Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration.

BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear. METHODS: To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively. RESULTS: In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model. CONCLUSION: MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.

INPP5A/HLA-G1/IL-10/MMP-21 Axis in Progression of Esophageal Squamous Cell Carcinoma

Background: Background: Type I inositol polyphosphate-5-phosphatase A (INPP5A) is involved in different cellular events, including cell proliferation. Since INPP5A, HLAG1, IL-10, and matrix metalloproteinases (MMP)-21 genes play fundamental roles in esophageal squamous cell carcinoma (ESCC) tumorigenesis, we aimed in this study to clarify the possible interplay of these genes and explore the potential of these chemistries as a predictor marker for diagnosis in ESCC disease. Methods: Methods: Gene expression analysis of INPP5A, HLAG-1, IL-10, and MMP-21 was performed using relative comparative real-time PCR in 56 ESCCs compared to their margin normal tissues. Immunohistochemical staining was accomplished for INPP5A in ESCCs. Analysis of ROC curves and the AUC were applied to evaluate the diagnostic capability of the candidate genes. Results: Results: High levels of HLA-G1, MMP-21, and IL-10 were detected in nearly 23.2%, 62.5%, and 53.5% of ESCCs compared to the normal tissues, respectively, whereas INPP5A underexpression was detected in 19.6% of ESCCs, which all tested genes indicated significant correlations with each other. The protein expression level of INPP5A in ESCC tissues was significantly lower than that of the non-tumor esophageal tissues (p = 0.001). Interestingly, the concomitant expression of the INPP5A/HLA-G1, INPP5A/MMP-21, INPP5A/IL-10, HLA-G1/MMP-21, HLA-G1/IL-10, and MMP-21/IL-10 was significantly correlated with several clinicopathological variables. INPP5A, HLA-G1, MMP-21, and IL-10 showed to be the most appropriate candidates to discriminate tumor/non-tumor groups due to the total AUCs of all combinations (>60%). Conclusion: Conclusion: Our results represent a new regulatory axis containing INPP5A/HLAG-1/IL-10/MMP-21 markers in ESCC development and may provide novel insight into the mechanism of immune evasion mediated by the INPP5A/HLAG-1/IL-10/MMP-21 regulatory network in the disease.

The effect of opine on matrix metalloproteinase expression in mice with breast cancer.

Regarding the anti-inflammatory and anti-tumour effects of arginine and its derivatives, this study evaluates matrix metalloproteinase (MMPs) expression in an animal model of breast cancer following administration of octopine. In this study, 40 animals of Balb/C mice were divided into 5 groups: the healthy control, the cancer control, the cancer group receiving 50 mg of octopine, the cancer group receiving 100 mg of octopine and the cancer group receiving 150 mg of octopine for 3 weeks. 4T1 cell line was used to induce cancer. Biopsy specimens were enrolled from mice and MMP-1, MMP-3 and MMP-9 gene expression evaluated using real-time PCR, while these protein amounts were measured using immunohistochemistry and ELISA methods. Data were analysed using one-way ANOVA, Kruskal-Wallis and Mann-Whitney U tests (p < .05). The results showed that 100 mg octopine consumption had significant decreasing effect on MMP-9 expression (p = .02) in the treatment group compared with cancerous non-treated mice. Furthermore, results from immunohistochemistry and ELISA confirmed this effect, the protein amount of MMP-9 was significantly decreased in group treating with 100 mg octopine (.005). The use of octopine has a beneficial effect on reducing MMP-9 in mice breast cancer.

Prolactin Protects the Structural Integrity of Human Fetal Membranes by Downregulating Inflammation-induced Secretion of Matrix Metalloproteinases.

