Decreased Matrix Metalloproteinase Research Articles

Efficient Suppression of Abdominal Aortic Aneurysm Expansion in Rats through Systemic Administration of Statin-Loaded Nanomedicine.

Abdominal aortic aneurysm (AAA) is a life-threatening disease. However, no systemically injectable drug has been approved for AAA treatment due to low bioavailability. Polymeric micelles are nanomedicines that have the potential to improve therapeutic efficacy by selectively delivering drugs into disease sites, and research has mainly focused on cancer treatments. Here, we developed a statin-loaded polymeric micelle to treat AAAs in rat models. The micelle showed medicinal efficacy by preventing aortic aneurysm expansion in a dose-dependent manner. Furthermore, the micelle-injected group showed decreased macrophage infiltration and decreased matrix metalloproteinase-9 activity in cases of AAA.

3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro.

The growth and differentiation of adipose tissue-derived stem cells (ASCs) is stimulated and regulated by the adipose tissue (AT) microenvironment. In lipedema, both inflammation and hypoxia influence the expansion and differentiation of ASCs, resulting in hypertrophic adipocytes and deposition of collagen, a primary component of the extracellular matrix (ECM). The goal of this study was to characterize the adipogenic differentiation potential and assess the levels of expression of ECM-remodeling markers in 3D spheroids derived from ASCs isolated from both lipedema and healthy individuals. The data showed an increase in the expression of the adipogenic genes (ADIPOQ, LPL, PPAR-γ and Glut4), a decrease in matrix metalloproteinases (MMP2, 9 and 11), with no significant changes in the expression of ECM markers (collagen and fibronectin), or integrin A5 in 3D differentiated lipedema spheroids as compared to healthy spheroids. In addition, no statistically significant changes in the levels of expression of inflammatory genes were detected in any of the samples. However, immunofluorescence staining showed a decrease in fibronectin and increase in laminin and Collagen VI expression in the 3D differentiated spheroids in both groups. The use of 3D ASC spheroids provide a functional model to study the cellular and molecular characteristics of lipedema AT.

Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism

Pharmacological ascorbate (P-AscH−, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH− have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH− on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH−. Serum from PDAC patients in clinical trials with P-AscH− were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH− inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo, P-AscH− significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH− on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH− decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH− attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.

Psychological Stress Up-Regulates CD147 Expression Through Beta-Arrestin1/ERK to Promote Proliferation and Invasiveness of Glioma Cells.

Psychological stress is closely related to the occurrence and prognosis of various malignant tumors, but the underlying mechanisms are not well studied. CD147 has been reported to be expressed in glioma and other malignant tumors. CD147 not only participates in lactic acid transport, but it also plays an important role in the invasion and metastasis of malignant tumor cells by stimulating the production of numerous matrix metalloproteinases (MMPs) and vascular endothelial growth factor by fibroblasts, and could also act as an autocrine factor stimulating MMPs production in metastatic tumor cells. Here, we found that silencing CD147 in chronically stressed nude mice not only inhibited the proliferation of xenografts but also decreased matrix metalloproteinase-2, 9 expression and lactic acid content in tumor tissues. Furthermore, norepinephrine (NE) was significantly increased in the serum of nude mice in glioma stress model. To determine the underlying cellular mechanism, we added exogenous NE into LN229 and U87 cells to simulate the stress environment in vitro. The invasiveness of the glioma cells was subsequently examined using a Matrigel invasion assay. We demonstrated that knockdown of CD147 inhibited glioma invasiveness and metastasis with norepinephrine stimulation. Luciferase reporter gene experiments further demonstrated that the expression of CD147 is up-regulated primarily by norepinephrine via the β-Adrenalin receptor (βAR)-β-arrestin1-ERK1/2-Sp1 pathway. High expression of CD147 promoted the secretion of MMP-2 and the increment of lactic acid, which accelerated the augmented invasion and metastasis of glioma induced by psychological stress. Taken together, these results suggest that psychological stress promotes glioma proliferation and invasiveness by up-regulating CD147 expression. Thus, CD147 might be a potential target site in the treatment of glioma progression induced by chronic psychological stress.

