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10-methacryloyloxidecyl dihydrogen phosphate monomer (10-MDP) is commonly used as a bonding monomer in universal adhesives. Adhesives that contain this monomer can directly contact the surrounding periodontium due to the chemical binding of 10-MDP with hydroxyapatite in hard tissue to form calcium salts. However, the effect of these calcium salts on the periodontium in the case of subgingival fillings remains poorly understood. The objective of this study was to investigate effects of 10-MDP calcium salts on osteoblasts and fibroblasts in the periodontal tissues. This study investigated the effects of different concentrations of 10-MDP calcium salts on the migration, proliferation, and differentiation of osteoblasts (MC3T3-E1) and fibroblasts (L929); additionally, the effect on apoptosis and matrix metalloproteinases (MMPs) expression in these cells was evaluated. Cell proliferation assay, alkaline phosphatase (ALP) activity assay, Western blotting, and quantitative real-time polymerase chain reaction were performed to determine the effects. The 10-MDP calcium salts (within a concentration of 0.5 mg/mL) showed no cytotoxicity and did not seem to influence the apoptosis, mitochondrial membrane potential, and reactive oxygen species (ROS) levels in the cells. However, they had an inhibitory effect on the secretion of MMP2 and MMP9 in the osteoblasts and fibroblasts. The ALP activity assay and Alizarin Red staining did not reveal any significant effects of the 10-MDP calcium salts on osteoblast differentiation. These results suggest that applying 10-MDP-containing adhesives to subgingival fillings may be safe and beneficial for the periodontal tissues. [Display omitted] • 10-MDP calcium salts directed contact the periodontium in the case of subgingival resin filling. • 10-MDP calcium salts have inhibitory effect on the secretion of MMP2 and MMP9 in the osteoblasts and fibroblasts. • 10-MDP calcium salts showed no cytotoxicity and influences on the mitochondria in osteoblasts and fibroblasts. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory condition marked by endothelial dysfunction, lipid accumulation, inflammatory cell infiltration, and extracellular matrix (ECM) remodeling within arterial walls, leading to plaque formation and potential cardiovascular events. Key players in ECM remodeling and inflammation are matrix metalloproteinases (MMPs) and CD147/EMMPRIN, a cell surface glycoprotein expressed on endothelial cells, vascular smooth muscle cells (VSMCs), and immune cells, that regulates MMP activity. Hydrogen sulfide (H₂S), a gaseous signaling molecule, has emerged as a significant modulator of these processes including oxidative stress mitigation, inflammation reduction, and vascular remodeling. This systematic review investigates the mechanistic pathways through which H₂S influences MMPs and CD147/EMMPRIN and assesses its impact on atherosclerosis progression. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases, focusing on studies examining H₂S modulation of MMPs and CD147/EMMPRIN in atherosclerosis contexts. Findings indicate that H₂S modulates MMP expression and activity through transcriptional regulation and post-translational modifications, including S-sulfhydration. By mitigating oxidative stress, H₂S reduces MMP activation, contributing to plaque stability and vascular remodeling. H₂S also downregulates CD147/EMMPRIN expression via transcriptional pathways, diminishing inflammatory responses and vascular cellular proliferation within plaques. The dual regulatory role of H₂S in inhibiting MMP activity and downregulating CD147 suggests its potential as a therapeutic agent in stabilizing atherosclerotic plaques and mitigating inflammation. Further research is warranted to elucidate the precise molecular mechanisms and to explore H₂S-based therapies for clinical application in atherosclerosis. [ABSTRACT FROM AUTHOR]

Mammary carcinoma is the leading cause of cancer related mortality in women globally. Human growth hormone (hGH) plays a vital role in the development of mammary glands by promoting cell proliferation. Hence, alteration in human growth hormone can contribute to mammary carcinoma. In the present study, we investigated the role of hGH in mammary carcinogenesis and metastasis. We used MTT assay for cell proliferation, and wound healing assay for cell invasion and migration, the cell cycle analysis and analysis of apoptosis. Luciferase reporter assay and Western blot analysis were performed to find out the role of HIF-1α signalling in association with hGH and also VEGF-A Western blot analysis was performed for angiogenesis regulating with hGH. Further, Western blot analysis was analysed for cadherin levels (E-cadherin and N-cadherin) and confocal microscopy and soft agar assay was performed to understand the role of hGH in metastasis through EMT. The results suggest that MCF-7 breast cancer cell lines transfected with hGH showed enhanced proliferation and cell cycle progression by decreasing apoptosis. This contributes to cancer cell progression via HIF-1α signalling pathway which also enhances the expression of VEGF-A contributing to angiogenesis. The EMT markers MMP-2 and N-cadherin expression also increased with decreased E-cadherin expression suggesting the role of hGH in metastasis. In conclusion, the present study establishes the role of hGH in breast cancer progression and suggests the possible signalling pathway involved is mediated by HIF-1α. These finding further helps in novel therapeutic interventions of mammary carcinoma. This present study reports that autocrine production of human growth hormone by human mammary cells alters cell morphology, proliferation and is responsible for enhanced migratory and invasive behaviour leading to breast cancer. Therefore, this study will further help in novel therapeutic interventions for the treatment of breast cancer, by utilizing knowledge of these signalling pathways as targets. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) plays a vital role in supporting neuronal survival, differentiation, and promoting synaptogenesis, thereby facilitating synaptic plasticity in the central nervous system. Administration of exogenous BDNF is a crucial approach for treating central nervous system injuries. However, the inability of sustained drug release to match disease activity often leads to insufficient drug accumulation in the injured area (ineffectiveness) and severe side effects induced by the drug (toxicity). Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are typically upregulated after tissue damage, and their upregulated expression levels represent the degree of disease activity. In this study, we utilized bioengineering techniques to prepare a BDNF that can specifically bind to collagen and be released in response to MMP substrate cleavage (collagen binding domain tissue inhibitor of matrix metalloproteinases brain-derived neurotrophic factor, CBD-TIMP-BDNF). We verified the ability of CBD-BDNF and CBD-TIMP-BDNF to specifically bind to collagen through collagen binding experiments, examined the characteristics of CBD-TIMP-BDNF in response to MMP-2 to release BDNF, and detected the biological activities of both recombinant proteins. The results demonstrated that the established microenvironment-controlled BDNF release system can respond to MMP-2 to release BDNF. The recombinant proteins CBD-BDNF and CBD-TIMP-BDNF exhibited similar biological activities to the BDNF standard. Targeting the upregulated expression of MMPs after spinal cord injury as a trigger for drug release, it is expected to achieve on-demand release of BDNF in response to the severity of the disease. [ABSTRACT FROM AUTHOR]