Prolactin (PRL) is a pleiotropic hormone with a key role in pregnancy. In fetal membranes, PRL can regulate the secretion of pro-inflammatory factors, which induces the activation of matrix metalloproteinases (MMPs). The increase and activation of MMPs deregulate the turnover of the extracellular matrix in the fetal membranes, altering its structure and function, causing premature rupture of the membranes and preterm labor. In this work, we evaluate the effect of PRL upon the secretion of MMP-1, MMP-2, MMP-9, MMP-13, and the tissue inhibitors of metalloproteinases (TIMPs) in human fetal membranes after lipopolysaccharide (LPS) challenge. Nine fetal membranes from healthy non-laboring cesarean deliveries at term were cultured in a 2-independent chamber system and pre-treated with 250, 500, 1000 or 4000 ng/ml of PRL for 24 h, then choriodecidual region was stimulated with 500 ng/ml of LPS plus fresh PRL for 24 h. The MMPs and TIMPs secretion were quantified by ELISA, additionally MMP-2 and MMP-9 gelatinolytic activity was measured by zymography. LPS induced the MMP-9 and MMP-1 secretion, but no MMP-2 or MMP-13 in comparison with basal levels. PRL co-treatment decreased the MMP-2, MMP-9 and MMP-1 secretion induced by LPS. The active forms were present in the tissue extract, showing a response consistent with the secretion profile. TIMP-1 and TIMP-2 secretion was decreased after LPS treatment and the PRL co-treatment reverts this effect. The present results support that PRL may favor the balance between these factors involved in the structural maintenance of fetal membranes in an inflammatory event.

Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support.

BACKGROUND: The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood. OBJECTIVES: The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling. METHODS: Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression. RESULTS: The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 µm pre-LVAD to 410 ± 209 µm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 a.u. post-LVAD (P < 0.0001). The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted. CONCLUSIONS: There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes.

High expression of MMP28 indicates unfavorable prognosis in pancreatic cancer.

ABSTRACT: To investigate the expression pattern and diagnostic performance of matrix metalloproteinase 28 (MMP28) in pancreatic cancer (PC).The RNA-seq data of PC and normal pancreas tissue were acquired from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression. Clinical information of PC that included prognostic data was obtained from TCGA. Later, Fisher exact test was applied for comparison of different clinicopathological features between high and low expression of MMP28 in PC. Afterwards, Kaplan-Meier survival analysis and Cox analysis (univariate and multivariate analysis) were used to explore the prognostic performance of MMP28 in PC cohort. Finally, gene set enrichment analysis (GSEA) revealed the potential signaling pathways related to high expression of MMP28 in PC.Upregulation of MMP28 was identified in PC tissue compared to normal pancreas tissue (P < .001). Overexpression of MMP28 was related to histological grade (P < .001), M classification (P = .014), and survival status (P = .028). Kaplan-Meier survival analysis revealed that high level of MMP28 implied unfavorable prognosis in PC (P = .002). Multivariate analysis confirmed that MMP28 was an independent risk factor in PC (hazard rate = 1.308, P = .018). Our GSEA analysis found that signaling pathways including glycolysis, p53 pathway, notch signaling, estrogen response late, cholesterol homeostasis, estrogen response early, mitotic spindle, and transforming growth factor beta signaling were enriched in the group with higher MMP28 expression.High expression of MMP28 could be identified in PC, which also served as an independent risk element for PC.

Identification of 6 gene markers for survival prediction in osteosarcoma cases based on multi-omics analysis.

Multiple-omics sequencing information with high-throughput has laid a solid foundation to identify genes associated with cancer prognostic process. Multiomics information study is capable of revealing the cancer occurring and developing system according to several aspects. Currently, the prognosis of osteosarcoma is still poor, so a genetic marker is needed for predicting the clinically related overall survival result. First, Office of Cancer Genomics (OCG Target) provided RNASeq, copy amount variations information, and clinically related follow-up data. Genes associated with prognostic process and genes exhibiting copy amount difference were screened in the training group, and the mentioned genes were integrated for feature selection with least absolute shrinkage and selection operator (Lasso). Eventually, effective biomarkers received the screening process. Lastly, this study built and demonstrated one gene-associated prognosis mode according to the set of the test and gene expression omnibus validation set; 512 prognosis-related genes (P < 0.01), 336 copies of amplified genes (P < 0.05), and 36 copies of deleted genes (P < 0.05) were obtained, and those genes of the mentioned genomic variants display close associations with tumor occurring and developing mechanisms. This study generated 10 genes for candidates through the integration of genomic variant genes as well as prognosis-related genes. Six typical genes (i.e. MYC, CHIC2, CCDC152, LYL1, GPR142, and MMP27) were obtained by Lasso feature selection and stepwise multivariate regression study, many of which are reported to show a relationship to tumor progressing process. The authors conducted Cox regression study for building 6-gene sign, i.e. one single prognosis-related element, in terms of cases carrying osteosarcoma. In addition, the samples were able to be risk stratified in the training group, test set, and externally validating set. The AUC of five-year survival according to the training group and validation set reached over 0.85, with superior predictive performance as opposed to the existing researches. Here, 6-gene sign was built to be new prognosis-related marking elements for assessing osteosarcoma cases' surviving state.

