to verify the relationship between SERPINE1 and miR-617.Results: SERPINE1 was aberrantly upregulated in OSCC tissues and cell lines. Genetically inhibiting SERPINE1 led to reduction of OSCC cell viability and proliferation while elevation of OSCC cell apoptosis. By bioinformatics analysis, miR-617 contained a response element for SERPINE1 overexpression, which is validated by the RNA pull-down and luciferase reporter assay. Furthermore, miR-617 was detected to be downregulated in OSCC tissues and cell lines as well as displayed a negative correlation with advanced stage. Besides, miR-617 mimic or inhibitor transfection could suppress or boost the SERPINE1 expression. More importantly, miR-617 mimic could block the effect of SERPINE1 overexpression on OSCC cells proliferation, viability and apoptosis.Conclusion: SERPINE1 acted as a pro-proliferative oncogenic factor which is partly regulated by miR-167 downregualtion in OSCC cells. Therefore, miR-617/SERPINE1 axis is a potential therapeutic target against OSCC.

Hsa_circ_0061395(circBACH1) and SERBP1(SERPINE1 mRNA binding protein 1) have been reported to play a carcinogenic role in HCC.In this study, circBACH1, microRNA(miR)-656-3p, and SERBP1 expression levels with quantitative real-time polymerase chain reaction (qRT-PCR) in HCC tissue specimens and cells.The protein levels of SERBP1, E-Cadherin, vimentin, and N-Cadherin were detected with western blotting.Cell proliferation, migration, invasion, and apoptosis were determined with CCK-8, colony formation, transwell, and flow cytometry assays.The targeting relatio-nship between circBACH1 or SERBP1 and miR-656-3p was verified by dual-lucifer- ase reporter assay.The role of circBACH1 was validated by xenograft assay.CircBAC- H1 and SERBP1 were upregulated in HCC tissues and cells.Both circBACH1 and SERBP1 knockdown constrained proliferation, migration, invasion, and EMT(epithel-ial-mesenchymal transition), and facilitated apoptosis of HCC cells in vitro.Knockdo-wn of circBACH1 reduced HCC growth in vivo. SERBP1 overexpression partially neutralized the repressive effect of circBACH1 silencing on malignant behaviors of HCC cells.CircBACH1 sponged miR-656-3p to elevate SERBP1 expression, thereby accelerating the progression of HCC.The research provided a new evidence to support the role of circBACH1 in HCC.

Keywords: HCC; SERBP1; circBACH1; miR-656–3p.

Complex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. In this study, the expression of ECM-related genes was explored for prognostic and immunological implication in clear cell renal clear cell carcinoma (ccRCC). Out of 964 ECM genes, higher expression (z-score > 2) of 35 genes showed significant association with overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS). On comparison to normal tissue, 12 genes (NUDT1, SIGLEC1, LRP1, LOXL2, SERPINE1, PLOD3, ZP3, RARRES2, TGM2, COL3A1, ANXA4, and POSTN) showed elevated expression in kidney tumor (n = 523) compared to normal (n = 100). Further, Cox proportional hazard model was utilized to develop 12 genes ECM signature that showed significant association with overall survival in TCGA dataset (HR = 2.45; 95% CI [1.78-3.38]; p < 0.01). This gene signature was further validated in 3 independent datasets from GEO database. Kaplan-Meier log-rank test significantly associated patients with elevated expression of this gene signature with a higher risk of mortality. Further, differential gene expression analysis using DESeq2 and principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters between ECM-rich high-risk and ECM-poor low-risk patients. Geneset enrichment analysis (GSEA) identified significant perturbations in homeostatic kidney functions in the high-risk group. Further, higher infiltration of immunosuppressive T-reg and M2 macrophages was observed in high-risk group patients. The present study has identified a prognostic signature with associated tumor-promoting immune niche with clinical utility in ccRCC. Further exploration of ECM dynamics and validation of this gene signature can assist in design and application of novel therapeutic approaches.