Abstract Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also associated with the susceptibility to a variety of tumors, including prostate cancer (PCa). However, previous studies have not systematically analyzed the association between MMP and prostate cancer, so we conducted systematic data collection and analyzed to evaluate the relationship among polymorphisms in MMPs and PCa susceptibility. We searched PubMed, Web of Science, Embase and Google Scholar for all papers published up to Apr 3rd, 2023, and systematically analyzed the relationship among MMP1-1607 2G/1G, MMP2-1306 T/C, MMP2-735 T/C, MMP7-181 G/A, MMP9-1562 T/C and PCa susceptibility using multiple comparative models and subgroup analyses. We found that MMP2-1306 T/C polymorphism showed associations with PCa susceptibility, with the Ethnicity subgroup (Asian) being more pronounced. Similarly, MMP9-1562 T/C has also had associations with PCa susceptibility. Our current study found that the polymorphisms of, MMP2-1306 T/C, and MMP9-1562 T/C had strong associations with PCa risk.

Matrix metalloproteinases (MMPs) had a variety of subtypes, which may be related to tumor invasion and angiogenesis, and the polymorphisms from MMPs have been also associated with the susceptibility to a variety of tumors, including prostate cancer (PCa). However, previous studies have not systematically analyzed the association between MMP and prostate cancer, so we conducted systematic data collection and analyzed to evaluate the relationship among polymorphisms in MMPs and PCa susceptibility. We searched PubMed, Web of Science, Embase and Google Scholar for all papers published up to Apr 3rd, 2023, and systematically analyzed the relationship among MMP1-1607 2G/1G, MMP2-1306 T/C, MMP2-735 T/C, MMP7-181 G/A, MMP9-1562 T/C and PCa susceptibility using multiple comparative models and subgroup analyses. We found that MMP2-1306 T/C polymorphism showed associations with PCa susceptibility, with the Ethnicity subgroup (Asian) being more pronounced. Similarly, MMP9-1562 T/C has also had associations with PCa susceptibility. Our current study found that the polymorphisms of, MMP2-1306 T/C, and MMP9-1562 T/C had strong associations with PCa risk. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory condition marked by endothelial dysfunction, lipid accumulation, inflammatory cell infiltration, and extracellular matrix (ECM) remodeling within arterial walls, leading to plaque formation and potential cardiovascular events. Key players in ECM remodeling and inflammation are matrix metalloproteinases (MMPs) and CD147/EMMPRIN, a cell surface glycoprotein expressed on endothelial cells, vascular smooth muscle cells (VSMCs), and immune cells, that regulates MMP activity. Hydrogen sulfide (H₂S), a gaseous signaling molecule, has emerged as a significant modulator of these processes including oxidative stress mitigation, inflammation reduction, and vascular remodeling. This systematic review investigates the mechanistic pathways through which H₂S influences MMPs and CD147/EMMPRIN and assesses its impact on atherosclerosis progression. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases, focusing on studies examining H₂S modulation of MMPs and CD147/EMMPRIN in atherosclerosis contexts. Findings indicate that H₂S modulates MMP expression and activity through transcriptional regulation and post-translational modifications, including S-sulfhydration. By mitigating oxidative stress, H₂S reduces MMP activation, contributing to plaque stability and vascular remodeling. H₂S also downregulates CD147/EMMPRIN expression via transcriptional pathways, diminishing inflammatory responses and vascular cellular proliferation within plaques. The dual regulatory role of H₂S in inhibiting MMP activity and downregulating CD147 suggests its potential as a therapeutic agent in stabilizing atherosclerotic plaques and mitigating inflammation. Further research is warranted to elucidate the precise molecular mechanisms and to explore H₂S-based therapies for clinical application in atherosclerosis.

The mechanism of extracellular matrix metalloproteinase inducer (EMMPRIN) in the regulation of liver fibrosis has not been clarified. This study aims to investigate the role of EMMPRIN S-nitrosylation (SNO) in the regulation of hepatic stellate cell (HSC) migration and matrix metalloproteinase (MMP) activities in liver fibrosis. The results from the tissue microarrays and rat/mouse liver tissues suggest that EMMPRIN mRNA and protein levels in the fibrotic livers are lower than those in the corresponding normal control livers, but higher SNO level of EMMPRIN in fibrotic liver area was shown by immunohistochemistry, immunofluorescence staining, and biotin-switch assay conversely in vivo. Primary EMMPRIN comes from hepatocytes and liver sinus epithelial cells (LSECs) rather than quiescent HSCs. To mimic the uptake of extrinsic EMMPRIN, supernatants from mouse primary hepatocytes/293 cells transfected with EMMPRIN wild-type plasmids (WT) and EMMPRIN SNO site (cysteine 87) mutation plasmids (MUT) were collected and added to JS-1/LX2 cell medium. The MUT EMMPRIN diminishes SNO successfully, enhances the activities of MMP2 and MMP9, and subsequently increases HSC migration. In conclusion, SNO of EMMPRIN influences HSC migration and MMP activities in liver fibrosis. This finding may shed light on the possible regulatory mechanism of MMPs in ECM accumulation in liver fibrosis.

Purpose: To evaluate the anti-inflammatory properties of Drynariae rhizome (Polypodiaceae) extract (DRE) on lipopolysaccharide RAW264.7 macrophage cells and its protective effects on interleukin (IL)-1β-stimulated SW1353 chondrocyte cells. Methods: The anti-inflammatory effect of DRE (12.5, 25, 50, and 100 μg/mL) were measured by 5-lipooxygenase (LO) and cyclooxygenase (COX)-2 enzyme inhibitory activities, nitric oxide (NO) production in LPS-stimulated RAW264.7 cells using Griess reagent assay. Prostaglandins (PGE2) and leukotriene (LTB4) production were measured using enzyme-linked immunosorbent assay (ELISA). To investigate the protective effect on chondrocytes, the level of matrix metalloproteinases (MMP)-3, -9, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was determined using zymography assay and ELISA kit in SW1353 cells stimulated with IL-1β. Results: Drynariae rhizome (Polypodiaceae) extract (DRE) had a significant (p < 0.05) inhibitory effect on 5-LO and COX-2 enzymes in a concentration-dependent manner compared to untreated group. In RAW264.7 cells, levels of NO, PGE2 and LTB4 of DRE group were significantly (p < 0.05) decreased in study group (treated with DRE) at 12.5 μg/mL compared to the group treated with LPS (100 ng/mL) alone. Additionally, in SW1353 human chondrocytes stimulated with IL-1β, MMP-3 and MMP-9 were significantly (p < 0.05) suppressed in DRE-treated group compared to IL-1β group alone, with no significant impact on TIMP-1 production. Conclusion: Drynariae rhizome (Polypodiaceae) extract (DRE) possesses anti-inflammatory and cartilage protection effects. It therefore has the potential to be developed as an effective natural pharmaceutical agent for inflammation or osteoarthritis. [ABSTRACT FROM AUTHOR]