Complex effect of continuous curcumin exposure on human bone marrow-derived mesenchymal stem cell regenerative properties through matrix metalloproteinase regulation.

Curcumin has been reported to be beneficial for cancers, cardiovascular and neurodegenerative diseases, based on its anti-oxidative, anti-inflammation, anti-tumorigenic and neuroprotective properties. With its high-dose application, curcumin toxicity to systemic tissues is a reasonable concern. Here, we report the responses of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) to continuous curcumin exposure. hBM-MSCs were treated with 0.01-100 µmol/L curcumin continuously in vitro for 7 days. 25 µmol/L curcumin or above significantly attenuated hBM-MSC maintenance, whereas 10 µmol/L curcumin reduced hBM-MSC proliferation and hindered their migration with increasing cell apoptosis. Besides, 5 µmol/L curcumin treatment inhibited hBM-MSC adipogenic differentiation, but enhanced osteogenic differentiation, which depended on matrix metalloproteinase (MMP)-13 expression and activity. Furthermore, curcumin treatment reduced MMP1 expression but up-regulated the immunomodulatory gene IDO1 expression. In summary, this study revealed the complex effects of continuous curcumin exposure on hBM-MSC maintenance and regenerative properties through MMP regulation. Given the complex effects of curcumin, its use for biomedical purposes should be carefully considered in treatment length and dosage.

Long noncoding RNA ZEB1-AS1 affects paclitaxel and cisplatin resistance by regulating MMP19 in epithelial ovarian cancer cells.

PURPOSE: The long noncoding RNA (lncRNA) ZEB1-AS1 is reported overexpressed in sensitive ovarian cancer cells A2780 compared with paclitaxel (PTX)-and cisplatin (DDP)- resistant. However, the function and mechanism of ZEB1-AS1 in EOC cells still unknown. METHODS: We used quantitative real-time PCR (qPCR) to detect ZEB1-AS1 expression in A2780 and A2780/R cells. A combination of siRNA, plasmids, CCK8 and flow cytometry was used to detect the effect of ZEB1-AS1 on ovarian cancer cell A2780 PTX and DDP resistance. Transcriptome sequencing, qPCR, and western blot were used for further mechanistic studies. RESULTS: ZEB1-AS1 depletion using siRNA in chemosensitive A2780 cells significantly increased PTX and DDP resistance. In contrast, ZEB1-AS1 overexpression in PTX- and DDP-resistant A2780/resistant (A2780/R) cells reversed the observed drug resistance. Thus, ZEB1-AS1 plays an important role in PTX and DDP resistance in EOC cells. However, quantitative real-time PCR (qPCR) and western blot results suggested that ZEB1-AS1 did not regulate chemoresistance through regulation of ZEB1 protein. We used sequencing to detect mRNA expression changes in A2780 cells after ZEB1-AS1 silencing. The results indicated that MMP19 was the likely downstream factor of ZEB1-AS1. We further examined whether ZEB1-AS1 played an important role in chemoresistance by silencing MMP19 in ZEB1-AS1-overexpressing cells. CCK8 assay results suggested that MMP19 knockdown promoted ZEB1-AS1-induced chemoresistance to PTX and DDP in A2780 cells. CONCLUSION: This study is the first to reveal that ZEB1-AS1 plays a pivotal role in cancer chemoresistance.

[Surgical treatment of internal carotid artery kinking following fibromuscular dysplasia]. / Rezul'taty khirurgicheskogo lecheniya patologicheskoi izvitosti vnutrennei sonnoi arterii na fone fibrozno-myshechnoi displazii.