Pheochromocytoma, as a neuroendocrine tumor with the highest genetic correlation in all types of tumors, has attracted extensive attention. Von Hipper Lindau (VHL) has the highest mutation frequency among the genes associated with pheochromocytoma. However, the effect of VHL on the proteome of pheochromocytoma remains to be explored. In this study, the VHL knockdown (VHL-KD) PC12 cell model was established by RNA interference (shRNA). We compared the proteomics of VHL-KD and VHL-WT PC12 cell lines. The results showed that the expression of 434 proteins (VHL shRNA/WT > 1.3) changed significantly in VHL-KD-PC12 cells. Among the 434 kinds of proteins, 83 were involved in cell proliferation, cell cycle and cell migration, and so on. More importantly, among these proteins, we found seven novel key genes, including Connective Tissue Growth Factor (CTGF), Syndecan Binding Protein (SDCBP), Cysteine Rich Protein 61 (CYR61/CCN1), Collagen Type III Alpha 1 Chain (COL3A1), Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type V Alpha 2 Chain (COL5A2), and Serpin Family E Member 1 (SERPINE1), were overexpressed and simultaneously regulated cell proliferation and migration in VHL-KD PC12 cells. Furthermore, the abnormal accumulation of HIF2α caused by VHL-KD significantly increased the expression of these seven genes during hypoxia. Moreover, cell-counting, scratch, and transwell assays demonstrated that VHL-KD could promote cell proliferation and migration, and changed cell morphology. These findings indicated that inhibition of VHL expression could promote the development of pheochromocytoma by activating the expression of cell proliferation and migration associated genes.

Keywords: Von Hippel-Lindau (VHL); cellular communication network factor 1 (CCN1); collagen type III alpha 1 chain (COL3A1); collagen type V alpha 2 chain (COL5A2); connective tissue growth factor (CTGF); pheochromocytoma; serpin family E member 1 (SERPINE1); syndecan binding protein (SDCBP).

Background: An increasing number of studies have found that long non-coding RNAs (lncRNAs) play an important role in carcinogenesis and tumor progression, whereas their molecular mechanisms of function remain largely unknown.

Aims: This study was aimed to explore the biological function and underlying mechanism of a new lncRNA LINC00200 in gastric cancer (GC).

Methods: qRT-PCR analysis was conducted to examine the LINC00200 expression level in both GC tissues and cell lines. Functional assays were carried out to detect the effect of LINC00200 on GC cell proliferation, invasion and migration. The interaction between LINC00200 and miR-143-3p was confirmed by luciferase reporter assays. Rescue assays were performed to confirm the influence of LINC00200-miR-143-3p-SERPINE1 axis on GC development.

Results: LINC00200 was found to be upregulated in GC tissues and cell lines. Moreover, knockdown of LINC00200 suppressed GC cell proliferation, invasion and migration in vitro and inhibited tumorigenesis in mouse xenografts. Finally, mechanism research indicated that LINC00200 functioned as a ceRNA to sponge for miR-143-3p, thus leading to the disinhibition of its target gene SERPINE1.

Conclusions: LINC00200 is significantly overexpressed in GC and accelerates GC progression through regulating miR-143-3p/SERPINE1 axis. Our results may provide a potential diagnostic biomarker and therapeutic target for the management of GC patients.

Keywords: Gastric cancer; LINC00200; Long non-coding RNA; SERPINE1; miR-143-3p.

Early‑onset preeclampsia (EOPE) is a serious threat to maternal and foetal health. The present study aimed to identify potential biomarkers and targets for the treatment of EOPE. Expression profiles of placenta from patients with EOPE and healthy controls (GSE103542, GSE74341 and GSE44711) were downloaded from the Gene Expression Omnibus database. Integrated analysis revealed 246 genes and 28 microRNAs (miRNAs) that were differentially expressed between patients with EOPE and healthy controls. Differentially expressed genes (DEGs) were primarily enriched in 'biological processes', such as 'cell adhesion', 'female pregnancy', 'extracellular matrix organization' and 'response to hypoxia'. Significant pathways associated with DEGs primarily included 'focal adhesion', 'ECM‑receptor interaction', 'PI3K‑Akt signaling' and 'ovarian steroidogenesis'. A Protein‑Protein Interaction network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database, and epidermal growth factor receptor, collagen α‑1(I) chain, secreted phosphoprotein 1, leptin (LEP), collagen α‑2(I) chain (COL1A2), plasminogen activator inhibitor 1 (SERPINE1), Thy‑1 membrane glycoprotein, bone morphogenetic protein 4, vascular cell adhesion protein 1 and matrix metallopeptidase 1 were identified as hub genes. The alterations of hsa‑miR‑937, hsa‑miR‑148b*, hsa‑miR‑3907, hsa‑miR‑367*, COL1A2, LEP and SERPINE1 in placenta were validated using our local samples. Our research showed that the expression of hsa‑miR‑937, hsa‑miR‑1486*, hsa‑miR‑3907, hsa‑miR‑367* and hub genes in the placenta were closely associated with the pathophysiology of EOPE. hsa‑miR‑937, hsa‑miR‑1486*, hsa‑miR‑3907, hsa‑miR‑367* and hub genes could serve as biomarkers for diagnosis and as potential targets for the treatment of EOPE.