To investigate the relationship between hydrogen sulfide(H 2 S) and the senescence level of the fetal membranes, and to elucidate how H 2 S affects the integrity of the fetal membranes. The H 2 S and the senescence levels of fetal membranes, and the expressions of H 2 S synthase CBS and CSE were detected in the preterm (PT) group and the preterm premature ruptured membranes (pPROM) group. The effects of H 2 S donors and knockdown of CBS on the senescence level of amniotic epithelial cells, and the expression level of matrix metalloproteinases (MMPs) and epithelial-mesenchymal translation (EMT) were observed. The level of H 2 S in the fetal membranes in the pPROM group is significantly lower than that in the PT group matched for gestational age. The level of H 2 S is negatively correlated with the senescence level of fetal membranes. Treatment with H 2 S donors reduced cell senescence and MMPs expression, but did not affect EMT. CBS siRNA transfection accelerated the senescence of amniotic epithelial cells, and promoted the expression of MMPs and EMT occurrence, but l -cysteine could reverse these effects. Our study suggests that H 2 S, through its anti-aging effect, can influence the expression of MMPs and EMT, thereby contributing to the maintenance of fetal membrane integrity. • Ruptured membranes show a higher level of senescence than intact membranes. • Ruptured membranes have lower levels of H 2 S than intact membranes. • H 2 S regulates MMPs expression by anti-aging effect to mainten fetal membrane integrity. • H 2 S regulates epithelial-mesenchymal transition to mainten fetal membrane integrity. [ABSTRACT FROM AUTHOR]

Intestinal epithelial homeostasis is maintained by intrinsic and extrinsic signals. The extrinsic signals include those provided by mesenchymal cell populations that surround intestinal crypts and is further facilitated by the extracellular matrix (ECM), which is modulated by proteases such as matrix metalloproteinases (MMPs). Extrinsic signals ensure an appropriate balance between intestinal epithelial proliferation and differentiation. This study explores the role of MMP17, which is preferentially expressed by smooth muscle cells in the intestine, in intestinal homeostasis and during immunity to infection. Mice lacking MMP17 expressed high levels of goblet-cell associated genes and proteins, such as CLCA1 and RELM-b, which are normally associated with immune responses to infection. Nevertheless, Mmp17 KO mice did not have altered resistance during a bacterial Citrobacter rodentium infection. However, when challenged with a low dose of the helminth Trichuris muris, Mmp17 KO mice had increased resistance, without a clear role for an altered immune response during infection. Mechanistically, we did not find changes in traditional modulators of goblet cell effectors such as the NOTCH pathway or specific cytokines. We found MMP17 expression in smooth muscle cells as well as lamina propria cells such as macrophages. Together, our data suggest that MMP17 extrinsically alters goblet cell maturation which is sufficient to alter clearance in a helminth infection model. [ABSTRACT FROM AUTHOR]

Abstract People have become increasingly concerned about skin beauty and health issues, especially skin photoaging. Previous studies showed that skin photoaging was characterized by skin roughness and dryness. It was caused by UV radiation‐related dysregulation of matrix metalloproteinases (MMPs) and oxidative stress. Therefore, to investigate the antiphotoaging activity of polysaccharides, it is critical to establish the skin photoaging model, including the in vitro cellular model and the in vivo animal model. The in vitro cellular model is judged by cell viability, the MMPs expression, oxidative detection, and the quantities of inflammation cytokines. Moreover, both the damage to the epidermis and dermis of nude mice and the change of collagen content in the skin are indicators of the in vivo animal model. Thus, in this guideline, we tried to summarize the practice of antiphotoaging activity for polysaccharides.

Intestinal epithelial homeostasis is maintained by intrinsic and extrinsic signals. The extrinsic signals include those provided by mesenchymal cell populations that surround intestinal crypts and is further facilitated by the extracellular matrix (ECM), which is modulated by proteases such as matrix metalloproteinases (MMPs). Extrinsic signals ensure an appropriate balance between intestinal epithelial proliferation and differentiation. This study explores the role of MMP17, which is preferentially expressed by smooth muscle cells in the intestine, in intestinal homeostasis and during immunity to infection. Mice lacking MMP17 expressed high levels of goblet-cell associated genes and proteins, such as CLCA1 and RELM-β, which are normally associated with immune responses to infection. Nevertheless, Mmp17 KO mice did not have altered resistance during a bacterial Citrobacter rodentium infection. However, when challenged with a low dose of the helminth Trichuris muris, Mmp17 KO mice had increased resistance, without a clear role for an altered immune response during infection. Mechanistically, we did not find changes in traditional modulators of goblet cell effectors such as the NOTCH pathway or specific cytokines. We found MMP17 expression in smooth muscle cells as well as lamina propria cells such as macrophages. Together, our data suggest that MMP17 extrinsically alters goblet cell maturation which is sufficient to alter clearance in a helminth infection model.

