scholarly journals Brusatol Inhibits Proliferation and Invasion of Glioblastoma by Down-Regulating the Expression of ECM1

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhang’an Dai ◽  
Lin Cai ◽  
Yingyu Chen ◽  
Silu Wang ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Herbal Extract ◽  
Extracellular Matrix Protein ◽  
Glioblastoma Cells ◽  
Primary Glioblastoma ◽  
Proliferation And Invasion

Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. RNA-seq analysis indicated that Bru possibly achieved these effects through inhibiting the expression of extracellular matrix protein 1 (ECM1). Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.

scholarly journals Low-Intensity Pulsed Ultrasound Promotes Autophagy-Mediated Migration of Mesenchymal Stem Cells and Cartilage Repair

2021 ◽  
Vol 30 ◽  
pp. 096368972098614
Author(s):  
Peng Xia ◽  
Xinwei Wang ◽  
Qi Wang ◽  
Xiaoju Wang ◽  
Qiang Lin ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Histopathological Analysis ◽  
Pulsed Ultrasound ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Autophagy Inhibitor

Mesenchymal stem cell (MSC) migration is promoted by low-intensity pulsed ultrasound (LIPUS), but its mechanism is unclear. Since autophagy is known to regulate cell migration, our study aimed to investigate if LIPUS promotes the migration of MSCs via autophagy regulation. We also aimed to investigate the effects of intra-articular injection of MSCs following LIPUS stimulation on osteoarthritis (OA) cartilage. For the in vitro study, rat bone marrow-derived MSCs were treated with an autophagy inhibitor or agonist, and then they were stimulated by LIPUS. Migration of MSCs was detected by transwell migration assays, and stromal cell-derived factor-1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR4) protein levels were quantified. For the in vivo study, a rat knee OA model was generated and treated with LIPUS after an intra-articular injection of MSCs with autophagy inhibitor added. The cartilage repair was assessed by histopathological analysis and extracellular matrix protein expression. The in vitro results suggest that LIPUS increased the expression of SDF-1 and CXCR4, and it promoted MSC migration. These effects were inhibited and enhanced by autophagy inhibitor and agonist, respectively. The in vivo results demonstrate that LIPUS significantly enhanced the cartilage repair effects of MSCs on OA, but these effects were blocked by autophagy inhibitor. Our results suggest that the migration of MSCs was enhanced by LIPUS through the activation autophagy, and LIPUS improved the protective effect of MSCs on OA cartilage via autophagy regulation.

Contrasting migratory response of astrocytoma cells to tenascin mediated by different integrins

1996 ◽  
Vol 109 (8) ◽  
pp. 2161-2168 ◽  
Author(s):  
A. Giese ◽  
M.A. Loo ◽  
S.A. Norman ◽  
S. Treasurywala ◽  
M.E. Berens
Keyword(s):  
Cell Adhesion ◽  
Matrix Protein ◽  
Glioma Cells ◽  
Extracellular Matrix Protein ◽  
Integrin Receptors ◽  
Migration Assay ◽  
Dose Dependent Fashion ◽  
Beta 1 Integrin

Tenascin, an extracellular matrix protein, is expressed in human gliomas in vitro and in vivo. The distribution of tenascin at the invasive edge of these tumors, even surrounding solitary invading cells, suggests a role for this protein as a regulator of glioma cell migration. We tested whether purified tenascin, passively deposited on surfaces, influenced the adhesion or migration of a human gliomaderived cell line, SF-767. Adhesion of glioma cells to tenascin increased in a dose-dependent fashion up to a coating concentration of 10 micrograms/ml. Higher coating concentrations resulted in progressively fewer cells attaching. Cell adhesion could be blocked to basal levels using anti-beta 1 integrin antibodies. In contrast, when anti-alpha v antibodies were added to the medium of cells on tenascin, cell adhesion was enhanced slightly. Using a microliter scale migration assay, we found that cell motility on tenascin was dose dependently stimulated at coating concentrations of 1 and 3 micrograms/ml, but migration was inhibited below levels of non-specific motility when tested at coating concentrations of 30 and 100 micrograms/ml. Migration on permissive concentrations of tenascin could be reversibly inhibited with anti-beta 1, while treatment with anti-alpha v antibodies increased migration rates. We conclude that SF-767 glioma cells express two separate integrin receptors that mediate contrasting adhesive and migratory responses to tenascin.

