Activity Of MMPs Research Articles

Angiogenic properties and intercellular communication of differentiated porcine endothelial cells in vascular therapy

Endothelial cell dysfunction can lead to various vascular diseases. Blood flow disorder is a common symptom of vascular diseases. Regenerative angiogenesis, which involves transplanting vascular cells or stem cells into the body to shape new vasculature, can be a good therapeutic strategy. However, there are several limitations to using autologous cells from the patients themselves. We sought to investigate the new vascular cells that can play a role in the formation of angiogenesis in vivo using stem cells from alternative animals suitable for cellular therapy. Porcine is an optimal animal model for xenotransplantation owing to its physiological similarity to humans. We used differentiated porcine endothelial cells (pECs) as a therapeutic strategy to restore vessel function. Differentiated pECs formed vessel-like structures in mice, distinguishing them from stem cells. MMPs activity and migration assays indicated that differentiated pECs possessed angiogenic potential. Tube formation and 3D spheroid sprouting assays further confirmed the angiogenic phenotype of the differentiated pECs. Immunofluorescence and immunoprecipitation analyses revealed claudin-mediated tight junctions and connexin 43-mediated gap junctions between human ECs and differentiated pECs. Additionally, the movement of small RNA from human ECs to differentiated pECs was observed under co-culture conditions. Our findings demonstrated the in vivo viability and angiogenetic potential of differentiated pECs and highlighted the potential for intercellular communication between human and porcine ECs. These results suggest that transplanted cells in vascular regeneration completed after cell therapy have the potential to achieve intercellular communication within the body.

Long-term hybrid stability and matrix metalloproteinase inhibition by fucosterol in resin-dentin bonding biomechanics

Fucosterols have been widely studied for their antioxidant, anticancer, and anti-inflammatory properties. However, they have not yet been studied in the field of dentistry. This study aimed to determine whether pretreatment of dentin with fucosterol before resin restoration enhances bond stability in resin-dentin hybrid layers. After applying 0.1, 0.5, and 1.0 wt% fucosterol to demineralized dentin, microtensile bond strength (MTBS) and nanoleakage tests were performed before and after collagenase aging, and the surface was observed using scanning electron microscope (SEM). The fucosterol-treated group showed better bond strength and less nanoleakage both before and after collagenase aging, and the corresponding structures were confirmed using SEM. MMP zymography confirmed that the activity of MMPs was relatively low along the concentration gradient of fucosterol, and the FTIR analysis confirmed the production of collagen crosslinks. In addition, fucosterol exhibits cytotoxicity against Streptococcus mutans, the main cause of dental decay. The results of this study suggest that fucosterol pretreatment improves bond strength and reduces nanoleakage at the resin-dentin interface, possibly through a mechanism involving collagen cross-link formation via the inhibition of endogenous and exogenous MMP activity. This study demonstrates the potential of fucosterol as an MMP inhibitor in dentin, which contributes to long-term resin-dentin bond stability and can be used as a restorative material.

Assessing the impact of different Urushiol primer solvents on dentin remineralization and bond strength.

To investigate urushiol's potential as a dentin cross-linking agent, promoting remineralization of etched dentin and preventing activation of endogenous proteases causing collagen degradation within the hybrid layer. The goal is to improve bond strength and durability at the resin-dentin interface. Urushiol primers with varying concentrations were prepared using ethanol and dimethyl sulfoxide (DMSO) as solvents. Dentin from healthy molars underwent grinding and acid etching for 15s, followed by a 1min application of urushiol primer. After 14 and 28days of remineralization incubation and remineralization were usedtoassessby Attenuated Total Reflection Fourier Transform Infrared spectroscopy (ATR-FTIR), Micro-Raman spectroscopy, X-ray Diffraction (XRD), Atomic Force Microscopy (AFM), Vickers Hardness, Scanning Electron Microscopy (SEM), and Energy X-ray dispersive spectroscopy (EDS). The overall performance of urushiol primers as dentin adhesives was observed by microtensile bond strength (μTBS) testing and nanoleakage assessment. Investigated the inhibitory properties of the urushiol primers on endogenous metalloproteinases (MMPs) utilizing in situ zymography, and the cytotoxicity of the primers was tested. Based on ATR-FTIR, Raman, XRD, EM-EDS and Vickers hardness analyses, the 0.7%-Ethanol group significantly enhanced dentin mineral content and improved mechanical properties the most. Pretreatment notably increased the μTBS of restorations, promoted the stability of the mixed layer, and reduced nanoleakage and MMPs activity after 28days. The urushiol primer facilitates remineralization in demineralized dentin, enhancing remineralization in etched dentin, effectively improving the bonding interface stability, with optimal performance observed at a 0.7 wt% concentration of the urushiol primer.