Objective: The blood–brain barrier (BBB) plays a critical role in central nervous system homeostasis, and the integrity of BBB is disrupted in many neurodegenerative diseases. Matrix metalloproteinases (MMPs) degrade the tight junctions (TJs) of endothelial cells and basement membrane components essential to BBB integrity, which leads to increased BBB permeability and allows inflammatory cells and neurotoxic substances to enter the brain. Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of MMPs, regulate MMP activity, thereby maintaining BBB integrity. Methods: The disruptive impacts of MMP-3 and MMP-9 on BBB and protective effect of TIMP-1 were investigated in a simplified in vitro model of the BBB, which was generated using rat brain microvascular endothelial cells (RBMEC). The main features of BBB formation, including permeability and the trans-endothelial electrical resistance (TEER), were monitored over time after the addition of MMP-3 and MMP-9 and their complexes with TIMP-1 inhibitor. Results: Our results indicated that MMP-3 and MMP-9 caused a dose-dependent disruption of the BBB, with 1.5 µM MMPs resulting in an over threefold increase in permeability, while TIMP-1 inhibition protected the integrity of the BBB model and recovered TEER and permeability of RBMECs. The disruption and recovery of tight junction proteins of RBMECs after MMP and TIMP treatment were also detected using fluorescent microscopy. Conclusion: MMP-9 and MMP-3 disrupt the BBB by degrading tight junctions in endothelial cells, and TIMP-1 could inhibit the disruptive effect of MMP-3 and MMP-9 by showing potential as therapeutic protein against MMP-related diseases where BBB disruption plays a role. [ABSTRACT FROM AUTHOR]

The coexistence of depression and diabetes is a serious challenge in cardiovascular disease. However, extracellular matrix (ECM) under stress model associated or not with diabetes remains unknown. This study aims to investigate the involvement of diabetes and unpredictable chronic mild stress (UCMS) on ECM remodelling. Rats were exposed to UCMS, diabetes or combined treatment. mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9), plasminogen activator (t-PA) and inhibitor (PAI-1) was examined by Q-RT-PCR. ECM was determined by ELISA. MMP-2 and MMP-9 mRNA was lower in diabetes (P <0.05). UCMS increased MMP-2 and MMP-9 compared to control and diabetic group. Compared to the control and diabetes groups, MMP-2 and MMP-9 mRNA was significantly increased in the combined treatment group. UCMS increased MMP-2 expression in the diabetic group (P <0.01). Compared to control, gelatinase activity was higher in diabetes and UCMS (P <0.05). Combined diabetes and UCMS significantly increased gelatinase activity compared to T2D and UCMS groups. Collagen, hydroxyproline and fibronectin content were significantly increased in diabetes and combined groups. UCMS combined with diabetes exacerbated diabetes-induced MMPs and fibronectin deposition. In conclusion, comorbidity between diabetes and UCMS may exacerbate ECM remodelling. These findings will be useful in understanding diabetes-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents. [ABSTRACT FROM AUTHOR]

Simple Summary: The ever-increasing number of CRC cases and the associated number of deaths from this type of cancer require the development of sensitive, accurate, and non-invasive biomarkers for the early detection of CRC. At the same time, it is necessary to characterize these biomarkers in relation to the individual stages of CRC. We achieved interesting results by creating a BDNF/MMP9 ratio. The tissue BDNF/MMP-9 ratio (evaluated immunohistochemically) decreased significantly with the progression of the disease in living patients. However, in deceased individuals, the ratio showed an opposite tendency. We can conclude that lower BNDF/MMP-9 ratio levels may predict patients with a favorable prognosis. Our results confirmed the existence of a direct connection between the pro-plastic molecules BDNF and MMP-9. Purpose: The development of sensitive and non-invasive biomarkers for the early detection of CRC and determination of their role in the individual stages of CRC. Methods: MMP-9 expression in serum and tissue, and BDNF expression in plasma were detected using the ELISA method. MMP-9 and BDNF in the tissue were also determined by immunohistochemical staining. Results: To assess the balance between changes in survival and tumor progression, we compared BDNF/MMP-9 ratios in tissues of living and deceased individuals. The tissue BDNF/MMP-9 ratio (evaluated immunohistochemically) decreased significantly with the progression of the disease in living patients. The BDNF/MMP-9 ratio was statistically significantly reduced in stages II and III compared to the benign group. However, in deceased individuals, the ratio showed an opposite tendency. Conclusion: The determination of the tissue BDNF/MMP9 ratio can be used as a prognostic biomarker of CRC. [ABSTRACT FROM AUTHOR]

Medullary Thyroid Carcinoma (MTC) constitutes around 5% of all thyroid cancers. Trace elements assessment has emerged as a useful strategy in the diagnostics of MTC combined with Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) analysis. The aim of this study was to compare the presence and content of trace elements (i.e., Copper (Cu), Zinc (Zn), Iron (Fe), and Manganese (Mn)) in MTC with respect to control samples and their potential relationship with markers of MTC in tissues. The study included 26 patients who had undergone thyroidectomy, due to the diagnosis of MTC and 17 patients as control. We combined tumour pathology and staging, immunohistochemical analysis of calcitonin, MMPs, and TIMPs, with analytical biochemistry using Inductively Coupled Plasma – Mass Spectrometry (ICP-MS) to determine the levels of trace elements. No differences by MTC type for MMPs and their TIPMs, although strong TIMP-1 and TIMP-2 immunohistochemical expression of MTC were unveiled. Additionally, Zn, Fe, and Mn tended to be decreased, and Cu to be increased in samples presenting MTC with respect to controls. Moreover, Zn was the unique trace element which seemed to be correlated with MMPs and TIMPs. Trace elements such as Zn, Fe, and Mn are decreased in tissues affected by MTC. In addition, Zn may be the trace element which saves more relationship with the proportion and intensity of MMPs, being considered altogether useful biomarkers of MTC. We therefore suggest the analysis of novel and traditional markers of MTC as a novel approach in this pathology. [ABSTRACT FROM AUTHOR]

Aims: Rheumatoid arthritis (RA) is a common chronic immune disease. Berberine, as its main active ingredient, was also contained in a variety of medicinal plants such as Berberaceae, Buttercup, and Rutaceae, which are widely used in digestive system diseases in traditional Chinese medicine with anti-inflammatory and antibacterial effects. The aims of this article were to explore the therapeutic effect and mechanism of berberine on rheumatoid arthritis. Methods: Cell Counting Kit-8 was used to evaluate the effect of berberine on the proliferation of RA fibroblast-like synoviocyte (RA-FLS) cells. The effect of berberine on matrix metalloproteinase (MMP)-1, MMP-3, receptor activator of nuclear factor kappa-Β ligand (RANKL), tumour necrosis factor alpha (TNF-α), and other factors was determined by enzyme-linked immunoassay (ELISA) kit. Transcriptome technology was used to screen related pathways and the potential targets after berberine treatment, which were verified by reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot (WB) technology. Results: Berberine inhibited proliferation and adhesion of RA-FLS cells, and significantly reduced the expression of MMP-1, MMP-3, RANKL, and TNF-α. Transcriptional results suggested that berberine intervention mainly regulated forkhead box O (FOXO) signal pathway, prolactin signal pathway, neurotrophic factor signal pathway, and hypoxia-inducible factor 1 (HIF-1) signal pathway. Conclusion: The effect of berberine on RA was related to the regulation of RAS/mitogen-activated protein kinase/FOXO/HIF-1 signal pathway in RA-FLS cells. Cite this article: Bone Joint Res 2023;12(2):91–102.

Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several nonmutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo. [ABSTRACT FROM AUTHOR]

Matrikines (MKs) can be a rich source of functional nutrition components and additional therapy, thereby contributing to human health care and reducing the risk of developing serious diseases, including cancer. Currently, functionally active MKs as products of enzymatic transformation by matrix metalloproteinases (MMPs) are used for various biomedical purposes. Due to the absence of toxic side effects, low species specificity, relatively small size, and presence of various targets at the cell membranes, MKs often exhibit antitumor properties and, therefore, are promising agents for antitumor combination therapy. This review summarizes and analyzes the current data on the antitumor activity of MKs of different origins, discusses the problems and prospects for their therapeutic use, and evaluates the experimental results of studying the antitumor properties of MKs from different echinoderm species generated with the help of a complex of proteolytic enzymes from red king crab Paralithodes camtschatica. Special attention is paid to the analysis of possible mechanisms of the antitumor action of various functionally active MKs, products of the enzymatic activity of various MMPs, and the existing problems for their use in antitumor therapy. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a class of zinc‐dependent endopeptidases that play important roles in disease progression. High expression of MMPs is associated with various diseases, including cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. For better understanding the roles of MMPs in these diseases' development and the potential in early diagnosis and treatment monitoring, a number of sensors have recently been developed for MMPs detection in vitro and in vivo. These sensors are designed mainly based on the exploration of MMPs' molecular structure and enzymatic activity. This review seeks to provide a summary for the development and application of the sensors for the detection of MMPs in the past three years. The research hotspots, current challenges, and further research directions in this field are also discussed. [ABSTRACT FROM AUTHOR]

Background: Despite improvements in acne treatment, post-acne scarring is still a widespread issue. Scarring is difficult to treat and difficult to avoid. Inflammatory mediators and enzymatic breakdown of collagen fibres and subcutaneous fat are likely involved in the aetiology of atrophic acne scarring. Objective: Review of the literature on options of treatment of post acne scar. Methods: PubMed, Google Scholar, and Science Direct were some of the places we explored for information about post-acne scarring and its treatment. Between January 2000 and May 2021, however, only the latest or most comprehensive study was considered. The authors also assessed the usefulness of references taken from similar books. We haven't paid attention to non-English documents because we don't have the time or money to translate them. Unpublished articles, oral presentations, conference abstracts, and doctoral dissertations were all widely acknowledged to not constitute valid scientific research. Conclusion: Facial resurfacing procedures like dermabrasion and microdermabrasion mechanically ablate damaged skin and stimulate re-epithelialization. When performed properly, dermabrasion can remove the epidermis and reach the reticular or papillary dermis underneath. Both invasive and noninvasive treatments have been tried with varied degrees of success to cure atrophic scars, but it is still difficult to reach the aim of complete improvement, even with the most expensive approaches. Consequently, there is a growing need for therapeutic approaches that are both highly successful and very inexpensive in the treatment of acne scars. [ABSTRACT FROM AUTHOR]

Alzheimer’s Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

The actin cytoskeleton plays a critical role in cancer cell invasion and metastasis; however, the coordination of its multiple functions remains unclear. Actin dynamics in the cytoplasm control the formation of invadopodia, which are membrane protrusions that facilitate cancer cell invasion by focusing the secretion of extracellular matrix-degrading enzymes, including matrix metalloproteinases (MMPs). In this study, we investigated the nuclear role of cysteine-rich protein 2 (CRP2), a two LIM domain-containing F-actin-binding protein that we previously identified as a cytoskeletal component of invadopodia, in breast cancer cells. We found that F-actin depolymerization stimulates the translocation of CRP2 into the nucleus, resulting in an increase in the transcript levels of pro-invasive and pro-metastatic genes, including several members of the MMP gene family. We demonstrate that in the nucleus, CRP2 interacts with the transcription factor serum response factor (SRF), which is crucial for the expression of MMP-9 and MMP-13. Our data suggest that CRP2 and SRF cooperate to modulate of MMP expression levels. Furthermore, Kaplan-Meier analysis revealed a significant association between high-level expression of SRF and shorter overall survival and distant metastasis-free survival in breast cancer patients with a high CRP2 expression profile. Our findings suggest a model in which CRP2 mediates the coordination of cytoplasmic and nuclear processes driven by actin dynamics, ultimately resulting in the induction of invasive and metastatic behavior in breast cancer cells.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade proteins of the extracellular matrix and the basement membrane. Thus, these enzymes regulate airway remodeling, which is a major pathological feature of chronic obstructive pulmonary disease (COPD). Furthermore, proteolytic destruction in the lungs may lead to loss of elastin and the development of emphysema, which is associated with poor lung function in COPD patients. In this literature review, we describe and appraise evidence from the recent literature regarding the role of different MMPs in COPD, as well as how their activity is regulated by specific tissue inhibitors. Considering the importance of MMPs in COPD pathogenesis, we also discuss MMPs as potential targets for therapeutic intervention in COPD and present evidence from recent clinical trials in this regard. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are an important class of enzymes in the body that function through the extracellular matrix (ECM). They are involved in diverse pathophysiological processes, such as tumor invasion and metastasis, cardiovascular diseases, arthritis, periodontal disease, osteogenesis imperfecta, and diseases of the central nervous system. MMPs participate in the occurrence and development of numerous cancers and are closely related to immunity. In the present study, we review the immunomodulatory role of MMPs in colitis-associated cancer (CAC) and discuss relevant clinical applications. We analyze more than 300 pharmacological studies retrieved from PubMed and the Web of Science, related to MMPs, cancer, colitis, CAC, and immunomodulation. Key MMPs that interfere with pathological processes in CAC such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, as well as their corresponding mechanisms are elaborated. MMPs are involved in cell proliferation, cell differentiation, angiogenesis, ECM remodeling, and the inflammatory response in CAC. They also affect the immune system by modulating differentiation and immune activity of immune cells, recruitment of macrophages, and recruitment of neutrophils. Herein we describe the immunomodulatory role of MMPs in CAC to facilitate treatment of this special type of colon cancer, which is preceded by detectable inflammatory bowel disease in clinical populations. [ABSTRACT FROM AUTHOR]

