Upregulation Of Matrix Metalloproteinases Research Articles

ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling

Temporomandibular joint osteoarthritis (TMJOA) is a common degenerative joint disease without effective intervention strategies. Previous research implied that alpha-kinase 1 (ALPK1) is involved in the inflammatory responses of gout, a chronic arthritis. Herein, we found the main distribution of ALPK1 in a proliferative layer of condylar cartilage and marrow cavity of subchondral bone, as well as a lining layer of synovial tissues in human temporomandibular joint. Moreover, the expression of ALPK1 was augmented in degraded condylar cartilage of monosodium iodoacetate (MIA)–induced TMJOA mice. After MIA induction, ALPK1 knockout mice exhibited attenuated damage of cartilage and subchondral bone, as well as synovitis, as compared with wide type mice. In contrast, intra-articular administration of recombinant human ALPK1 aggravated the pathology of MIA-induced TMJOA. Furthermore, ex vivo study demonstrated that ALPK1 exacerbated chondrocyte catabolism by upregulating matrix metalloproteinase 13 and cyclooxygenase 2 by activating NF-κB (nuclear factor–kappaB) signaling and suppressed anabolism by downregulating aggrecan by inhibiting ERK1/2 (extracellular signal–regulated kinase 1/2) in articular chondrocytes. Taken together, ALPK1 exacerbates the degradation of condylar cartilage during TMJOA through the NF-κB and ERK1/2 signaling pathway. This study provides a new insight regarding the role of ALPK1 during TMJOA pathology.

Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model.

Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

Brain Protective Effect of Resveratrol via Ameliorating Interleukin-1β-Induced MMP-9-Mediated Disruption of ZO-1 Arranged Integrity.

In the central nervous system (CNS), the matrix metalloproteinase-9 (MMP-9) is induced by several factors and contributes to CNS disorders, including inflammation and neurodegeneration. Thus, the upregulation of MMP-9 has been considered to be an indicator of inflammation. Interleukin-1β (IL-1β) is an important proinflammatory cytokine which can induce various inflammatory factors, such as MMP-9, in many inflammatory disorders. Several phytochemicals are believed to reduce the risk of several inflammatory disorders, including the CNS diseases. Among them, the resveratrol, a principal phenolic compound of the grape, blueberry, and mulberry peels and Cassia plants, has been shown to possess several medicinal properties, including antioxidative, anti-inflammatory, and antitumor function. Herein, we used mouse-brain microvascular endothelial cells (bMECs) to demonstrate the signaling mechanisms of IL-1β-induced MMP-9 expression via zymographic, RT-PCR, Western blot, reactive oxygen species (ROS) detection, immunofluorescence stain, and promoter reporter analyses. Then we evaluated the effects of resveratrol on IL-1β-induced MMP-9 expression in bMECs and its mechanism of action. We first demonstrated that IL-1β induced MMP-9 expression in bMECs. Subsequently, IL-1β induced MMP-9 expression via ROS-mediated c-Src-dependent transactivation of EGFR, and then activation of the ERK1/2, p38 MAPK, JNK1/2, and NF-κB signaling pathway. Finally, we determined that IL-1β-induced upregulation of MMP-9 may cause the disruption of the arranged integrity of zonula occludens-1 (ZO-1), but this could be inhibited by resveratrol. These data indicated that resveratrol may have antioxidative and brain-protective activities by reducing these related pathways of ROS-mediated MMP-9 expression and tight junction disruption in brain microvascular endothelial cells.

Oxidative stress generated by polycyclic aromatic hydrocarbons from ambient particulate matter enhance vascular smooth muscle cell migration through MMP upregulation and actin reorganization

BackgroundEpidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined.ResultsVSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or α-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK.ConclusionsPAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.

Porcine Epidemic Diarrhea Virus Infection Disrupts the Nasal Endothelial Barrier To Favor Viral Dissemination.