Transcription Factor ELF1 Activates MEIS1 Transcription and Then Regulates the GFI1/FBW7 Axis to Promote the Development of Glioma

Glioma is the most common malignancy in the central nervous system with no immediate prospect of a cure. Comprehensive understanding on the pathogenesis of the disorder contributes to a better outcome. Herein, we aimed to investigate whether transcription factors erythroblast transformation-specific (ETS) transcription factor (ELF1), myeloid ecotropic viral integration site 1 (MEIS1), and growth factor independence 1 (GFI1)/F-box/WD repeat-containing protein 7 (FBW7) mediate progression of glioma. ELF1, MEIS1, and GFI1 were upregulated in glioma cells and tissues, as ELF1 was correlated with poor prognosis. Bioinformatics analysis identified the binding between ELF1 and MEIS1 as well as between GFI1 and FBW7, confirmed by chromatin immunoprecipitation (ChIP) experiments. Functional experiment indicated that silencing of ELT1 decreased MEIS1 expression and that overexpression of MEIS1 increased GFI1 expression by activating GFI1 enhancer but decreased FBW7 expression. Importantly, silencing of ELF1 decreased the capacities of proliferation, migration, and invasion of glioma cells whereas it increased apoptosis, supported by increased capase-3 and decreased matrix metalloproteinase-9 (MMP-9) and proliferating cell nuclear antigen (PCNA) expression. Moreover, an in vivo experiment confirmed the inhibitory role of silenced ELF1 in tumor growth, with a decreased level of MEIS1 and GFI1. Taken together, our study elucidated a potential mechanism that ELF1 promoted cell progression by increasing GFI1 and METS1 as well as decreasing FBW7 expression in glioma.

Prevalence and Predictors of Urinary Incontinence at 1 Year Postpartum.

Postpartum urinary incontinence estimates range from 13% to 47%. Clinical factors associated with incontinence 1 year after first delivery are varied. We assessed the prevalence of and factors associated with urinary incontinence in primiparous women at 12 months postpartum. Ancillary analysis of 99 nulliparous women from a prospective cohort study that assessed participants during the first and third trimesters and 12 months postpartum. Our primary outcome was urinary incontinence 12 months postpartum. Women were asked "How often do you experience urine leakage?" and considered to have urinary incontinence if a response other than "never" was reported. We collected vaginal swabs for assessment of matrix metalloproteinase-9 activity, a measure of tissue remodeling. Bivariable and logistic regression analyses were used to compare women with and without postpartum urinary incontinence. Of 99 primiparous women, 55% (n = 54) reported urinary incontinence at 12 months postpartum. Logistic regression demonstrated that urinary incontinence during pregnancy (odds ratio, 34.3; 95% confidence interval, 7.9-149.2) and a decrease in matrix metalloproteinase 9 activity between the first and third trimesters (odds ratio, 19.34; 95% confidence interval, 3.47-107.84) were associated with postpartum urinary incontinence. The sensitivity and specificity of urinary incontinence during pregnancy for predicting postpartum urinary incontinence were 87% and 67%, respectively. The positive and negative predictive values were 76% and 81%, respectively. Urinary incontinence affected 55% of primiparous women at 12 months postpartum. Urinary incontinence during pregnancy was strongly associated with postpartum incontinence. Importantly, vaginal tissue protease activity during pregnancy represents a possible mechanism for and biomarker of postpartum urinary incontinence.

Knockout of miR-21-5p alleviates cartilage matrix degradation by targeting Gdf5 in temporomandibular joint osteoarthritis.

AimsThe study aimed to determine whether the microRNA miR21-5p (MiR21) mediates temporomandibular joint osteoarthritis (TMJ-OA) by targeting growth differentiation factor 5 (Gdf5).MethodsTMJ-OA was induced in MiR21 knockout (KO) mice and wild-type (WT) mice by a unilateral anterior crossbite (UAC) procedure. Mouse tissues exhibited histopathological changes, as assessed by: Safranin O, toluidine blue, and immunohistochemistry staining; western blotting (WB); and quantitative real-time polymerase chain reaction (RT-qPCR). Mouse condylar chondrocytes were transfected with a series of MiR21 mimic, MiR21 inhibitor, Gdf5 siRNA (si-GDF5), and flag-GDF5 constructs. The effects of MiR-21 and Gdf5 on the expression of OA related molecules were evaluated by immunofluorescence, alcian blue staining, WB, and RT-qPCR.ResultsUAC altered the histological structure and extracellular matrix content of cartilage in the temporomandibular joint (TMJ), and KO of MiR21 alleviated this effect (p < 0.05). Upregulation of MiR21 influenced the expression of TMJ-OA related molecules in mandibular condylar chondrocytes via targeting Gdf5 (p < 0.05). Gdf5 overexpression significantly decreased matrix metalloproteinase 13 (MMP13) expression (p < 0.05) and reversed the effects of MiR21 (p < 0.05).ConclusionMiR21, which acts as a critical regulator of Gdf5 in chondrocytes, regulates TMJ-OA related molecules and is involved in cartilage matrix degradation, contributing to the progression of TMJ-OA.Cite this article: Bone Joint Res 2020;9(10):689–700.