Abstract Extracellular matrix (ECM) is characterized as widespread, abundant, and pluripotent. Among ECM members, collagen is widely accepted as one of the most prominent components for its essential structural property that can provide a scaffold for other components of ECM and the rich biological functions, which has been extensively used in tissue engineering. Emerging evidence has shown that the balance of ECM degradation and remodeling is vital to regulations of maternal–fetal interface including menstrual cycling, decidualization, embryo implantation and pregnancy maintenance. Moreover, disorders in these events may eventually lead to failure of pregnancy. Although the improvement of assisted conception and embryo culture technologies bring hope to many infertile couples, some unfavorable outcomes, such as recurrent implantation failure (RIF), recurrent pregnancy loss (RPL) or recurrent miscarriage (RM), keep troubling the clinicians and patients. Recently, in vitro three-dimensional (3D) model mimicking the microenvironment of the maternal–fetal interface is developed to investigate the physiological and pathological conditions of conception and pregnancy. The progress of this technology is based on clarifying the role of ECM in the endometrium and the interaction between endometrium and conceptus. Focusing on collagen, the present review summarized the degradation and regulation of ECM and its role in normal menstruation, endometrium receptivity and unsatisfying events occurring in infertility treatments, as well as the application in therapeutic approaches to improve pregnancy outcomes. More investigations about ECM focusing on the maternal–fetal interface interaction with mesenchymal stem cells or local immunoregulation may inspire new thoughts and advancements in the clinical application of infertility treatments. Graphical abstract

Crohn's Disease (CD) and Ulcerative Colitis (UC) are the two major forms of inflammatory bowel disease (IBD), which are incurable chronic immune-mediated diseases of the gastrointestinal tract. Both diseases present with chronic inflammation that leads to epithelial barrier dysfunction accompanied by loss of immune tolerance and inflammatory damage to the mucosa of the GI tract. Despite extensive research in the field, some of the mechanisms associated with the pathology in IBD remain elusive. Here, we identified a mechanism by which the MAPK-activated protein kinase 2 (MK2) pathway contributes to disease pathology in CD by regulating the expression of matrix metalloproteinases (MMPs), which cleave checkpoint molecules on immune cells and enhance T cell activity. By utilizing pharmaceuticals targeting MMPs and MK2, we show that the cleavage of checkpoint molecules and enhanced T cell responses may be reduced. The data presented here suggest the potential for MK2 inhibitors as a therapeutic approach for the treatment of CD. [ABSTRACT FROM AUTHOR]

Cancer is a predominant cause of mortality all over the world. Lung, prostate, and colorectal cancer are the more frequent in men while breast and colorectal have a high incidence in women. Major progress aside, some cancers are still frequent and one major issue is improvements in detection methods. Imaging techniques have a major role, but inflammatory, tumoral markers and calculated scores may contribute to the assessment of prognosis. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and carcinoembryonic antigen cell adhesion molecule (CEACAM) have been used for decades and do not have a clear use for diagnosis or prognosis yet. The CEACAM family includes 12 human members, and some of them have a cluster differentiation (CD). CD66 may be an interesting indicator of disease severity. Beside interleukin-6 (IL-6), the high level of which is observed in patients with a high mortality rate, other cytokines IL-17A, IL-22, and transforming growth factor -β (TGF-β) are expressed at the tumor level. The detection of circulating tumor cells has been improved but is still of undetermined value. Circulating tumor DNA (ctDNA) was recently studied in CRC stage II patients and may be helpful for chemotherapy management. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.

Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases. [ABSTRACT FROM AUTHOR]

The pathophysiology of post-traumatic arthritis (PTOA) is not fully understood. This study used non-invasive repetitive mechanical loading (ML) mouse models to study biochemical, biomechanical, and pain-related behavioral changes induced in mice. Mouse models reflected the effects of the early stages of PTOA in humans. For the PTOA model, cyclic comprehensive loading (9N) was applied to each mouse's left knee joint. ML-induced biochemical and molecular changes were analyzed after loading completion. Cartilage samples were examined using gene expression analysis. Tissue sections were used in subsequent OA severity scoring. Biomechanical features and pain-related behavior were studied after 24 h and three weeks post-ML sessions to examine the development of PTOA. The loaded left knee joint showed a greater ROS/RNS signal than the right knee, which was not loaded. There was a significant increase in cartilage damage and MMP activity in the mechanically loaded joints relative to non-loaded control knee joints. Similarly, we found a difference in the viscoelastic tangent, which highlights significant changes in mechanical properties. Biochemical analyses revealed significant increases in total NO, caspase-3 activity, H2O2, and PGE2 levels. Gene expression analysis highlighted increased catabolism (MMP-13, IL-1β, TNF-α) with a concomitant decrease in anabolism (ACAN, COL2A1). Histopathology scores clearly indicated increases in OA progression and synovitis. The gait pattern was significantly altered, suggesting signs of joint damage. This study showed that biomechanical, biochemical, and behavioral characteristics of the murine PTOA groups are significantly different from the control group. These results confirm that the current mouse model can be considered for translational PTOA studies. [ABSTRACT FROM AUTHOR]

Hematopoietic stem/progenitor cells (HSPCs) originate from endothelial cells (ECs) localized on the ventral side of the dorsal aorta (DA), and hemodynamic parameters may suffer sharp changes in DA at HSPCs development stage for intersegmental vessel formation. However, the temporal-spatial shear stress parameters and biomechanics mechanisms of HSPC budding remain unknown. Here, we found that the hematopoietic endothelium (HE) in the aorta-gonad-mesonephros was heterogeneous; that is, HEs were mainly distributed at the ventral side of the vascular bifurcation in zebrafish embryos, which was found to show low shear stress (LSS) through numerical simulation analysis. Furthermore, HSPCs localized in the posterior somite of aorta-gonad-mesonephros with slow velocity. On the temporal scale, there was a slow velocity and LSS during HE budding from 36 h post-fertilization and decreased shear stress with drug expanded HSPC numbers. Mechanistically, matrix metalloproteinase (MMP) expression and macrophage chemotaxis were significantly increased in HEs by RNA-seq. After treatment with an MMP13 inhibitor, HSPCs were significantly reduced in both the aorta-gonad-mesonephros and caudal hematopoietic tissue in embryos. Our results show that HSPC budding is heterogeneous, and the mechanism is that physiological LSS controls the emergence of HSPCs by promoting the accumulation of macrophages and subsequent MMP expression. [ABSTRACT FROM AUTHOR]