ABSTRACTCrossing the endothelium from the entry site and spreading in the bloodstream are crucial but obscure steps in the pathogenesis of many emerging viruses. Previous studies confirmed that porcine epidemic diarrhea virus (PEDV) caused intestinal infection by intranasal inoculation. However, the role of the nasal endothelial barrier in PEDV translocation remains unclear. Here, we demonstrated that PEDV infection causes nasal endothelial dysfunction to favor viral dissemination. Intranasal inoculation with PEDV compromised the integrity of endothelial cells (ECs) in nasal microvessels. The matrix metalloproteinase 7 (MMP-7) released from the PEDV-infected nasal epithelial cells (NECs) contributed to the destruction of endothelial integrity by degrading the tight junctions, rather than direct PEDV infection. Moreover, the proinflammatory cytokines released from PEDV-infected NECs activated ECs to upregulate ICAM-1 expression, which favored peripheral blood mononuclear cells (PBMCs) migration. PEDV could further exploit migrated cells to favor viral dissemination. Together, our results reveal the mechanism by which PEDV manipulates the endothelial dysfunction to favor viral dissemination and provide novel insights into how coronavirus interacts with the endothelium.IMPORTANCE The endothelial barrier is the last but vital defense against systemic viral transmission. Porcine epidemic diarrhea virus (PEDV) can cause severe atrophic enteritis and acute viremia. However, the mechanisms by which the virus crosses the endothelial barrier and causes viremia are poorly understood. In this study, we revealed the mechanisms of endothelial dysfunction in PEDV infection. The viral infection activates NECs and causes the upregulation of MMP-7 and proinflammatory cytokines. Using NECs, ECs, and PBMCs as in vitro models, we determined that the released MMP-7 contributed to the destruction of endothelial barrier, and the released proinflammatory cytokines activated ECs to facilitate PBMCs migration. Moreover, the virus further exploited the migrated cells to promote viral dissemination. Thus, our results provide new insights into the mechanisms underlying endothelial dysfunction induced by coronavirus infection.

Thelephoric acid, p-terphenyl, induces bone-forming activities in pre-osteoblasts

• Thelephoric acid is a p-terphenyl compound isolated from the mushrooms of Polyozellus multiplex. • Thelephoric acid enhances ALP enzymatic activities in pre-osteoblasts. • Thelephoric acid enhances bone matrix mineralization in pre-osteoblasts. • Thelephoric acid enhances nuclear RUNX2 expression and accumulation via Smad1/5/8 phosphorylation. • Thelephoric acid enhances cell adhesion and migration in osteoblast differentiation. • Thelephoric acid is a potentially beneficial compound for prevention and treatment in bone diseases. Polyozellus multiplex , a wild mushroom belonging to Thelephoracea, is distributed in Korea, Japan, and China. Thelephoric acid (Thel), a terphenylquinone found in P. multiplex , reportedly exhibits beneficial effects, including antioxidant, anticancer, and neuroprotective activities. Herein, we extracted Thel from P. multiplex (>95.8% purity) and examined its osteogenic effects on pre-osteoblasts. Thel exerted no cytotoxicity in pre-osteoblasts. Based on alkaline phosphatase staining and activity, Thel promoted osteoblast differentiation and bone matrix mineralization. Biochemical investigations revealed that Thel enhanced nuclear runt-related transcription factor 2 (RUNX2) expression and accumulation via Smad1/5/8 phosphorylation, while exhibiting synergistic activities following cotreatment with bone morphogenetic protein 2 or fibroblast growth factor 2 in pre-osteoblast cultures. Thel increased cell adhesion and migration in differentiating osteoblasts by upregulating matrix metalloproteinase 13 (MMP13). Collectively, these findings indicate that Thel induced osteogenic properties by regulating RUNX2 and MMP13 expression, suggesting that Thel could be further developed to treat bone disorders.