Insulin-like growth factor-binding protein 3 inhibits angiotensin II-induced aortic smooth muscle cell phenotypic switch and matrix metalloproteinase expression.

What is the central question of this study? Insulin-like growth factor 1 and its major binding protein insulin-like growth factor binding protein 3 (IGFBP3) are involved in collagen deregulation in several cardiovascular diseases: what is the role of IGFBP3 in thoracic aortic dissection and does it regulate aortic smooth muscle cells' phenotypic switch? What is the main finding and its importance? IGFBP3 inhibits aortic smooth muscle cells' phenotypic switch from a contractile to a synthetic phenotype, decreases matrix metalloproteinase 9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. Thoracic aortic dissection (TAD) is characterized by aortic media degeneration and is a highly lethal disease. An aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin-like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present work aimed to study the function of IGFBP3 in AoSMCs' phenotypic switch and matrix metalloproteinase (MMP) expression. We established a mouse model of TAD by angiotensin (Ang) II infusion to β-aminopropionitrile-administrated mice, and found decreased IGFBP3 expression accompanied by aortic dilatation and elastin degradation in vivo. Further, mouse (m)AoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increasing tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II-induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II-induced elastin degradation in vitro. IGFBP3 inhibited Ang II-induced mAoSMCs' phenotypic switch as evidenced by increased smooth muscle actin α-2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs' contractile state and reducing MMP9 activation and thus promoting elastic fibre synthesis, which provides a better understanding of the pathogenesis of TAD.

Mechanism of transmembrane and coiled-coil domain 1 in the regulation of proliferation and migration of A549 cells.

Bioinformatics analyses have shown that transmembrane and coiled-coil domain 1 (TMCO1) may be associated with lung adenocarcinoma. However, to the best of our knowledge, no current research has determined whether TMCO1 is involved in the development of lung adenocarcinoma. The present study aimed to identify the association between TMCO1 and lung adenocarcinoma. The present study demonstrated that the positive immunohistochemical staining of TMCO1 in lung adenocarcinoma tissues was significantly higher compared with paracarcinoma tissues. Additionally, knockdown of TMCO1 was demonstrated to downregulate B-cell lymphoma-2 protein expression levels and upregulate cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 protein expression levels in A549 cells. These changes resulted in decreased apoptosis of A549 cells uponTMCO1 downregulation. In addition, knockdown of TMCO1 decreased matrix metalloproteinase (MMP)-2 and MMP-9 expression levels. The expression of N-cadherin and vimentin also decreased. By contrast, the expression levels of E-cadherin protein increased. Knockdown of TMCO1 resulted in the inhibition of A549 cell migration. The results of the present study demonstrated that TMCO1 was associated with lung adenocarcinoma and that inhibition of TMCO1 expression levels negatively regulated the apoptosis and migration of lung adenocarcinoma cells. Therefore, the present study suggests the potential for TMCO1 to be used in the clinical treatment of lung adenocarcinoma.

Abstract 5030: Vitamin D exhibits therapeutic anti-tumor and anti-angiogenic potential by reducing VEGF levels and altering TIMP/MMP system in breast cancer