Metastasis is a multisequential process that allows tumor cells to migrate to tissues distant from the primary tumor. Only a small number of cells escape from the primary tumor; however, the metastases generated are responsible for more than 90% of cancer deaths. Many metastatic processes initially require the total or partial start‐up of a program for the transformation of tumor epithelial cells into mesenchymal cells (EMT). The launching of the EMT program is stimulated by cytokines and other elements produced by the diverse types of cells composing the tumor stroma. In parallel, a process of destabilization of the extracellular matrix (ECM) takes place by means of the synthesis of proteases of the matrix metalloproteinases (MMPs) family. EMC degradation allows the exportation of some tumor cells as mesenchymal cells to the circulatory system and their subsequent implantation in a tissue distant from the primary tumor. The blocking of these both processes appears as a hypothetical stop point in the metastatic mechanism. The present review deals with the different options to achieve the inhibition of MMPs, focusing on MMP7 as a target given its involvement in the metastatic processes of a wide variety of tumors. Significance statement: The simultaneous implantation of the epithelial–mesenchymal program and the synthesis and activation of matrix metalloproteinases during the first phases of the metastasis process is known. The inhibition of proteases could constitute a possible blockage of the process. The review describes the evolution of the different inhibition mechanisms that could inform applicable therapeutic mechanisms for the paralysis of the metastatic process. [ABSTRACT FROM AUTHOR]

Simple Summary: Atypical teratoid rhabdoid tumor (ATRT) is a deadly type of human pediatric brain cancer without effective treatments. ATRT is mainly linked to the inactivation of a tumor suppressor gene, SMARCB1; however, additional biomarkers remain to be identified to develop novel therapeutic strategies. Therefore, different tumor antigens and extracellular matrix modulators were investigated in two human ATRT and one kidney malignant rhabdoid tumor cell lines and compared with the nonmalignant HEK293 cell line. Alpha-fetoprotein (AFP), mucin-16 (MUC16 or cancer antigen 125/CA125), osteopontin (OPN), and mesothelin (MSLN) are highly expressed in these human malignant rhabdoid cancer cell lines. Inhibiting MMPs using a small-molecule inhibitor decreased cell survival. This biomarker discovery process may lead to the identification of novel diagnostic and therapeutic strategies, such as the development of targeted and immunotherapies against cancer biomarkers, to treat cancer patients. Introduction: Atypical teratoid rhabdoid tumor (ATRT) is a lethal type of malignant rhabdoid tumor in the brain, seen mostly in children under two years old. ATRT is mainly linked to the biallelic inactivation of the SMARCB1 gene. To understand the deadly characteristics of ATRT and develop novel diagnostic and immunotherapy strategies for the treatment of ATRT, this study investigated tumor antigens, such as alpha-fetoprotein (AFP), mucin-16 (MUC16/CA125), and osteopontin (OPN), and extracellular matrix modulators, such as matrix metalloproteinases (MMPs), in different human malignant rhabdoid tumor cell lines. In addition, the roles of MMPs were also examined. Materials and methods: Five human cell lines were chosen for this study, including two ATRT cell lines, CHLA-02-ATRT and CHLA-05-ATRT; a kidney malignant rhabdoid tumor cell line, G401; and two control cell lines, human embryonic kidney HEK293 and HEK293T. Both ATRT cell lines were treated with a broad-spectrum MMP inhibitor, GM6001, to investigate the effect of MMPs on cell proliferation, viability, and expression of tumor antigens and biomarkers. Gene expression was examined using a reverse transcription polymerase chain reaction (RT-PCR), and protein expression was characterized by immunocytochemistry and flow cytometry. Results: All the rhabdoid tumor cell lines tested had high gene expression levels of MUC16, OPN, AFP, and MSLN. Low expression levels of neuron-specific enolase (ENO2) by the two ATRT cell lines demonstrated their lack of neuronal genotype. Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were highly expressed in these malignant rhabdoid tumor cells, indicating their invasive phenotypes. GM6001 significantly decreased ATRT cell proliferation and the gene expression of MSLN, OPN, and several mesenchymal markers, suggesting that inhibition of MMPs may reduce the aggressiveness of rhabdoid cancer cells. Conclusion: The results obtained from this study may advance our knowledge of the molecular landscapes of human malignant rhabdoid tumors and their biomarkers for effective diagnosis and treatment. This work analyzed the expression of human malignant rhabdoid tumor antigens that may serve as biomarkers for the development of novel therapeutic strategies, such as cancer vaccines and targeted and immunotherapies targeting osteopontin and mesothelin, for the treatment of patients with ATRT and other malignant rhabdoid tumors. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic periodontitis is associated with an increased risk for systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. During chronic periodontitis, endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis provokes monocyte accumulation and differentiation into macrophages and increased secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs). While normal levels of MMPs are important in cellular function, increased levels of cytokines and MMPs can cause connective tissue destruction. Results In the current study, we investigated the therapeutic capability of a novel semi-synthetic sulfated polysaccharide (SAGE) on the production of cytokines and MMPs by cultured human mononuclear cells and macrophages stimulated with endotoxin LPS produced by P. gingivalis, a periodontally-relevant cell culture model. Our research demonstrated SAGE inhibited the LPS induced synthesis of inflammatory mediators including TNF-α, IL-1β, PGE2, and MMP-9 in this periodontal-relevant cell culture model. In addition, TLR-2 and TLR-4 levels were also reduced with the SAGE treatment. Conclusions The therapeutic potential of this novel semi-synthetic sulfated polysaccharide compound may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases.