Regulatory Mechanisms of Natural Active Ingredients and Compounds on Keratinocytes and Fibroblasts in Mitigating Skin Photoaging.

The mechanism underlying skin photoaging remains elusive because of the intricate cellular and molecular changes that contribute to this phenomenon, which have yet to be elucidated. In photoaging, the roles of keratinocytes and fibroblasts are vital for maintaining skin structure and elasticity. But these cells can get photo-induced damage during photoaging, causing skin morphological changes. Recently, the function of natural active ingredients in treating and preventing photoaging has drawn more attention, with researches often focusing on keratinocytes and fibroblasts. We searched for studies published from 2007 to January 2024 in the Web of Science, PubMed, and ScienceDirect databases through the following keywords: natural plant, natural plant products or phytochemicals, traditional Chinese Medicine or Chinese herbal, plant extracts, solar skin aging, skin photoaging, and skin wrinkling. This review conducted the accordance of Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 87 researches were included in this review (Figure 1). In keratinocytes, natural compounds may primarily regulate signal pathways such as the NF-κB, MAPK, PI3K/AKT, and Nrf2/ARE pathways, reducing inflammation and cellular damage, thus slowing skin photoaging. Additionally, in fibroblasts, natural active ingredients primarily promote the TGF-β pathway, inhibit MMPs activity, and enhance collagen synthesis while potentially modulating the mTOR pathway, thereby protecting the dermal collagen network and reducing wrinkle formation. Several trials showed that natural compounds that regulate keratinocytes and fibroblasts responses have significant and safe therapeutic effects. The demand for natural product-based ingredients in sunscreen formulations is rising. Natural compounds show promising anti-photoaging effects by targeting cellular pathways in keratinocytes and fibroblasts, providing potential therapeutic strategies. However, comprehensive clinical studies are needed to verify their efficacy and safety in mitigating photoaging, which should use advanced pharmacological methods to uncover the complex anti-photoaging mechanisms of natural compounds.

Effect of nonsurgical periodontal therapy with additional photodynamic therapy on the level of MMP-9 and TIMP-1 in GCF in chronic periodontitis patients-a preliminary pilot study

PurposeMatrix metalloproteinases (MMPs) catalyze degradation of extracellular matrix proteins. The activity of MMPs is controlled by tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the MMP-9/TIMP-1 ratio has been linked with chronic periodontitis (CP). Photodynamic therapy (PDT) uses visible light, photosensitizer and oxygen to eradicate pathogens. The aim of the study was to evaluate the presence of MMP-9 and TIMP-1 in gingival crevicular fluid (GCF) in chronic periodontitis patients before and after nonsurgical periodontal therapy with additional PDT. MethodsNineteen patients, each with CP, were included in the study. After periodontal examination one site with a probing depth (PD) ​≥ ​4 ​mm was selected. The patients received scaling and root planing (SRP) with additional PDT by means of HELBO® diode minilaser. Prior to treatment, and after 3 and 6 months, the following parameters were estimated from the same site: PD, gingival recession (GR), clinical attachment level (CAL), plaque index (PI), bleeding on probing (BOP) and sulcus fluid flow rate (SFFR). The levels of MMP-9 and TIMP-1 in GCF were determined. ResultsCompared to baseline, the levels of MMP-9 and TIMP-1 did not show statistically significant differences after 3 and 6 months. According to Spearman's rank correlations, MMP-9 was positively correlated with SFFR at all time points. PD, CAL and PI showed a statistically significant decrease compared to baseline (p ​< ​0.001). SFFR decreased but not significantly. ConclusionNonsurgical periodontal therapy in conjunction with PDT was clinically effective but it had no effect on the levels of MMP-9 and TIMP-1 in GCF.

Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Platelet-rich plasma attenuates the UPEC-induced cystitis via inhibiting MMP-2,9 activities and downregulation of NGF and VEGF in Canis Lupus Familiaris model

One of the most prevalent disorders of the urinary system is urinary tract infection, which is mostly brought on by uropathogenic Escherichia coli (UPEC). The objective of this study was to evaluate the regenerative therapeutic and antibacterial efficacy of PRP for induced bacterial cystitis in dogs in comparison to conventional antibiotics. 25 healthy male mongrel dogs were divided into 5 groups (n = 5). Control negative group that received neither induced infection nor treatments. 20 dogs were randomized into 4 groups after two weeks of induction of UPEC cystitis into; Group 1 (control positive; G1) received weekly intravesicular instillation of sodium chloride 0.9%. Group 2 (syst/PRP; G2), treated with both systemic intramuscular antibiotic and weekly intravesicular instillation of PRP; Group 3 (PRP; G3), treated with weekly intravesicular instillation of PRP, and Group 4 (syst; G4) treated with an intramuscular systemic antibiotic. Animals were subjected to weekly clinical, ultrasonographic evaluation, urinary microbiological analysis, and redox status biomarkers estimation. Urinary matrix metalloproteinases (MMP-2, MMP-9) and urinary gene expression for platelet-derived growth factor -B (PDGF-B), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) were measured. At the end of the study, dogs were euthanized, and the bladder tissues were examined macroscopically, histologically, and immunohistochemically for NF-κB P65 and Cox-2. The PRP-treated group showed significant improvement for all the clinical, Doppler parameters, and the urinary redox status (p < 0.05). The urinary MMPs activity was significantly decreased in the PRP-treated group and the expression level of urinary NGF and VEGF were downregulated while PDGFB was significantly upregulated (p < 0.05). Meanwhile, the urinary viable cell count was significantly reduced in all treatments (P < 0.05). Gross examination of bladder tissue showed marked improvement for the PRP-treated group, expressed in the histopathological findings. Immunohistochemical analysis revealed a marked increase in Cox-2 and NF-κB P65 in the PRP-treated group (P < 0.05). autologous CaCl2-activated PRP was able to overcome the bacterial infection, generating an inflammatory environment to overcome the old one and initiate tissue healing. Hence, PRP is a promising alternative therapeutic for UPEC cystitis instead of conventional antibiotics.

Effects of Etching Time and Ethanol Wet Bonding on Bond Strength and Metalloproteinase Activity in Radicular Dentin.

(1) Background: The objective of this in vitro study was to evaluate the impact of different etching times and ethanol pre-treatments on the immediate bond strength of a hydrophilic multi-mode universal adhesive (Clearfil Universal Bond Quick, Kuraray, UBQ) and on the consequent gelatinolytic activity of metalloproteinases (MMPs) on radicular dentin. (2) Methods: Sixty single-root teeth were selected and divided into four groups according to the adhesive protocol applied for fiber post cementation: (G1) 15 s H3PO4 application + UBQ; (G2) 30 s H3PO4 application + UBQ; (G3) 15 s H3PO4 application + ethanol pre-treatment + UBQ; (G4) 30 s H3PO4 + ethanol pre-treatment + UBQ. After adhesive procedures, fiber posts were luted into the post space with a dual-curing cement (DC Core, Kuraray) and light-cured for 40 s. To perform the push-out test and nanoleakage analyses for both coronal end apical areas, 1 mm slices were prepared, following a 24 h storage period in artificial saliva. Additionally, an in situ zymographic assay was conducted to explore endogenous MMP activity within the radicular layer. Results were statistically analyzed with ANOVA and Tukey post hoc tests. Statistical significance was set at p < 0.05. (3) Result: ANOVA revealed a statistically significant difference in push-out bond strength related to the pre-treatment variable but did not highlight any significance of etching time. Specimens pre-treated with ethanol wet bond application showed higher bond strength (p < 0.01). In situ zymography quantification analyses revealed that all tested groups, independently of etching time end ethanol pre-treatment, activated MMP gelatinolytic activity. A significant increase in MMP activity was detected for the 30 s etching time. However, ETOH pre-treatment significantly reduced MMP activity within the adhesive interface (p < 0.01). (4) Conclusions: The tested adhesive showed similar results regardless of the etching time protocol. The gelatinolytic activity of MMPs was observed in all the groups. Further investigations and extended follow-ups are required to validate the results of the present study in vivo.