Abstract Background: Clinical and experimental observations suggest that Vitamin D deficiency associates with increased risk of breast cancer. Furthermore, studies concluded that Vitamin D precipitates in significant anti-neoplastic effects against breast, and inducing apoptosis and affecting angiogenesis in other types of cancer. However, the exact mechanism underlying this anti-angiogenic effect of Vitamin D is still elusive. This study aims to investigate the anti-cancer role of Vitamin D anti-cancer and its association with modulation of major factors involved in angiogenesis and metastasis in breast cancer cell lines. Experimental methods: The hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 (calcitriol), was used to evaluate anti-proliferative effect, inhibition of cell cycle progression and apoptosis induction in two breast cancer cell lines, MCF-7 and MDA-MB-231. Furthermore, impact of calcitriol on expression and activity of tissue inhibitors of metalloproteinases (TIMP), major groups of the matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and tumor growth factor (TGF-β1) among others involved in tumor progression and angiogenesis were also examined. Results and Discussions: Calcitriol treatment (10 µM) significantly inhibited cell proliferation in a timely dependent manner. Both cell lines showed G1 cell cycle arrest, decreased levels of the cell death inhibitor, survivin, and apoptosis induction in response to calcitriol treatment. Proteome Profiler array analysis revealed that calcitriol resulted in reducing the levels of major pro-angiogenesis regulators, especially VEGF, TGF-β1, Urokinase-type plasminogen activator (uPA), and Amphiregulin. Analysis of mRNA and proteins expression upon calcitriol exposure showed an increase of TIMP1, TIMP2 and a decrease in MMP 2, 3 and 9 levels. Finally, quantitative analysis using ELISA revealed that calcitriol treatment reduced MMP2 and MMP9 activities. Conclusion: Our study demonstrates potential therapeutic property of calcitriol through inhibiting of pro-angiogenetic markers in breast cancer. Citation Format: Khuloud Bajbouj, Jasmin Shafarin, Ahmad Sawan, Ahmed Shehada, Walaa Eldin Elkhalifa. Vitamin D exhibits therapeutic anti-tumor and anti-angiogenic potential by reducing VEGF levels and altering TIMP/MMP system in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5030.

THU316 - The FXR agonist obeticholic acid decreases matrix metalloproteinase activity via RECK and TIMP modulation in hepatic ischemia/reperfusion injury

THU316 - The FXR agonist obeticholic acid decreases matrix metalloproteinase activity via RECK and TIMP modulation in hepatic ischemia/reperfusion injury

Downregulation of miR-1225-5p is pivotal for proliferation, invasion, and migration of HCC cells through NFκB regulation.

BackgroundAs one of the most frequently seen malignancies, hepatocellular carcinoma (HCC) serves as the second largest contributor to malignancy‐specific mortality worldwide. MicroRNA‐1225‐5p (miR‐1225) exerts an essential impact on the growth and metastasis of many malignancies. However, the contribution of miR‐125 to HCC and the molecular mechanism of cancer cell viability and apoptosis are still unclear. We focused our research on exploring the function and molecular mechanism of miR‐1225 in regulating HCC cell growth, migration, and invasion.MaterialQuantitative PCR data showed that miR‐1225 expression was repressed in HCC cell lines and in the tissues of HCC patients, compared to that in normal human hepatic cells and tissues. Transfection of a miR‐1225 mimic inhibited cell viability and proliferation as indicated by CCK‐8 staining and MTT assay. Transwell invasion, wound healing assay, and Western blotting were performed to assess whether miR‐1225 repressed the metastasis and invasion of HCC cells, and decreased matrix metalloproteinase 9 (MMP9) expression. Further bioinformatic prediction and dual‐luciferase reporter assay suggested that miR‐1225 targeted the 3′‐UTR of NFκB p65.ResultsOverexpression of p65 protein counteracted the repressive impact of miR‐1225 on invasion, migration, and proliferation of HCC cells.ConclusionThis research provided new evidences that miR‐1225 inhibits the viability, migration, and invasion of HCC cells by downregulation of p65.

Predifferentiated Smooth Muscle-Like Adipose-Derived Stem Cells for Bladder Engineering.