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection

2021 ◽  
Author(s):  
Pingping Jia ◽  
Yi Zhang ◽  
Jian Xu ◽  
Mei Zhu ◽  
Shize Peng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterial Infection ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Dependent Manner ◽  
High Potency ◽  
Resistance Development

Abstract Background Resistance to anti-tuberculosis (TB) drug is a major issue in TB control, and demands the discovery of new drugs targeting virulence factor ESX-1. Methods We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacterium and reducing bacterial virulence. We further investigated the probability of inducing drug-resistance and the underlying mechanism using M-PFC. Results A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drug, and exhibit high potency against chronic mycobacterial infection. Conclusion Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

scholarly journals The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3854-3859 ◽  
Author(s):  
Wei Jia ◽  
Hong Li ◽  
You-Wen He
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Inflammatory Cell ◽  
Neutrophil Migration ◽  
Extracellular Matrix Protein ◽  
Hek 293 ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Leukocyte recruitment to inflammation sites depends on interactions between integrins and extracellular matrix (ECM). In this report we show that mice lacking the ECM protein mindin exhibit severely impaired recruitment of neutrophils and macrophages in 4 different inflammation models. Furthermore, neutrophils directly bind to immobilized mindin, and mindin matrix mediates neutrophil migration in vitro. The adhesion of neutrophils to mindin is blocked by anti–integrin α4, anti–integrin αM, and anti–integrin β2 antibodies. We also show that HEK-293 cells transfected with cDNA encoding these integrins exhibit enhanced binding to immobilized mindin matrix and the increased binding can be blocked by anti-integrin antibodies. Our results suggest that mindin serves as a novel ligand for integrins and mindin-integrin interactions are critical for inflammatory cell recruitment in vivo.

scholarly journals Armadillo Repeat-Containing Protein 8 (ARMC8) Silencing Inhibits Proliferation and Invasion in Osteosarcoma Cells

2016 ◽  
Vol 24 (5) ◽  
pp. 381-389 ◽  
Author(s):  
Feng Jiang ◽  
Yan Shi ◽  
Hong Lu ◽  
Guojun Li
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Armadillo Repeat ◽  
Proliferation And Invasion

Armadillo repeat-containing protein 8 (ARMC8) plays an important role in regulating cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. However, the expression pattern and role of ARMC8 in osteosarcoma are still unclear. In this study, our aims were to examine the effects of ARMC8 on osteosarcoma and to explore its underlying mechanism. Our results demonstrated that ARMC8 was overexpressed in osteosarcoma cell lines. Knockdown of ARMC8 significantly inhibited osteosarcoma cell proliferation in vitro and markedly inhibited xenograft tumor growth in vivo. ARMC8 silencing also suppressed the epithelial‐mesenchymal transition (EMT) phenotype, as well as inhibited the migration and invasion of osteosarcoma cells. Furthermore, knockdown of ARMC8 obviously inhibited the expression of β-catenin, c-Myc, and cyclin D1 in MG-63 cells. In conclusion, this report demonstrates that ARMC8 silencing inhibits proliferation and invasion of osteosarcoma cells. Therefore, ARMC8 may play an important role in the development and progression of human osteosarcoma and may represent a novel therapeutic target in the treatment of osteosarcoma.

Phosphorylation of the carboxyl-terminal region of dystrophin

1996 ◽  
Vol 74 (4) ◽  
pp. 431-437 ◽  
Author(s):  
Marek Michalak ◽  
Susan Y. Fu ◽  
Rachel E. Milner ◽  
Jody L. Busaan ◽  
Jacqueline E. Hance
Keyword(s):  
Extracellular Matrix ◽  
Muscular Dystrophy ◽  
Protein Kinases ◽  
Protein Interactions ◽  
Matrix Protein ◽  
Casein Kinase ◽  
Terminal Region ◽  
Extracellular Matrix Protein