The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart.

Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals' cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants.

Mixture of Doxycycline, ML-7 and L-NAME Restores the Pro- and Antioxidant Balance during Myocardial Infarction-In Vivo Pig Model Study.

The restoration of blood flow to the ischemic myocardium inflicts ischemia/reperfusion (I/R) heart injury (IRI). The main contributors to IRI are increased oxidative stress and subsequent excessive production of ROS, increased expression of NOS and peroxinitate, activation of MMPs, and enhanced posttranslational modifications of contractile proteins, which make them more susceptible to proteolytic degradation. Since the pathophysiology of IRI is a complex issue, and thus, various therapeutic strategies are required to prevent or reduce IRI and microvascular dysfunction, in the current study we proposed an innovative multi-drug therapy using low concentrations of drugs applied intracoronary to reach microvessels in order to stabilize the pro- and antioxidant balance during a MI in an in vivo pig model. The ability of a mixture of doxycycline (1 μM), ML-7 (0.5 μM), and L-NAME (2 μM) to modulate the pro- and antioxidative balance was tested in the left ventricle tissue and blood samples. Data showed that infusion of a MIX reduced the total oxidative status (TOS), oxidative stress index (OSI), and malondialdehyde (MDA). It also increased the total antioxidant capacity, confirming its antioxidative properties. MIX administration also reduced the activity of MMP-2 and MMP-9, and then decreased the release of MLC1 and BNP-26 into plasma. This study demonstrated that intracoronary administration of low concentrations of doxycycline in combination with ML-7 and L-NAME is incredibly efficient in regulating pro- and antioxidant balance during MI.

Proline Metabolism in WHO G4 Gliomas Is Altered as Compared to Unaffected Brain Tissue.

Proline metabolism has been identified as a significant player in several neoplasms, but knowledge of its role in gliomas is limited despite it providing a promising line of pursuit. Data on proline metabolism in the brain are somewhat historical. This study aims to investigate alterations of proline metabolism in gliomas of WHO grade 4 (GG4) in the context of the brain. A total of 20 pairs of samples were studied, consisting of excised tumor and unaffected brain tissue, obtained when partial brain resection was required to reach deep-seated lesions. Levels of proline oxidase/proline dehydrogenase (POX/PRODH), Δ1-pyrroline-5-carboxylate reductases (PYCR1/2/3), prolidase (PEPD), and metalloproteinases (MMP-2, MMP-9) were assessed, along with the concentration of proline and proline-related metabolites. In comparison to normal brain tissue, POX/PRODH expression in GG4 was found to be suppressed, while PYCR1 expression and activity of PEPD, MMP-2, and -9 were upregulated. The GG4 proline concentration was 358% higher. Hence, rewiring of the proline metabolism in GG4 was confirmed for the first time, with a low-POX/PRODH/high-PYCR profile. High PEPD and MMPs activity is in keeping with GG4-increased collagen turnover and local aggressiveness. Further studies on the mechanisms of the interplay between altered proline metabolism and the GG4 microenvironment are warranted.

Vitamin A, D, E, and K as Matrix Metalloproteinase-2/9 Regulators That Affect Expression and Enzymatic Activity

Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases’ (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.

Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity

The aim of the study was to evaluate the role of kisspeptin-10 (KiSS-10) in the regulation of collagen content in cardiac fibroblasts. An attempt was also made to describe the mechanism of the effect of KiSS-10 on collagen metabolism. The studies indicate that kisspeptin-10 significantly increases the content of intracellular collagen in the myocardium. KiSS-10 also elevates the level of phosphorylated focal adhesion kinase (FAK) in human cardiac fibroblasts. The inhibition of FAK negates the stimulatory effect of KiSS-10 on collagen deposition in vitro. These changes correlate with an increase in the level of propeptides of procollagen type I (PICP) and III (PIIICP) in fibroblast culture medium and mouse PIIICP in serum. Moreover, this hormone inhibits the release of metalloproteinases (MMP-1,-2,-9) and elevates the secretion of their tissue inhibitors (TIMP-1,-2,-4). KiSS-10 also enhances the expression of α1 chains of procollagen type I and III in vitro. Thus, KiSS-10 is involved in the regulation of collagen metabolism and cardiac fibrosis. Augmentation of collagen deposition by KiSS-10 is dependent on the protein synthesis elevation, inhibition of MMPs activity (increase of TIMPs release) or decrease of MMPs concentration. The profibrotic activity of KiSS-10 is mediated by FAK and is not dependent on TGF-β1.