Introduction: All organs of human body are a conglomerate of various cell types with multidirectional interplay between the different cells and the surrounding microenvironment, leading to a stable tissue formation, homeostasis, and function. To develop a functional smooth muscle tissue, we need to simulate and create a multicellular microenvironment. The multilineage adipose-derived stem cells (ADSCs), which can be easily harvested in large numbers, may provide an alternative cell source for the replacement of smooth muscle cells (SMCs) in cell-based detrusor bioengineering therapeutic approaches. The aim of this study was to investigate whether predifferentiated smooth muscle-like ADSC (pADSC) can support SMCs to generate stable smooth muscle tissue through remodeling of extracellular matrix (ECM) and factor secretion. Methods: Rat SMC and pADSC were mono- and cocultured in the cell ratios 1:1, 1:2, 1:3, and 1:5 (SMC-pADSC) and grown for up to 2 weeks in vitro. The expression of the SMC-specific markers alpha-smooth muscle actin, calponin, myosin heavy chain 11 (MyH11), and smoothelin was assessed, and cell proliferation and contractility were analyzed. Proteomic analysis of the secretome (cell-cell contact was compared with a noncontact transwell 1:1 coculture) and the cell pellets was performed, with the focus on ECM deposition and remodeling, integrin expression and growth factor secretion. Results: SMC and pADSC were strongly positive for all smooth muscle markers. After 1 and 2 weeks of culture, the 1:1 cell ratio developed a significantly higher number of smooth muscle organoids and improved contractility. These organoids were highly structured, consisting of an SMC core surrounded by a pADSC layer. The deposition of various EMC proteins, such as collagens 1a1, 1a2, 2a1, 3a1, 5a2, 6a2, 12a1, and fibrillin 1, was significantly increased. A decreased matrix metalloproteinase 3 (MMP3), MMP9 and MMP13 secretion, as well as increased tissue inhibitors of metalloproteinase 1 (TIMP1) and TIMP2 secretion were found in the contact coculture compared with the monoculture controls. Conclusion: SMC-pADSC 1:1 cocultures exhibit an improved cell proliferation, contractility, and organoid formation compared with all other ratios and monoculture, while retaining a stable phenotype that is comparable with the SMC monoculture. These effects are mediated by increased ECM deposition and tight ECM remodeling by the secreted MMP and TIMP. Impact statement Harvesting smooth muscle cells (SMCs) from diseased bladders represents a significant limitation for clinical translation of bladder Tissue Engineering. Our results suggest that autologous predifferentiated smooth muscle-like adipose-derived stem cell can substitute SMCs, and may be used in combination with SMCs to generate contractile detrusor muscle tissue for patients suffering from end-stage bladder diseases. We demonstrate a beneficial effect when using these cells in a 1:1 ratio with improved deposition of extracellular matrix (ECM) molecules and superior remodeling of the ECM by matrix metalloproteinases and decreased tissue inhibitors of metalloproteinase activity.

DMBT1 suppresses cell proliferation, migration and invasion in ovarian cancer and enhances sensitivity to cisplatin through galectin-3/PI3k/Akt pathway.

Ovarian cancer (OC) is one of the most common gynaecologic malignancies. Deleted in malignant brain tumors 1 (DMBT1) was considered as a tumour suppressor in multiple cancers, but there have been no systemic profiling studies of DMBT1 in OC until now. The aim of this study is to explore the role and the potential mechanism of DMBT1 in OC. mRNA levels and protein expressions of corresponding genes were detected by quantitative real-time polymerase chain reaction and western blot. Cell proliferation was detected by CCK-8 assay and cell colony formation. Cell migration and invasion were detected by wound healing and transwell assay. The combination between DMBT1 and galectin-3 was demonstrated by immunoprecipitation. We demonstrated that DMBT1 was downregulated in OC cell lines, especially SKOV3 cells. Overexpression of DMBT1 significantly inhibited cell proliferation, colony formation, migration and invasion, as well as decreased Matrix Metalloproteinase-2 (MMP-2) and MMP-7. DMBT1 caused a reduction of cell viability by treatment with cisplatin. Immunoprecipitation assay revealed a combination between DMBT1 and galectin-3. DMBT1 could decrease the expression of galectin-3 and inhibit the phosphorylation of PI3K and AKT, while overexpression of galectin-3 reversed this effect. In summary, DMBT1 might inhibit the progression of OC and improve the sensitivity of SKOV3 cells to cisplatin through galectin-3/PI3K/AKT pathway, giving a new insight into the role of DMBT1 in OC and enriching the potential strategies for OC treatment. SIGNIFICANCE OF THE STUDY: The present study focus on the role and the potential mechanism of DMBT1 in ovarian cancer (OC). We demonstrated that DMBT1 might inhibit the progression of ovarian by inhibiting cell proliferation, migration and invasion and increased the sensitivity to cisplatin through galectin-3/PI3K/AKT pathway. The findings ensure the interaction relation between DMBT1 and galectin-3 in OC, providing a novel biological marker for OC and enriching the potential strategies for OC treatment.