Despite increasing research on the gut-skin axis, there is a lack of comprehensive studies on the improvement of skin health through the regulation of the intestinal condition in humans. In this study, we investigated the benefits of Lactobacillus plantarum HY7714 (HY7714) consumption on skin health through its modulatory effects on the intestine and ensuing immune responses. HY7714 consumption led to differences in bacterial abundances from phylum to genus level, including increases in Actinobacteria followed by Bifidobacterium and a decrease in Proteobacteria. Additionally, HY7714 significantly ameliorated inflammation by reducing matrix metallopeptidases (MMP-2 and MMP-9), zonulin, and calprotectin in plasma, all of which are related to skin and intestinal permeability. Furthermore, RNA-seq analysis revealed its efficacy at restoring the integrity of the gut barrier by regulating gene expression associated with the extracellular matrix and immunity. This was evident by the upregulation of IGFBP5, SERPINE1, EFEMP1, COL6A3, and SEMA3B and downregulation of MT2A, MT1E, MT1X, MT1G, and MT1F between TNF- α and TNF- α plus HY7714 treated Caco-2 cells. These results propose the potential mechanistic role of HY7714 on skin health by the regulation of the gut condition.

OBJECTIVE

To detect the expressions of receptor tyrosine kinases (RTKs) mRNA and protein and to explore potentially promising tumor markers and conceivable drug target in bladder cancer.

METHODS

The expressions of RTKs mRNA and protein in tissue from invasive urothelial carcinoma of the bladder were examined by real-time quantitative PCR array and cytokine antibody array, with normal bladder tissue as control. The Results were analyzed using bioinformatic approaches.

RESULTS

The expressions of TGFA, STAB1, SERPINE1, ANGPT2, SPINK5, ANGPTL1, PROK1, MDK, CXCL9, GRN, RUNX1, VEGFA, and TGFB1 were obviously upregulated in bladder cancer tissue, while those of EDIL3, PTN, CCL2, PDGFD, FGF13, KITLG, FGF2, SERPINF1, and TNF were downregulated. ALK, Btk, EphB2, ErbB4, PDGFR-α, ROS, Tie-2, Tyk2, and VEGFR3 were over-expressed in bladder cancer, while FRK, Fyn, IGF-IR, Insulin R, Itk, JAK1, JAK3, and LCK were low-expressed.

CONCLUSIONS

Vascular endothelial growth factor/platelet-derived growth factor-targeted therapies may play an active role in treating carcinoma of bladder.

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

Keywords: developmental biology; human; mouse; neuroscience.

There may be a mutually reinforcing relationship between hepatocellular carcinoma (HCC) and depression, but the mechanism is unknown. This study used bioinformatics to evaluate the relationship between HCC and depression at the genetic level. Genes associated with HCC and depression were obtained from pubmed2ensemble. Overlapping genes were annotated by gene ontology (GO) function and enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway. The cluster-1 genes obtained by Cytoscape were analyzed by GEPIA for expression and overall survival in HCC and, finally, introduced target genes to DGIdb to get associated drugs. A total of 199 genes were found to be in common between HCC and depression. GO term enrichment analysis on DAVID found the top-6 biological processes to be mainly associated with cell death and apoptosis. The top-6 cellular component terms are extracellular. The top-6 of molecular function terms are mainly associated with receptor binding. The top-6 pathways enriched by KEGG are mainly related to inflammatory response. IGF1, VEGFA, and SERPINE1 had statistical differences in expression and 10-year survival rate. There are total 45 drugs that act on VEGFA and SERPINE1. Based on our findings, we hypothesize that the mechanism of the interaction between HCC and depression may be related to cell death or apoptosis. Further studies are needed to verify this hypothesis.

Keywords: Hepatocellular carcinoma; cell death or apoptosis; depression; text mining.