The miR-145–MMP1 axis is a critical regulator for imiquimod-induced cancer stemness and chemoresistance

Cancer stemness, chemoresistance, and metastasis are related biological events. However, whether they have common molecular mechanisms remains to be determined. Here, we report that imiquimod (IMQ) facilitates the acquisition of stem-cell-like properties and chemoresistance via the upregulation of matrix metalloproteinase 1 (MMP1) and downregulation of microRNA-145 (miR-145). MiR-145–5p was found to suppress MMP1 expression through direct binding, and miR-145-mediated downregulation of MMP1 reversed the effects of IMQ. In addition, IMQ downregulated miR-145 by promoting DNA methylation at its promoter. DNA methyltransferase inhibitors limited IMQ-induced MMP1 expression, stemness, and chemoresistance. Collectively, our results highlight the miR-145–MMP1 axis as a potential coordinator of cancer stemness and chemoresistance. Given the role of MMP1 in the initiation of metastasis, the miR-145–MMP1 axis serves as a promising therapeutic target for improved cancer treatment.

Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion

Background & aimsHepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. Approach & resultsWe characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl4)-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H2O2 or transforming growth factor β1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix–encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl4-induced mouse liver fibrosis. ConclusionsThese findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease.

Urinary MMP-7: A Predictive, Noninvasive Early Marker for Chronic Kidney Disease Development in Patients with Hypertension.

Upregulation of matrix metalloproteinase-7 (MMP-7) is associated with hypertension and kidney fibrosis, which can progress to chronic kidney disease (CKD). Currently, kidney fibrosis is only detectable by an invasive procedure. Therefore, we set out to determine whether MMP-7 can act as a noninvasive biomarker in patients with hypertension to enable early detection of kidney fibrosis. Diagnosed patients with hypertension and control patients were sampled. We diagnosed CKD using clinical and laboratory parameters. Serum urea, creatinine, urinary microalbumin, the albumin-to-creatinine ratio, and urinary MMP-7 were analyzed. The 195 patients with hypertension had significantly elevated MMP-7. Of these patients, 166 had MMP-7 >25.8 μg/L, whereas only 29 had MMP-7 <25.8 μg/L. Thirty-two patients with hypertension showed features of CKD, all of whom had urinary MMP-7 >25.8 μg/L. However, the urinary MMP-7 level did not differ with the severity of CKD or with the duration of hypertension. Elevated urinary MMP-7 can be a potential noninvasive, early indicator in patients with hypertension progressing to CKD, thus enabling early therapeutic intervention.

Exosomes Derived From miR-212-5p Overexpressed Human Synovial Mesenchymal Stem Cells Suppress Chondrocyte Degeneration and Inflammation by Targeting ELF3.

Excessive chondrocyte degeneration and inflammation are the pathological features of osteoarthritis (OA), and altered miR-212-5p may contribute to meniscus and cartilage degeneration. Whether exosomes derived from miR-212-5p overexpressed synovial mesenchymal stem cells (SMSC-212-5p-Exos) could be utilized to treat degenerative chondrocytes is investigated in this study. Down-regulated miR-212-5p and up-regulated E74 Like ETS Transcription Factor 3 (ELF3) expression were detected in OA synovial tissues, which showed a negative correlation (r = −0.55, p = 0.002). miR-212-5p directly targeted ELF3 and regulated the relative expression of ELF3 in SMSCs as indicated by luciferase reporter assay and RT-PCR. The relative expression of ELF3, chondrocyte degeneration-related molecules, matrix metalloproteinase, and inflammatory molecules were detected in chondrocytes stimulated with interleukin (IL)-1β or co-incubated with SMSC-212-5p-Exos or SMSCs-derived exosomes (SMSC-Exos). IL-1β induced up-regulation of ELF3, down-regulation of degeneration molecules (Collagen II, Aggrecan, and Sox9), up-regulation of matrix metalloproteinase (MMP-1, MMP-3, and MMP-13), and up-regulation of inflammatory molecules (IL-6, MCP-1, TNF-α, COX-2, and iNOS) could be inhibited by SMSC-212-5p-Exos or SMSC-Exos administration. When compared with the SMSC-Exos, SMSC-212-5p-Exos showed more treatment benefits. All of these indicate that SMSC-212-5p-Exos could suppress chondrocyte degeneration and inflammation by targeting ELF3, which can be considered as a disease-modifying strategy.