Uncovering the Mystery of Idiopathic Adhesive Capsulitis: Commentary on an article by Hyung Bin Park, MD, PhD, et al.: "Association Between High-Sensitivity C-Reactive Protein and Idiopathic Adhesive Capsulitis".

Uncovering the Mystery of Idiopathic Adhesive Capsulitis: Commentary on an article by Hyung Bin Park, MD, PhD, et al.: "Association Between High-Sensitivity C-Reactive Protein and Idiopathic Adhesive Capsulitis".

Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice.

AimAbdominal aortic aneurysms (AAA) is a life-threatening weakening and expansion of the abdominal aorta due to inflammatory cell infiltration and gradual degeneration of extracellular matrix (ECM). There are no pharmacological therapies to treat AAA. We tested the hypothesis that nanoparticle (NP) therapy that targets degraded elastin and delivers anti-inflammatory, anti-oxidative, and ECM stabilizing agent, pentagalloyl glucose (PGG) will reverse advance stage aneurysm in an elastase-induced mouse model of AAA.Method and resultsPorcine pancreatic elastase (PPE) was applied periadventitially to the infrarenal aorta in mice and AAA was allowed to develop for 14 days. Nanoparticles loaded with PGG (EL-PGG-NPs) were then delivered via IV route at 14-day and 21-day (10 mg/kg of body weight). A control group of mice received no therapy. The targeting of NPs to the AAA site was confirmed with fluorescent dye marked NPs and gold NPs. Animals were sacrificed at 28-d. We found that targeted PGG therapy reversed the AAA by decreasing matrix metalloproteinases MMP-9 and MMP-2, and the infiltration of macrophages in the medial layer. The increase in diameter of the aorta was reversed to healthy controls. Moreover, PGG treatment restored degraded elastic lamina and increased the circumferential strain of aneurysmal aorta to the healthy levels.ConclusionOur results support that site-specific delivery of PGG with targeted nanoparticles can be used to treat already developed AAA. Such therapy can reverse inflammatory markers and restore arterial homeostasis.

Curcumin attenuates endothelial cell fibrosis through inhibiting endothelial-interstitial transformation.

Curcumin (Cur) has various pharmacological activities, including anti‐inflammatory, antiapoptotic and anticancer effects. However, there is no report on the effect of Cur on endothelial cell fibrosis. This study was designed to investigate the effect and mechanism of Cur on endothelial cell fibrosis. An endothelial cell fibrosis model was established by using transforming growth factor (TGF) induction. Proliferation assays, qRT‐PCR, western blotting and immunostaining were performed to investigate the effects and mechanism of Cur on endothelial cell fibrosis. We found that in human umbilical vein endothelial cells (HUVECs), TGF‐β1 treatment significantly decreased the expression of nuclear factor erythroid‐2‐related factor 2 (NRF‐2), dimethylarginine dimethylaminohydrolase‐1 (DDAH1), and VE‐cadherin, the secretion of cellular nitric oxide (NO) and the activity of nitrous oxide synthase (NOS), while asymmetric dimethylarginine (ADMA) and the release of inflammatory factors were elevated. Immunofluorescence showed decreased CD31 and increased α‐smooth muscle actin (α‐SMA). Overexpression of NRF‐2 significantly attenuated the effects of TGF‐β1, while downregulation of DDAH1 potently counteracted the effect of NRF‐2. In addition, ADMA treatment resulted in similar results to those of TGF‐β1, and Cur significantly attenuated the effect of TGF‐β1, accompanied by increased VE‐cadherin, DDAH1 and NRF‐2 and decreased matrix metalloproteinase‐9 (MMP‐9) and extracellular regulated protein kinases 1/2 (ERK1/2) phosphorylation. The NRF‐2 inhibitor ML385 had the opposite effect as that of Cur. These results demonstrated that Cur inhibits TGF‐β1‐induced endothelial‐to‐mesenchymal transition (EndMT) by stimulating DDAH1 expression via the NRF‐2 pathway, thus attenuating endothelial cell fibrosis.