OBJECTIVE: To evaluate the results of surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. MATERIAL AND METHODS: There were 32 patients who underwent surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Structural changes of carotid artery wall were analyzed using immunohistochemical survey. Considering destructive changes revealed, we divided all patients into 2 groups in order to assess long-term postoperative outcomes: 1 - ICA resection followed by anastomosis in end-to-end fashion; 2 - ICA replacement. Postoperative analysis included incidence of stroke, thrombosis and deformities of anastomosis zone, regression of cerebrovascular insufficiency. RESULTS: The main «phenotype¼ of arterial wall in patients with ICA kinking following fibromuscular dysplasia is a large number of smooth muscle cells releasing matrix matelloproteinases-2 and -9 and low level of their tissue inhibitor type 1. Postoperative deformities are more common within a year after surgery. Maximum incidence is observed after 12 months. Both ICA resection and replacement are followed by similar incidence of deformity later. No severe deformities were diagnosed. Resection of ICA kinking on the background of fibromuscular dysplasia is followed by comparable results with ICA replacement regarding the incidence stroke, thrombosis and regression of cerebrovascular insufficiency. CONCLUSION: Despite degradation of extracellular matrix, destruction of elastic fibers and their fragmentation, no significant deformities are observed in long-term postoperative period in patients with ICA kinking and fibromuscular dysplasia.

Expression and Clinical Significance of MMP-28 in Bladder Cancer.

AIMS: The aim of this study to determine the expression of MMP-28 in bladder urothelial carcinoma and to analyze the correlation between MMP-28 and the clinicopathological characteristics of human bladder carcinoma, and its relationship with patient prognosis. METHODS: A total of 491 surgically resected bladder cancer samples and 80 normal tissue adjacent to the tumor were stained by immunohistochemistry. The expression of MMP-28 in these samples was quantitated, and the value of MMP-28 as a marker of bladder cancer and prognosis was assessed. RESULTS: The expression of MMP-28 in urinary bladder carcinoma was higher than in normal bladder mucosa. The high level of MMP-28 was significantly correlated with tumor histology grade, lymphatic metastasis, lymph node infiltration, and distant metastasis (P < 0.05). The upregulation of MMP-28 was also closely related to the risk of cancer progression and the survival of patients. Further analysis documented that high expression of MMP-28 was associated with decreased overall survival in bladder cancer patients. CONCLUSIONS: The abnormal expression of MMP-28 may be related to the initiation and development of urothelial carcinoma. The upregulation of MMP-28 can be used as one of the effective indicators to diagnose bladder cancer and predict tumor progression.

Therapeutic effects of triptolide from Tripterygium wilfordii Hook. f. on interleukin-1-beta-induced osteoarthritis in rats.

Osteoarthritis (OA) is a common yet destructive disease affecting the articular cartilage, and is a major cause of immense suffering and disability for millions of people. Previous studies have shown that triptolide (TPL), an active compound derived from Tripterygium wilfordii, has potent immunosuppressive and anti-inflammatory activities useful for treating chronic diseases. However, whether TPL has immunosuppressive activity against OA is not known. In this study, we assessed the therapeutic effects of TPL on interleukin-1-beta (IL-1ß)-induced OA in rats. Histological and protein analyses revealed that TPL not only could inhibit interleukin-6 (IL-6) and cyclooxygenase-2 (COX2) protein expression in cells and disrupt inflammation, but it also reduced the expression of matrix metalloproteinase (MMP)-3 and 13. Our results also supported the ability of TPL to suppress the osteoprotegerin/receptor activator of nuclear factor kappa-beta (NF-κB)/receptor activator of NF-κB ligand (OPG/RANK/RANKL) and NF-κB signaling pathways induced by IL-1ß. Together these data suggest that TPL may be a potentially valuable treatment for OA, regulating associated inflammation and pain.

The prognostic value and potential mechanism of Matrix Metalloproteinases among Prostate Cancer.