Boswellia serrata Extracts Ameliorates Symptom of Irregularities in Articular Cartilage through Inhibition of Matrix Metalloproteinases Activation and Apoptosis in Monosodium-Iodoacetate-Induced Osteoarthritic Rat Models.

The research examined the effects of Boswellia serrata extracts (BSE) on a rat model of osteoarthritis induced by monosodium iodoacetate (MIA). The severity and progression of MIA-induced osteoarthritis were assessed using microcomputed tomography imaging. Additionally, the study investigated the impact of BSE various the biomarkers associated with osteoarthritis, including anabolic and catabolic factors, pro-inflammatory factors, and apoptosis factors. The evaluation methods employed included western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction analysis in osteoarthritic rats. Supplementing osteoarthritic rats with BSE reduced tissue injury, cartilage destruction, and decreased in MIA-induced roughness on the articular cartilage surface. MIA-treated rats exhibited increased expressions of phosphorylation of Smad3, MMPs, p-IκB, p-NF-κB, and pro-inflammatory factors (IL-1β, IL-6, TNF-α, and COX-2), which were mitigated by BSE supplementation. Furthermore, protein expressions related to apoptosis pathways were significantly reduced in MIA-induced rats supplemented with BSE. These findings suggested that BSE ingestion may enhance the inflammatory response, decrease JNK-dependent MMPs activation, and alleviate caspase-3-dependent apoptosis in MIA-induced osteoarthritic rat models. Consequently, BSE exhibits potential as a therapeutic agent for treating osteoarthritis.

Interferon-β decreases LPS-induced neutrophil recruitment to cardiac fibroblasts.

Introduction: Cardiac fibroblasts (CF) are crucial cells in damaged heart tissues, expressing TLR4, IFN-receptor and responding to lipopolysaccharide (LPS) and interferon-β (IFN-β) respectively. While CF interact with immune cells; however, their relationship with neutrophils remains understudied. Additionally, theimpact of LPS and IFN-β on CF-neutrophil interaction is poorly understood. Methods: Isolated CF from adult rats were treated with LPS, with or without IFN-β. This study examined IL-8 secretion, ICAM-1 and VCAM-1 expression, and neutrophil recruitment, as well as their effects on MMPs activity. Results: LPS triggered increased IL-8 expression and secretion, along with elevated ICAM-1 and VCAM-1 expression, all of which were blocked by TAK-242. Pre-treatment with IFN-β countered these LPS effects. LPS treated CF showed higher neutrophil recruitment (migration and adhesion) compared to unstimulated CF, an effect prevented by IFN-β. Ruxolitinib blocked these IFN-β anti-inflammatory effects, implicating JAK signaling. Analysis of culture medium zymograms from CF alone, and CF-neutrophils interaction, revealed that MMP2 was mainly originated from CF, while MMP9 could come from neutrophils. LPS and IFN-β boosted MMP2 secretion by CF. MMP9 activity in CF was low, and LPS or IFN-β had no significant impact. Pre-treating CF with LPS, IFN-β, or both before co-culture with neutrophils increased MMP2. Neutrophil co-culture increased MMP9 activity, with IFN-β pre-treatment reducing MMP9 compared to unstimulated CF. Conclusion: In CF, LPS induces the secretion of IL-8 favoring neutrophils recruitment and these effects were blocked by IFN-. The results highlight that CF-neutrophil interaction appears to influence the extracellular matrix through MMPs activity modulation.

CircEIF3I facilitates the recruitment of SMAD3 to early endosomes to promote TGF-β signalling pathway-mediated activation of MMPs in pancreatic cancer