Resistance training decreases matrix metalloproteinase-2 activity in quadriceps tendon in a rat model of osteoarthritis

BackgroundOsteoarthritis (OA) is a degenerative disease that induces peri-articular tissue degradation. OA induces an imbalance between synthesis and degradation of the extracellular matrix components in favor of catabolic events, promoting pathological remodeling and involving degradative enzymes, such as matrix metalloproteinases (MMPs). ObjectiveThis study aimed to investigate the effects of 8-weeks resistance training (RT) on MMP-2 activity in the quadriceps tendon and patellar tendon in an OA model. MethodsTwenty-four Wistar rats were randomly divided into six groups: Control, Exercise, Sham, Sham with Exercise, OA, and OA with Exercise (OAE). The OA model was performed by anterior cruciate ligament transection surgery on the left knee. The 8-week RT consisted of climbing a 1.1-m vertical ladder three times per week with progressive weights secured to the animals’ tails. MMP-2 activity was analyzed by zymography. ResultsThe OAE group displayed lower pro, intermediate, and active MMP-2 activity in the quadriceps tendon compared with the OA group (p<0.05). For the patellar tendon, there was no significant difference between the OAE group compared with the other groups (p>0.05) for pro, intermediate, and active MMP-2 activity. Moreover, MMP-2 activity differed between tissues, the OA and OAE groups presented lower pro, intermediate, and active MMP-2 activity in the quadriceps tendon compared to the patellar tendon. ConclusionRT induced down-regulated MMP-2 activity in the quadriceps tendon. RT is a potential therapeutic approach to minimize the deleterious effects of extracellular matrix degeneration.

Total saponins from Lilium lancifolium: a promising alternative to inhibit the growth of gastric carcinoma cells.

Bulbus Lilii, as a medicinal and edible plant, has anti-inflammatory, anti-oxidative and immunopotentiating pharmacological activities, which seems to be therapeutic on cancer prevention. The purpose of this study was to investigate the effects of total saponins from Lilium lancifolium (TSLL) on proliferation, apoptosis and migration of human gastric carcinoma cells lines SGC-7901 and HGC-27 and its underlying mechanism. The results showed that TSLL inhibited the proliferation of gastric carcinoma cells by suppressing the level of proliferating cell nuclear antigen (PCNA) and increased p21 level. TSLL induced cells apoptosis by up-regulating expression of pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2 expression. Meanwhile, TSLL remarkably inhibited cell migration and invasion, decreased matrix metalloproteinase-2 (MMP-2) expression and increased tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. Notably, TSLL had stronger anti-cancer effect on undifferentiated HGC-27 cells than differentiated SGC-7901 cells. Accordingly, TSLL might be a promising candidate to prevent and suppress the growth of gastric carcinoma cells.

Scrophularia buergeriana attenuates allergic inflammation by reducing NF-κB activation

BackgroundScrophularia buergeriana Miq. (Scrophulariaceae) (SB) has been used as an oriental medicine for the treatment of inflammatory diseases, such as neuritis and pharyngolaryngitis. PurposeWe explored the therapeutic effects of S. buergeriana ethanol extract (SBE) on airway inflammation in ovalbumin (OVA)-induced asthmatic mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. MethodsMice were intraperitoneally injected with OVA on days 0 and 14 to elevate the immune response. On days 21 to 23, the mice were challenged with OVA solution and SBE (20 and 40 mg/kg) was administered daily by oral gavage from days 18 to 23. RAW264.7 cells were pretreated with SBE 1 h before LPS stimulation. ResultsSBE administration effectively suppressed inflammatory cell infiltration, the expression of interleukin (IL)-5, IL-13, and IL-17, immunoglobulin E, and airway hyperresponsiveness in an OVA-induced allergic asthma model. A reduction in histological alterations, including airway inflammation and mucus hypersecretion, was observed. These effects of SBE were accompanied by a decrease in matrix metalloproteinase-9 (MMP-9) expression and nuclear factor kappa B (NF-κB) phosphorylation. These responses were observed in LPS-stimulated RAW264.7 cells. SBE treatment reduced the mRNA expression of tumor necrosis factor (TNF)-α, IL-6, and MMP-9, and NF-κB phosphorylation, in LPS-stimulated RAW264.7 cells. ConclusionOur results indicated that SBE effectively attenuated airway inflammation in an OVA-induced allergic asthma model. These properties of SBE were thought to be involved in the suppression of NF-κB phosphorylation, suggesting that the material has the potential to regulate the development of allergic asthma.