Background: Matrix Metalloproteinases (MMPs) play an indispensable role in the initial alteration and development of PCa. We tried to generate an MMP-related prognostic signature (MMPS) in prostate cancer (PCa). Methods: TCGA-PRAD, MSKCC/GSE21032, GSE116918, GSE70769 cohorts were enrolled to assess the prognostic value of MMPs. The least absolute shrinkage and selection operator (LASSO) Cox regression was employed to generate the MMPS signature. The log-rank test and Kaplan-Meier (K-M) survival curve were applied to show the difference RFS, The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) was plotted to predict the accuracy of signature. CIBERSORT was conducted to analyze the different immune infiltration in MMPS-H and MMPS-L groups. Potential signaling pathways activated in the MMPS-H groups by Metascape. Results: MMP1, MMP7, MMP11, MMP24 and MMP26 were selected by LASSO regression and established the MMPS predict signature. The MMPS showed the high prognostic value in TCGA-PRAD training cohort (AUC=0.714) and validation cohorts (GSE116918: AUC=0.976, GSE70769: AUC=0.738, MSKCC: AUC=0.793). Pid integrin1 pathway, G2M checkpoint, and response to growth factor signaling pathways were activated in MMPS-H group, patients with the high MMPS risk score and low M2 macrophage showed the worst recurrence-free survival (RFS). Conclusion: MMPs involved and played an essential role in the tumorigenesis and biochemical recurrence in PCa patients. The MMPS signature could accurately predict the recurrence of PCa patients and validated in several cohorts.

Gumiganghwal-tang ameliorates cartilage destruction via inhibition of matrix metalloproteinase.

ETHNOPHARMACOLOGICAL RELEVANCE: Kyung-Bang Gumiganghwal-tang tablet (GMGHT) is a standardized Korean Medicine that could treat a cold, headache, arthralgia and fever. Although GMGHT has been used for arthritis-related diseases including a sprain, arthralgia, unspecified arthritis and knee arthritis, there is no pre-clinical evidence to treat osteoarthritis (OA). This study determined the drug dosage and the mechanisms of GMGHT for OA. METHODS: OA was induced by intra-articular monoiodoacetic acid (MIA) injection in Sprague-Dawley rats. As calculated from the human equivalent dose formula, GMGHT was orally administered at the doses of 9.86, 98.6 and 986 mg/kg for 4 weeks. The arthritis score was performed by a blind test, and histological changes in articular cartilage were indicated by hematoxylin and eosin, Safranin O and toluidine blue staining. SW1353 chondrocytes were stimulated by interleukin (IL)-1ß recombinant to analyze the expressions of Type II collagen, matrix metalloproteinases (MMPs) and nuclear factor (NF)-κB. RESULTS: Rough and punctate surfaces of the femoral condyle induced by MIA, were recovered by the GMGHT treatment. The arthritis score was significantly improved in the 968 mg/kg of GMGHT-treated cartilage. Loss of chondrocytes and proteoglycan were ameliorated at the deep zone of the subchondral bone plate by the GMGHT administration in OA rats. The expression of Type II collagen was increased, while MMP-1, -3 and -13 levels were decreased in the GMGHT-treated SW1353 chondrocytes. In addition, the GMGHT treatment regulated NF-κB activation along with IL-6, transforming growth factor-ß and IL-12 production. CONCLUSIONS: GMGHT promoted the recovery of articular cartilage damage by inhibiting MMPs, accompanied with its anti-inflammatory effects in OA. GMGHT might be an alternative therapeutic treatment for OA.

Mechanical injury and IL-1ß regulated LOXs and MMP-1, 2, 3 expression in ACL fibroblasts co-cultured with synoviocytes.