This study aimed to investigate the underlying molecular pathogenic mechanism of Sec62 in hepatocellular carcinoma (HCC). Microarray analysis was conducted to profile the global gene expression in the HCC cell line Huh7 cells transfected with Sec62^high vs. NC and Sec62^low vs. NC. Ingenuity pathway analysis and gene set enrichment analysis were used to perform Sec62-related signaling pathway analysis from screened differentially expressed genes (DEGs). A protein-protein interaction network was constructed. Experimental validation of the expression of key DEGs was conducted. Hypoxia-induced tube formation was undertaken to investigate the role of Sec62 in angiogenesis. A total of 74 intersected DEGs were identified from Huh7 cells with Sec62^high vs. NC and Sec62^low vs. NC. Among them, 65 DEGs were correlated with the expression of Sec62. The P53 signaling pathway was found to be enriched in Huh7 cells with Sec62^high vs. NC, while the acute phase response signaling pathway was enriched in Huh7 cells with Sec62^low vs. NC. DEGs, such as serine protease inhibitor E (SERPINE) and tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B), were not only identified as the lead genes of these enriched pathways, but were also found to be closely related to Sec62. Moreover, knockdown of Sec62 decreased the expression of SERPINE1 (plasminogen activator inhibitor type 1 (PAI-1)) and TNFRSF11B, whereas overexpression of Sec62 had the opposite effects. In addition, knockdown of Sec62 inhibited hypoxia-induced tube formation via PAI-1. Sec62 promoted pro-angiogenesis of HCC under hypoxia by regulating PAI-1, and it may be a crucial angiogenic switch in HCC.

Keywords: Angiogenesis; Hepatocellular carcinoma; Hypoxia; PAI-1; Sec62.

The tumor microenvironment (TME) is related to extracellular matrix (ECM) dynamics and has a broad fundamental and mechanistic role in tumorigenesis and cancer progression. We hypothesized that ECM regulators might play an essential role in pan-cancer attribution by causing a generic effect through its regulation of the dynamics of ECM alteration. By analyzing data from TCGA using GSEA and univariate Cox regression analysis, we found that ECM regulator genes were significantly enriched and contributed to mortality in various cancer types. Notably, UMAP analysis revealed that ECM regulator genes dominated the differences between tumor and adjacent normal tissues based on 59 or 31 pan-survival-related ECM gene sets. Subsequently, a five-gene signature consisting of the predominant ECM regulators ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 was identified. We found that this five-gene signature was pro-mortality in 18 types of cancer in TCGA, and validated eleven other cancer types in TCGA and seven types in the TARGET and CoMMpass databases using overall survival analysis. KEGG pathway enrichment and Pearson correlation analysis indicated that these five component genes that were correlated with specific ECM proteins involved in tumorigenesis from the ECM receptor interaction gene set. Additionally, the fitted results of a linear model were applied to strengthen the discovery, demonstrating that the five genes were correlated with immune infiltration score and especially associated with typically immunologically "cold" tumors. We thus conclude that the ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 signature showed a close association with a pan-cancer effect on prognosis and is related to ECM proteins in the TME which corresponding with immunologically "cold" cancer types.

Keywords: ECM deposition; ECM regulator; immune cell infiltration; immunologically cold; pan-cancer signature.

Atrial fibrillation is the most common form of cardiac arrhythmia. Atrial fibrosis is a significant feature of atrial fibrillation though its mechanism is not well understood. We searched the Gene Expression Omnibus database to compare mRNA expression patterns between atrial fibrillation and sinus rhythm samples; one hundred and forty eight differentially expressed genes were identified. Most of these genes were significantly enriched in the extracellular matrix organization process and collagen-activated tyrosine kinase receptor signaling pathway. To screen hub genes involved in atrial fibrosis, we constructed a protein-protein interaction network and found that three hub genes (SERPINE1/plasminogen activator inhibitor-1/PAI-1, TIMP Metallopeptidase Inhibitor 3/TIMP3 and decorin/DCN) play vital roles in atrial fibrosis, especially plasminogen activator inhibitor-1. Elevated plasminogen activator inhibitor-1 expression was positively correlated with the p53 signaling pathway. Plasminogen activator inhibitor-1 and p53 protein expression levels were verified in patients with sinus rhythm and atrial fibrillation by Western blot analysis. Compared with the sinus rhythm controls, p53 and plasminogen activator inhibitor-1 protein expressions were upregulated in the atrial tissues of patients with atrial fibrillation. p53 was also found to regulate plasminogen activator inhibitor-1 based on the results of cellular and molecular experiments. Thus, the p53/plasminogen activator inhibitor-1 signaling axis may participate in the pathophysiological processes of atrial fibrillation, and plasminogen activator inhibitor-1 may serve as a new therapeutic biomarker in atrial fibrillation.

Keywords: Atrial fibrillation; Atrial fibrosis; Bioinformatics analysis; Plasminogen activator inhibitor-1; p53.