Metformin Alleviates Endometriosis and Potentiates Endometrial Receptivity via Decreasing VEGF and MMP9 and Increasing Leukemia Inhibitor Factor and HOXA10.

Background: Endometriosis affects endometrial receptivity, a key factor for successful embryo implantation. Metformin treatment is associated with alleviating the symptoms of endometriosis; however the mechanism of metformin action is unclear. Neoangiogenesis plays an important role in the development and recurrence of endometriosis. In addition, the leukemia inhibitor factor (LIF) and HOXA10 genes are also distinguishing markers of endometriosis (decrease) and endometrial receptivity (increase). This study investigated the therapeutic potentials of metformin and the underlying mechanism using an in vivo rat endometriosis model. Methods: Female Wistar albino mature rats with experimentally induced endometriosis were used in this study. Metformin was administered at doses of 100 mg/kg/d and 200 mg/kg/d. The volume of endometriotic implants was assessed. The protein and mRNA expression of the vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), the endometrial receptivity markers, LIF and HOXA10, were measured in the endometrium of rats with endometriosis. Results: Metformin treatment significantly suppressed the growth of endometriotic implants. Further, the expression of VEGF and MMP-9 protein and mRNA in endometriotic implants were significantly reduced. Metformin also significantly upregulated LIF and HOXA10 expression in endometrium from rats with endometriosis. The inhibitory effect of metformin on the growth of endometriotic implants, VEGF and MMP-9, and upregulating effect on LIF and HOXA10, was optimal at a dose of 100 mg/kg/d. Conclusion: Our in vivo data demonstrates that metformin treatment alleviates endometriosis and potentiates endometrial receptivity. The underlying mechanisms are associated with decreased expression of VEGF and MMP-9 genes and upregulation of the LIF and HOXA10 genes. The effect of metformin was optimal at 100 mg/kg/d. These findings provide a potential alternative for women with endometriosis with the potential to increase fertility. Metformin is an approved drug by FDA for diabetes and this study may add another potential clinical use for metformin.

Alteration of Ethanol Reward by Prior Mephedrone Exposure: The Role of Age and Matrix Metalloproteinase-9 (MMP-9).

Mephedrone, a synthetic cathinone, is widely abused by adolescents and young adults. The aim of this study was to determine: (i) whether prior mephedrone exposure would alter ethanol reward and (ii) whether age and matrix metalloproteinase-9 (MMP-9) are important in this regard. In our research, male Wistar rats at postnatal day 30 (PND30) received mephedrone at the dose of 10 mg/kg, i.p., 3 times a day for 7 days. To clarify the role of MMP-9 in the mephedrone effects, one mephedrone-treated group received minocycline, as an MMP-9 antagonist. Animals were then assigned to conditioned place preference (CPP) procedure at PND38 (adolescent) or at PND69 (adult). After the CPP test (PND48/79), expression of dopamine D1 receptors (D1R), Cav1.2 (a subtype of L-type calcium channels), and MMP-9 was quantified in the rat ventral striatum (vSTR). The influence of mephedrone administration on the N-methyl-D-aspartate glutamate receptors (NMDAR) subunits (GluN1, GluN2A, and GluN2B) was then assessed in the vSTR of adult rats (only). These results indicate that, in contrast with adolescent rats, adult rats with prior mephedrone administration appear to be more sensitive to the ethanol effect in the CPP test under the drug-free state. The mephedrone effect in adult rats was associated with upregulation of D1R, NMDAR/GluN2B, MMP-9, and Cav1.2 signaling. MMP-9 appears to contribute to these changes in proteins expression because minocycline pretreatment blocked mephedrone-evoked sensitivity to ethanol reward. Thus, our results suggest that prior mephedrone exposure differentially alters ethanol reward in adolescent and adult rats.