BackgroundAmong digestive tract tumours, pancreatic ductal adenocarcinoma (PDAC) shows the highest mortality trend. Moreover, although PDAC metastasis remains a leading cause of cancer-related deaths, the biological mechanism is poorly understood. Recent evidence demonstrates that circular RNAs (circRNAs) play important roles in PDAC progression.MethodsDifferentially expressed circRNAs in normal and PDAC tissues were screened via bioinformatics analysis. Sanger sequencing, RNase R and actinomycin D assays were performed to confirm the loop structure of circEIF3I. In vitro and in vivo functional experiments were conducted to assess the role of circEIF3I in PDAC. MS2-tagged RNA affinity purification, mass spectrometry, RNA immunoprecipitation, RNA pull-down assay, fluorescence in situ hybridization, immunofluorescence and RNA–protein interaction simulation and analysis were performed to identify circEIF3I-interacting proteins. The effects of circEIF3I on the interactions of SMAD3 with TGFβRI or AP2A1 were measured through co-immunoprecipitation and western blotting.ResultsA microarray data analysis showed that circEIF3I was highly expressed in PDAC cells and correlated with TNM stage and poor prognosis. Functional experiments in vitro and in vivo revealed that circEIF3I accelerated PDAC cells migration, invasion and metastasis by increasing MMPs expression and activity. Mechanistic research indicated that circEIF3I binds to the MH2 domain of SMAD3 and increases SMAD3 phosphorylation by strengthening the interactions between SMAD3 and TGFβRI on early endosomes. Moreover, AP2A1 binds with circEIF3I directly and promotes circEIF3I-bound SMAD3 recruitment to TGFβRI on early endosomes. Finally, we found that circEif3i exerts biological functions in mice similar to those of circEIF3I in humans PDAC.ConclusionsOur study reveals that circEIF3I promotes pancreatic cancer progression. circEIF3I is a molecular scaffold that interacts with SMAD3 and AP2A1 to form a ternary complex, that facilitates the recruitment of SMAD3 to early endosomes and then activates the TGF-β signalling pathway. Hence, circEIF3I is a potential prognostic biomarker and therapeutic target in PDAC.

Triptolide attenuates pulmonary fibrosis by inhibiting fibrotic extracellular matrix remodeling mediated by MMPs/LOX/integrin

BackgroundFibrotic extracellular matrix (ECM) remodeling characterized different types of pulmonary fibrosis, and its regulation could be a potential shared treatment strategy for pulmonary fibrosis. PurposeWe aimed to investigate the effect of triptolide on pulmonary fibrosis through the inhibition of several important aspects of fibrotic ECM remodeling. MethodsBleomycin-induced pulmonary fibrosis mice and TGF-β1-induced primary lung fibroblasts were used. The effect of triptolide on pulmonary fibrosis was detected using histopathology, immunostaining, RT-qPCR, western blotting, ELISA, and protein activity assay. ResultsTriptolide significantly alleviated bleomycin-induced pulmonary fibrosis in mice. It inhibited the expression of fibrotic genes α-SMA, collagen I, fibronectin, and vimentin and blocked the TGF-β-SMAD signaling pathway both in vivo and in vitro. In addition, triptolide regulated the expression and activity of MMPs during fibrosis. Interestingly, it suppressed the expression of lysyl oxidase, which was responsible for matrix cross-linking and elevated ECM stiffness. Furthermore, triptolide blocked the biomechanical stress transduction pathway integrin-β1-FAK-YAP signaling and attenuated the pro-fibrotic feedback of fibrotic ECM on fibroblasts via integrin inhibition. ConclusionThese findings show that triptolide prevents the key linkages of fibrotic ECM remodeling, including deposition, degradation, cross-linking, and pro-fibrotic feedback and, therefore, has potential therapeutic value for pulmonary fibrosis.

Effect of low-dose hydrocortisone and inhaled nitric oxide on inflammatory mediators and local pulmonary metalloproteinases activity in LPS-induced sepsis in piglets