Dystrophin is a protein product of the gene responsible for Duchenne and Becker muscular dystrophy. The protein is localized to the inner surface of sarcolemma and is associated with a group of membrane (glyco)proteins. Dystrophin links cytoskeletal actins via the dystrophin-associated protein complex to extracellular matrix protein, laminin. This structural organization implicates the role of dystrophin in stabilizing the sarcolemma of muscle fibers. Precisely how dystrophin functions is far from clear. The presence of an array of isoforms of the C-terminal region of dystrophin suggests that dystrophin may have functions other than structural. In agreement, many potential phosphorylation sites are found in the C-terminal region of dystrophin, and the C-terminal region of dystrophin is phosphorylated both in vitro and in vivo by many protein kinases, including MAP kinase, p34cdc2 kinase, CaM kinase, and casein kinase, and is dephosphorylated by calcineurin. The C-terminal domain of dystrophin is also a substrate for hierarchical phosporylation by casein kinase-2 and GSK-3. These observations, in accordance with the finding that the cysteine-rich region binds to Ca2+, Zn2+, and calmodulin, suggest an active involvement of dystrophin in transducing signals across muscle sarcolemma. Phosphorylation–dephosphorylation of the C-terminal region of dystrophin may play a role in regulating dystrophin–protein interactions and (or) transducing signal from the extracellular matrix via the dystrophin molecule to the cytoskeleton.Key words: Duchenne muscular dystrophy, protein phosphorylation, protein kinases, calcineurin, cytoskeleton.

scholarly journals EPCO-11. IN VIVO FUNCTIONAL GENOMIC SCREEN IDENTIFIES WISP1 AS AN OVEREXPRESSED DRIVER OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii71-ii71
Author(s):  
Pushan Dasgupta ◽  
Joy Gumin ◽  
Piergiorgio Pettazzoni ◽  
Floris Barthel ◽  
Angela Deem ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Matrix Protein ◽  
Therapeutic Potential ◽  
Functional Characterization ◽  
Extracellular Matrix Protein ◽  
Functional Genomic ◽  
In Vivo Models ◽  
Genomic Screen

Abstract There is a tremendous need to identify new genetic drivers of glioblastoma which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor growth in vivo. Rescue experiments validated that the shRNAs were on target. Functional characterization of the protein revealed that the TSP module is necessary for the phenotype. Intriguingly, overexpression of WISP1 lacking the signal peptide module for secretion resulted in a strong phenotype. Co-culture and conditioned medium experiments further supported a secretion independent intracellular role of WISP1 in GBM. Though WISP1 is a secreted protein we have found some basal localization in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target. This study has expanded our understanding of WISP1 by supporting a new role as a driver in GBM which can function in a non-canonical manner in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target.

scholarly journals Sevoflurane-Induced miR-211-5p Promotes Neuronal Apoptosis by Inhibiting Efemp2

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110350
Author(s):  
Yousu Shen ◽  
Tao Zhou ◽  
Xiaobing Liu ◽  
Yanlong Liu ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Neuronal Apoptosis ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
The Impact

Sevoflurane exposure can result in serious neurological side effects including neuronal apoptosis and cognitive impairment. Although the microRNA miR-211-5p is profoundly upregulated following sevoflurane exposure in neonatal rodent models, the impact of miR-211-5p on neuronal apoptosis and cognitive impairment postsevoflurane exposure has not yet been elucidated. Here, we found that sevoflurane upregulated miR-211-5p and downregulated EGF-Containing Fibulin Extracellular Matrix Protein 2 (Efemp2, Fibulin-4) levels in vitro and in vivo. Sevoflurane's effect on miR-211-5p expression was based on enhancing primary miR-211 transcription. miR-211-5p targets Efemp2's mRNA 3′-untranslated region, reducing Efemp2 expression. RNA immunoprecipitation revealed significant enrichment of the miR-211-5p:Efemp2 mRNA dyad in the RNA-induced silencing complex. miR-211-5p mimics downregulated Efemp2, leading to phosphorylation of Smad2 and Smad3, upregulation of pro-apoptotic Bim, and mitochondrial release of allograft inflammatory factor 1 and cytochrome C. In contrast, miR-211-5p hairpin inhibitor (AntimiR-211-5p) negatively regulated this apoptotic pathway and reduced neuronal apoptosis in an Efemp2-dependent manner. Sevoflurane-exposed mice administered AntimiR-211-5p displayed reduced cortical apoptosis levels and near-term cognitive impairment. In conclusion, sevoflurane-induced miR-211-5p promotes neuronal apoptosis via Efemp2 inhibition. Summary statement: This study revealed the significance of sevoflurane-induced increases in miR-211-5p on the promotion of neuronal apoptosis via inhibition of Efemp2 and its downstream targets.