Correlation Between Matrix Metalloproteinases With Coronary Artery Lesion Caused by Kawasaki Disease.

This study was designed to clarify the role of matrix metalloproteinases (MMPs) in coronary artery lesions (CAL). Serum samples were acquired from healthy, febrile, and Kawasaki disease (KD) children with or without CAL. Standard blood parameters were examined and enzyme-linked immunosorbent assay (ELISA) was used to assess the levels of MMP-2 and MMP-9. Intravenous immunoglobulin (IVIG) therapy was conducted on the KD patients and the changes of MMPs before and after treatment were compared. The correlations between MMP levels and clinical parameters were also evaluated. Compared to febrile and healthy controls, KD patients demonstrated clinical signs characteristic of abnormal immunoregulation. However, the clinical parameters of KD patients with or without CAL were not significantly different. MMP-2 and MMP-9 levels, however, were significantly higher in KD patients with CAL than those without CAL. IVIG treatment effectively downregulated the levels of MMPs in KD patients, which was more prominent in those with CAL. Significant correlations were found between MMP levels and some clinical parameters of KD, such as fever time, white blood cell count, etc. The upregulation of MMPs significantly correlates with coronary artery aneurysms (CAAs) in KD patients, making it important biomarkers of CAL in KD patients.

RETRACTED ARTICLE: The protective effects of Olmesartan against interleukin-29 (IL-29)-induced type 2 collagen degradation in human chondrocytes

Statement of Retraction Yunlong Liu, Junyi Liu, Yan Ma, Yongyong Zhang, Qiong Chen, Xin Yang, Yanchun Shang- 2022, The protective effects of Olmesartan against interleukin-29 (IL-29)-induced type 2 collagen degradation in human chondrocytes, Bioengineered 13(1), doi: 10.1080/21655979.2021.1997090 Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. All authors listed in this publication have been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Effects of

BackgroundParticulate matter (PM) is one of the air pollutants that can damage human skin; the recent increase in the amount of PM may be detrimental to skin health.ObjectiveWe aimed to investigate the effects of PM on cultured human sebocytes and outer root sheath (ORS) cells and the effects of Siegesbeckia Herba extract (SHE) on PM-treated cultured cells.MethodsSebocytes and ORS cells were cultured. The cultured cells were treated with various concentrations of PM of <10 µm in size (PM10) (10 µg/ml, 25 µg/ml, 50 µg/ml, and 100 µg/ml) for 24 h. Real-time polymerase chain reaction, measurement of reactive oxygen species (ROS), small interfering (si) RNA transfection, Oil Red O and Nile red staining, and immunofluorescence staining were performed to analyze the presence of inflammatory cytokines, matrix metalloproteinases (MMPs), aryl hydrocarbon receptor (AhR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS, and lipid production. In addition, PM10 (100 µg/ml)-treated cultured cells were treated with 10 mg/ml of SHE.ResultsPM10 upregulates the expression of inflammatory cytokines, MMPs, AhR, NF-κB, and ROS in cultured human sebocytes and ORS cells. The production of ROS was dramatically reduced in AhR siRNA-transfected cells. In addition, PM10 upregulates sebum production in cultured sebocytes. SHE inhibited the upregulation of inflammatory cytokines, MMPs, AhR, NF-κB, ROS, and sebum production in cultured human sebocytes and/or ORS cells by PM10.ConclusionEffects of PM10 on cultured human sebocytes and ORS cells can be regulated by SH.