Hospital mortality in sepsis varies between 30–45%. It has been shown that administration of inhaled nitric oxide (iNO) and intravenous corticosteroid in a porcine endotoxemia model attenuated the systemic inflammatory response. We explored the anti-inflammatory effect of a double-treatment strategy (iNO + low-dose steroid) on the lungs in a long-term porcine endotoxic shock model. As metalloproteinases (MMPs) are involved in the initiation of multiple organ dysfunction in septic shock, we evaluated the influence of this combination therapy on MMP2 and MMP9 activity and proIL-1β maturation. A shock-like condition was established in 23 animals by continuous infusion of E. coli lipopolysaccharide (LPS) for 10 h. Then the animals were observed for 10 h. Twelve pigs received iNO and hydrocortisone (iNO treatment started 3 h after the initial LPS infusion and continued until the end of the experiment). Eleven pigs were controls. Pigs treated with iNO and hydrocortisone displayed less inflammatory infiltrates in the lungs than the controls and a lower level of IL-1β. The proMMP2 was significantly decreased in the iNO and hydrocortisone group. The amount of an active MMP9 (~ 60 kDa) was decreased in the iNO and hydrocortisone group. Total gelatinolytic activity was lower in the iNO and hydrocortisone group. Reduced MMP activity was accompanied by a 2.5-fold decrease of the active IL-1β form (17 kDa) in the pulmonary tissue of iNO combined with hydrocortisone exposed pigs. We demonstrated that in a porcine endotoxemia model the NO inhalation combined with intravenous hydrocortisone led to the attenuation of the inflammatory cascade induced by bacterial LPS. The decrease in pulmonary MMPs activities was accompanied by reduced proIL-1β processing.

The Effect of Calcineurin Inhibitors on MMPs Activity in Heart and Their Side Effects-A Review of Literature.

This review focuses on the role of metalloproteinases in the pathogenesis of myocardial injury in various disease entities. It reveals how the expression and serum levels of metalloproteinases and their inhibitors change in many disease states. At the same time, the study offers a review of the impact of immunosuppressive treatment on this relationship. Modern immunosuppressive treatment is based mainly on the use of calcineurin inhibitors, including cyclosporine A and tacrolimus. The use of these drugs may carry a number of side effects, specifically to the cardiovascular system. The scale and degree of long-term influence on the organism remains unclear, but a significant risk of complications for transplant recipients who take immunosuppressive drugs as part of their daily treatment is to be expected. Therefore, the knowledge on this subject should be expanded and the negative effects of post-transplant therapy minimized. Immunosuppressive therapy plays an important role in the expression and activation of tissue metalloproteinases and their specific inhibitors, which leads to many tissue changes. The presented study is a collection of research results on the effects of calcineurin inhibitors on the heart, with particular emphasis placed on the participation of MMP-2 and MMP-9. It is also an analysis of the effects of specific heart diseases on myocardial remodeling through inductive or inhibitory effects on matrix metalloproteinases and their inhibitors.

The effect of carbodiimide on push-out bond strength of fiber posts and endogenous enzymatic activity

BackgroundTo investigate the effect of 0.3 M 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC) aqueous solution pretreatment on push-out bond strength (PBS) and matrix-metalloproteinases (MMPs) activity within radicular dentin when different post cementation strategies were employed.MethodsOne hundred and twenty monoradicular human teeth were endodontically treated and randomly divided into six groups, depending on the cementation strategy and root dentin pretreatment (n = 20): EAR: cementation with an etch-and-rinse adhesive (LuxaBond Total Etch, DMG) and resin cement (LuxaCore Z Dual, DMG); EAR/EDC: 1 min EDC pretreatment after etching + EAR; SE: cementation with a self-etch primer (Multilink Primer, Ivoclar Vivadent) and corresponding cement (Multilink Automix, Ivoclar Vivadent); SE/EDC: self-etch primer + EDC pretreatment + SE; SA: cementation with a universal self-adhesive cement (RelyX Universal, 3 M); SA/EDC: EDC pretreatment + SA. Slices were submitted to PBS test and interfacial nanoleakage evaluation 24 h after cementation or after thermocycling (40.000 cycles, 5–55 °C). To investigate the effect of EDC on MMPs activity, 4 additional first maxillary premolars per group were processed for in situ zymography analysis. Multivariate ANOVA and post hoc Tukey tests were used to analyze PBS values. The data from in situ zymography were analyzed with Kruskal-Wallis test and Dunn’s pairwise multiple comparison procedures (α = 0.05).ResultsThe variables “EDC pretreatment”, “root region” and “thermocycling” significantly influenced PBS (p < 0.05), while the variable “cementation strategy” had no influence (p > 0.05). Thermocycling significantly reduced PBS in SE and SA groups (p < 0.05). EDC was effective in preserving PBS after artificial aging. EDC pretreatment significantly reduced enzymatic activity at baseline in EAR and SE groups, and in SA group after thermocycling (p < 0.05).ConclusionsThe use of EDC prevents the reduction of bond-strength values after artificial aging and silences endogenous enzymatic activity within radicular dentin when different cementation strategies were employed.