OBJECTIVE: Interleukin (IL)-1ß in the joint cavity increases to promote healing after anterior cruciate ligament (ACL) injury. Synovial tissue is a major joint microenvironmental regulator after ACL injury. The purpose of this study was to investigate the effects of synovial cells (SCs) on lysyl oxidase (LOX) and matrix metalloproteinase (MMP) production by ACL fibroblasts (ACLfs) in the presence of IL-1ß. RESULTS: This study sheds light on the regulation of LOX and MMP-1, -2, -3 expression by ACLfs co-cultured with SCs and treated with IL-1ß. LOX and MMP-1, 2, 3 gene/protein expression in IL-1ß/stretch-stimulated ACLfs co-cultured with SCs were measured by real-time quantitative PCR and Western blot. Meanwhile, MMP-2 activity was analyzed by zymogram. The results showed that co-culture with SCs increased LOX and MMP-1, -2, -3 gene and protein expression in the presence of IL-1ß. Next, ACLfs were subjected to 12% mechanical stretch to simulate pathological injury. Under these conditions, SCs inhibited IL-1ß-mediated upregulation of LOXs. However, IL-1ß enhanced the expression of MMP-1, -2, -3 in injured ACLfs. CONCLUSIONS: SCs can either inhibit or increase LOX production in the presence of IL-1ß, while promoting the accumulation of MMP in injured ACLfs. These results may provide crucial insights into the mechanisms underlying ACL poor healing capacity after injury.

LncRNA ILF3-AS1 mediated the occurrence of epilepsy through suppressing hippocampal miR-212 expression.

Increased expression of some matrix metalloproteinases (MMPs) is closely associated with epilepsy. However, factors that promote their expression have not been clarified. Long noncoding RNAs (lncRNAs) play crucial roles in the development of human diseases, including various cancers, but its potential function in temporal lobe epilepsy (TLE) has remained unexplored. In this study, we showed that hippocampal and serum ILF3-AS1 levels are higher in TLE patients than in matched controls. Interleukin (IL)-1ß and tumor necrosis factor (TNF)-α induced ILF3-AS1 expression in astrocytes, while ectopic expression of ILF3-AS1 enhanced IL-6 and TNF-α expression. Ectopic ILF3-AS1 in astrocytes also increased expression of MMP2, MMP3, MMP9 and MMP14, but suppressed expression of miR-212. Consistent with that finding, miR-212 levels were lower in the hippocampus and serum of TLE patients than their controls. This suggests that ILF3-AS1 promotes expression of inflammatory cytokines and MMPs by targeting miR-212 and that ILF3-AS1 plays a crucial role in the development of TLE.

Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts.

BACKGROUND: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. MATERIALS AND METHODS: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the "Extracellular Matrix and Adhesion Molecules" pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. RESULTS: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. CONCLUSION: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.

Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons.

Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like motor traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This will help to understand the role of nucleocytoplasmic transport in the differential vulnerability of neuronal cell types to ALS and to uncover non-motor endophenotypes with pathognomonic signs of ALS. Here, we ascertain Ranbp2's function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway's evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified CD11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. Further, there was the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Hence, Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neuronal-type selective substrates. Immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuronal-glial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of motoneuron diseases, such as ALS.

Upregulated MMP28 in Hepatocellular Carcinoma Promotes Metastasis via Notch3 Signaling and Predicts Unfavorable Prognosis.

MMP28 belongs to the matrix metalloproteinases (MMPs) family and functions in tissue homeostasis and development. Although many other MMPs have been reported to regulate tumor progression, the roles of MMP28 in cancer remain largely elusive. In this study, we investigated the potential roles of MMP28 in hepatocellular carcinoma (HCC). The upregulation of MMP28 was first determined by the analysis on different public datasets. Further quantitative real-time PCR (qPCR) analysis, western blot (WB) assay and immunohistochemistry (IHC) assay on tumor and tumor-adjacent samples from HCC patients confirmed the aberrant elevation of MMP28 in HCC. Pathological analysis showed that increased MMP28 was associated with tumor size, vascular invasion, TNM stage and overall survival in HCC patients. Meanwhile, upregulated MMP28 was identified as an independent prognosis factor in multivariate analysis, and the incorporation of MMP28 expression with TNM staging system established a novel model to improve the accuracy of the predictions. In vivo and in vitro data revealed that MMP28 promoted migration and invasion of HCC cells, and enhanced epithelial-mesenchymal transition (EMT) via elevating zinc finger E-box binding homeobox (ZEB) homologues levels. Furthermore, we determined that Notch3 signaling was critical for the functions of MMP28 in HCC. In conclusion, upregulated MMP28 in HCC promoted migration and invasion and predicted poor prognosis for HCC patients, and the effects of MMP28 depended on Notch3 signaling.