Circular RNA hsa_circ_0002360 promotes non-small cell lung cancer progression through upregulating matrix metalloproteinase 16 and sponging multiple micorRNAs

ABSTRACT Dysregulated circular RNAs (circRNAs) are involved in the progression of non-small cell lung cancer (NSCLC). However, the role of has_circ_0002360 (circ_0002360) in NSCLC has rarely been reported. In this study, circ_0002360 expression in NSCLC tissues and cell lines was measured using microarray data and quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function, cell models were established; 5-bromo-2-deoxyuridine (BrdU) and transwell assays were conducted to detect NSCLC cell growth, migration, and invasion. What is more, bioinformatic analysis and dual-luciferase reporter assay were adopted to show how circ_0002360, microRNAs (miR-127-5p, miR-145-5p, miR-585-3p, and miR-758-3p), and matrix metalloproteinase 16 (MMP16) 3ʹUTR interact with each other. Western blotting was executed to probe the regulatory effects of circ_0002360 and these miRNAs on MMP16 protein expression in NSCLC cells. We found that circ_0002360 expression was raised in NSCLC tissues. High circ_0002360 expression predicted a short overall survival time for NSCLC patients. Circ_0002360 overexpression promoted NSCLC cell proliferative, migrative, and invasive abilities, and circ_0002360 depletion worked oppositely. MiR-127-5p, miR-145-5p, miR-585-3p, and miR-758-3p were the targets of circ_0002360, and circ_0002360 could regulate MMP16 expression by competitively binding with the above miRNAs. In summary, circ_0002360 serves as a competitive endogenous RNA to raise MMP16 expressions by competitively binding to miR-127-5p, miR-145-5p, miR-585-3p, and miR-758-3p, thereby promoting NSCLC progression.

Self-Healing Hydrogel Embodied with Macrophage-Regulation and Responsive-Gene-Silencing Properties for Synergistic Prevention of Peritendinous Adhesion.

Antiadhesion barriers such as films and hydrogels used to wrap repaired tendons are important for preventing the formation of adhesion tissue after tendon surgery. However, sliding of the tendon can compress the adjacent hydrogel barrier and cause it to rupture, which may then lead to unexpected inflammation. Here, a self-healing and deformable hyaluronic acid (HA) hydrogel is constructed as a peritendinous antiadhesion barrier. Matrix metalloproteinase-2 (MMP-2)-degradable gelatin-methacryloyl (GelMA) microspheres (MSs) encapsulated with Smad3-siRNA nanoparticles are entrapped within the HA hydrogel to inhibit fibroblast proliferation and prevent peritendinous adhesion. GelMA MSs are responsively degraded by upregulation of MMP-2, achieving on-demand release of siRNA nanoparticles. Silencing effect of Smad3-siRNA nanoparticles is around 75% toward targeted gene. Furthermore, the self-healing hydrogel shows relatively attenuated inflammation compared to non-healing hydrogel. The mean adhesion scores of composite barrier group are 1.67 ± 0.51 and 2.17 ± 0.75 by macroscopic and histological evaluation, respectively. The proposed self-healing hydrogel antiadhesion barrier with MMP-2-responsive drug release behavior is highly effective for decreasing inflammation and inhibiting tendon adhesion. Therefore, this research provides a new strategy for the development of safe and effective antiadhesion barriers.

Transglutaminase 2 mediates UVB-induced matrix metalloproteinase-1 expression by inhibiting nuclear p65 degradation in dermal fibroblasts.