scholarly journals Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development

2021 ◽  
Author(s):  
Kosei Nagata ◽  
Hironori Hojo ◽  
Song Ho Chang ◽  
Hiroyuki Okada ◽  
Fumiko Yano ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Matrix Protein ◽  
Target Genes ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Conditional Knockout ◽  
Extracellular Matrix Protein ◽  
Surgically Induced

Abstract The Runt-related transcription factor (Runx) family plays various roles in the homeostasis of cartilage. Here, we examined the role of Runx2 and Runx3 for osteoarthritis (OA) development in vivo and in vitro. Runx3 knockout mice accelerated OA by surgical induction, accompanied with decreased expression of lubricin and aggrecan. Meanwhile, Runx2 conditional knockout mice showed biphasic phenotypes; OA was inhibited by hetero-knockout accompanied with decreased matrix metallopeptidase 13 (Mmp13) expression, but accelerated in homo-knockout of Runx2 accompanied with reduction of type II collagen (Col2a1) expression. Comprehensive transcriptional analyses revealed lubricin and aggrecan as transcriptional target genes of Runx3, and indicated that Runx2 sustained Col2a1 expression through an intron 6 enhancer when Sox9 was decreased. Intra-articular administration of Runx3 adenovirus ameliorated development of surgically induced OA. Runx3 protects adult articular cartilage through extracellular matrix protein production under the normal condition, while Runx2 exerts both catabolic and anabolic effects under the inflammatory condition.

Abstract 198: Angiotensin II Inhibits Cardiac Angiogenesis via the Cooperation of p53 and Jagged 1

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Aili Guan ◽  
Hui Gong ◽  
Yong Ye ◽  
Jianguo Jia ◽  
Guoping Zhang ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Tube Formation ◽  
Ang Ii ◽  
Capillary Formation ◽  
Angiogenic Effect ◽  
Endothelial Growth Factor

It is well established that angiotension II (Ang II) is an important regulator in vascular homeostasis. Under certain conditions, Ang II could exert anti-angiogenic effects in cardiovascular system. However, the potential mechanism is unclear. P53 has been reported to suppress angiogenesis by promoting hypoxia-inducible factor-1 (Hif-1α) degradation. This study was conducted to determine the contribution of P53 and the underlying mechanism to the anti-angiogenic effect of Ang II. Angiogenesis was determined by tube formation from the cardiac microvascular endothelial cells (ECs). Microvessel density and cardiac function were analyzed in mice subjected to Ang II infusion (200 ng/kg/min ) or vehicle for 2 weeks. Ang II (1μM) greatly inhibited tube formation and stimulated phosphorylation and upregulation of P53 in cultured cardiac ECs. P53 inhibitor, pifithrin-α (PFT-α,3.0mg/kg), significantly reversed the inhibitory effect of Ang II on tube formation. Vascular endothelial growth factor (VEGF ) and Hif-1α has been reported as important pro-angiogenetic factors. The present study indicated that Ang II decreased VEGF concentration in cultured medium and downregulated Hif-1α expression in cultured ECs. Interestingly, Ang II also stimulated the upregulation of Jagged 1, a ligand of Notch, but it didn't affect the Delta-like 4 (Dll 4) , another ligand of Notch, expression in cardiac ECs. However, PFT-α partly abolished these effects of Ang II. These results were consistent with the study in vivo. Further research revealed that siRNA-Jagged 1 transfection in cultured ECs dramatically abolished the phosphorylation of P53 and the downregulation of Hif-1α induced by Ang II. Additionally, Ang II- induced inhibitory effect on capillary formation was blocked by siRNA-Jagged 1 transfection in cultured cardiac ECs. In conclusion, Ang II promoted the phosphorylation and upregulation of P53, and increased Jagged 1 expression, the upregulation of Jagged 1 in turn stimulated the phosphorylation of P53, which resulted in the downregulation of Hif-1α and VEGF, then induced the inhibitory effects of Ang II on capillary formation. The present data suggest that Ang II exerts anti-angiogenesis via the cooperation of P53 and Jagged 1 in vitro and in vivo.

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