Matrix metalloproteinases (MMPs) play a key role in tissue remodelling by cleaving extracellular matrix (ECM) components. In the skin, UV irradiation increases expression of MMPs that causes dysregulation of ECM homeostasis in dermis, leading to acceleration of skin aging. However, the mediator(s) that links UV irradiation to the upregulation of MMPs have not been fully defined. Previously, we showed that UVB irradiation activated transglutaminase 2 (TG2) in keratinocytes, eliciting an inflammatory response by activating NF-κB signalling. In this study, we reported the role of TG2 in mediating the UVB-induced expression of MMP-1. In human dermal fibroblasts, UVB irradiation enhanced the expression and activity of TG2, which in turn promotes the expression of MMP-1. Analyses of MMP-1 promoter showed that activation of the NF-κB signalling pathway, rather than AP-1, was responsible for the TG2-mediated upregulation of MMP-1. Moreover, Western blot analysis revealed that TG2 increased the activity of NF-κB by inhibiting degradation of p65 in the nucleus. Furthermore, ex vivo skin from TG2-knockout mice exhibited significantly reduced levels of MMP-1 compared to that from wild-type mice. These results indicate that TG2 functions as a mediator for the UVB-induced expression of MMP-1 in dermal fibroblasts, providing a new target for preventing skin photodamage.

Kunming mouse strain is less susceptible to elastase-induced abdominal aortic aneurysms.

BackgroundPorcine pancreatic elastase (PPE) is successfully used to induce abdominal aortic aneurysm (AAA) in mice. However, differences between mouse strains in susceptibility to PPE induction have been reported. Kunming mouse is one of the most frequently used strains in China but whether it is suitable for induction of AAA by PPE application remains unclear.MethodsPPE infusion (1.5 units/ml) in temporary controlled aorta was performed to induce AAAs in both C57BL/6J and Kunming mice. Phosphate‐buffered saline (PBS) application was used as vehicle control. The aorta diameters of all mice were measured at days 0 and 14 after surgery to evaluate the AAA formation.ResultsAfter 14 days of PPE or PBS infusion, all mice were sacrificed and aorta tissues were collected for histological staining analysis. At the 14th day after infusion, PPE successfully induced aortic dilation in Kunming mice and typical AAA in C57BL/6J mice. The aorta diameter increased by 0.23 mm in Kunming mice after PPE infusion, while it was 0.72 mm in the C57BL/6J strain. PPE induced mild elastin degradation, smooth muscle cell (SMC) depletion and mural leucocyte infiltration in Kunming mice, but in PPE‐sensitive C57BL/6J mice, it induced total loss of SMCs, elastin disappearance and diffused infiltrated leucocytes in aortic aneurysmal segments. The effects of PPE in inducing angiogenesis and upregulating matrix metalloproteinase 2 and 9 expression in Kunming mice were also weaker than that in C57BL/6J mice.ConclusionAt the reported dose of PPE, Kunming mouse is not as susceptible to AAA formation as C57BL/6J mice. The failure of PPE to induce AAA formation in Kunming mice may be associated to its inability to boost a strong inflammatory response.

Salvianolic acid B targets mortalin and inhibits the migration and invasion of hepatocellular carcinoma via the RECK/STAT3 pathway

BackgroundTumor migration and invasion is a complex and diverse process that involves the epithelial–mesenchymal transition (EMT) of tumor cells and degradation of the extracellular matrix by matrix metalloproteases (MMPs). Mortalin is an important oncogene. It has been reported to play an important role in tumor migration and invasion through various signaling pathways, but the underlying mechanism is not fully understood.MethodsHere, we investigated the role of mortalin in the migration of the hepatocellular carcinoma (HCC) cell lines HepG2 and HCCLM3.ResultsThe overexpression of mortalin in HepG2 cells decreased the protein level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and activated the phosphorylation and acetylation of STAT3, thereby up-regulating matrix metalloproteinase 9 (MMP9) and promoting cell migration and invasion. In contrast, in HCCLM3 cells, mortalin knockdown increased the expression of RECK, inhibited the STAT3 pathway and the activity of MMP9, and inhibited cell migration and invasion. Furthermore, we found that salvianolic acid B, a caffeic acid phenethyl ester analog, specifically bound to mortalin and increased the degradation of mortalin proteasomes through ubiquitination, thereby up-regulating RECK, inhibiting STAT3, and finally inhibiting the migration and invasion of HCC cells.ConclusionOur work suggested that mortalin is a potential therapeutic target for hepatocellular carcinoma.