Ischaemic stroke characterises impulsive cerebral-region hypoxia due to deep intracerebral arteriole blockage, often accompanied by permanent cerebral infarction and cognitive impairment. Thrombolysis with recombinant tissue plasminogen activator (rtPA) and thrombectomy remain the only guidance-approved therapies. However, emerging data draws clear links between such therapies and haemorrhage transformation, which occur when cerebral vasculature is damaged during ischaemia/reperfusion. Studies have shown that matrix metalloproteinases (MMPs) play a significant role in haemorrhage transformation, by depleting the extracellular matrix (ECM) and disrupting the blood brain barrier (BBB). Inhibitors of MMPs may be used to prevent ischaemic stroke patients from BBB disruption and haemorrhage transformation, particularly for those receiving rtPA treatment. Preclinical studies found that inhibition of MMPs with agents or in knock out mice, effectively reduced BBB disruption and infarct volume, leading to improved ischaemic stroke outcomes. At present, MMP inhibition is not an approved therapy for stroke patients. There remain concerns about timing, dosing, duration of MMP inhibition and selection of either broad spectrum or specific MMP inhibitors for stroke patients. This review aims to summarize current knowledge on MMP inhibition in ischaemic stroke and explore whether a broad spectrum or a specific MMP inhibitor should be used for ischaemic stroke patient treatment. It is crucial to inhibit MMP activities early and sufficiently to ensure BBB intact during ischaemia and reperfusion, but also to reduce side effects of MMP inhibitors to minimum. Recent advance in stroke therapy by thrombectomy could aid in such treatment with intra-arterially delivery of MMP inhibitors (and/or antioxidants). • MMP activation during ischaemic stroke disrupts BBB leading to haemorrhagic transformation. • Pharmacological inhibition of MMP reduce BBB disruption and improve outcomes of ischaemic stroke in preclinical studies. • MMP-2 and MMP-9 are well studied for their roles in BBB disruption, while other isoforms also participate in stroke pathophysiology. • The "ideal" MMP inhibitors would inhibit specific MMP isoforms and sufficiently prevent BBB from disruption. • Thrombectomy can be used to deliver the MMP inhibitors (and/or anti-oxidants) locally to avoid systemic side effects. [ABSTRACT FROM AUTHOR]

Abstract The entry of blood-borne molecules into the brain is restricted by the blood–brain barrier (BBB). Various physical, transport and immune properties tightly regulate molecule movement between the blood and the brain to maintain brain homeostasis. A recent study utilizing a pan-endothelial, constitutive Tie2-Cre showed that paracellular passage of blood proteins into the brain is governed by endocytic and cell signaling protein low-density lipoprotein receptor–related protein 1 (LRP1). Taking advantage of conditional Slco1c1-CreER T2 specific to CNS endothelial cells and choroid plexus epithelial cells we now supplement previous results and show that brain endothelial Lrp1 ablation results in protease-mediated tight junction degradation, P-glycoprotein (P-gp) reduction and a loss of BBB integrity.

Purpose: The development of sensitive and non-invasive biomarkers for the early detection of CRC and determination of their role in the individual stages of CRC. Methods: MMP-9 expression in serum and tissue, and BDNF expression in plasma were detected using the ELISA method. MMP-9 and BDNF in the tissue were also determined by immunohistochemical staining. Results: To assess the balance between changes in survival and tumor progression, we compared BDNF/MMP-9 ratios in tissues of living and deceased individuals. The tissue BDNF/MMP-9 ratio (evaluated immunohistochemically) decreased significantly with the progression of the disease in living patients. The BDNF/MMP-9 ratio was statistically significantly reduced in stages II and III compared to the benign group. However, in deceased individuals, the ratio showed an opposite tendency. Conclusion: The determination of the tissue BDNF/MMP9 ratio can be used as a prognostic biomarker of CRC.

Extracellular matrix (ECM) is characterized as widespread, abundant, and pluripotent. Among ECM members, collagen is widely accepted as one of the most prominent components for its essential structural property that can provide a scaffold for other components of ECM and the rich biological functions, which has been extensively used in tissue engineering. Emerging evidence has shown that the balance of ECM degradation and remodeling is vital to regulations of maternal–fetal interface including menstrual cycling, decidualization, embryo implantation and pregnancy maintenance. Moreover, disorders in these events may eventually lead to failure of pregnancy. Although the improvement of assisted conception and embryo culture technologies bring hope to many infertile couples, some unfavorable outcomes, such as recurrent implantation failure (RIF), recurrent pregnancy loss (RPL) or recurrent miscarriage (RM), keep troubling the clinicians and patients. Recently, in vitro three-dimensional (3D) model mimicking the microenvironment of the maternal–fetal interface is developed to investigate the physiological and pathological conditions of conception and pregnancy. The progress of this technology is based on clarifying the role of ECM in the endometrium and the interaction between endometrium and conceptus. Focusing on collagen, the present review summarized the degradation and regulation of ECM and its role in normal menstruation, endometrium receptivity and unsatisfying events occurring in infertility treatments, as well as the application in therapeutic approaches to improve pregnancy outcomes. More investigations about ECM focusing on the maternal–fetal interface interaction with mesenchymal stem cells or local immunoregulation may inspire new thoughts and advancements in the clinical application of infertility treatments. [ABSTRACT FROM AUTHOR]

Chronic, non-healing wounds represent a challenging socio-economic burden, demanding innovative approaches for successful wound management. Resveratrol (RSV) represents a promising therapeutic candidate, but its therapeutic efficacy and clinical applicability have been hampered by its rapid degradation and/or depletion. Herein, RSV was encapsulated into poly(ε-caprolactone) (PCL) microparticles by electrospraying with the aim to prolong and preserve RSV's release/activity, without affecting its therapeutic properties. Electrospraying led to the fabrication of spherical (2 to 10 μm in size), negatively charged (<−1 mV), and quasi-monodisperse (PDI < 0.3) microparticles, with 60% RSV release after 28 days. Microencapsulation of RSV into PCL prevented its photochemical degradation and preserved its antioxidant properties over 72 h. The RSV-PCL microparticles did not exhibit any cytotoxicity on human dermal fibroblasts. RSV released from the microparticles was biologically functional and induced a significant increase in collagen type I deposition. Furthermore, the produced RSV-PCL microparticles reduced the expression of inflammatory (IL-6, IL-8, COX-2) and proteolytic (MMP-2, MMP-9) mediators. Collectively, our data clearly illustrate the potential of electrosprayed polymeric carriers for the sustained delivery of RSV to treat chronic wounds. [ABSTRACT FROM AUTHOR]

Abstract Objective Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. They exhibit proteolytic activity implicating the efficiency of trophoblast invasion to the uterine wall involving marked hemodynamic and uterine changes. In this pilot study sera of 13 women with normal pregnancy was analyzed to evaluate the usage of MMPs as diagnostic tool. The concentrations of circulating MMP-9, MMP-2/TIMP-2 complex and TIMP-1 in different time points during normal pregnancy has not been studied. The serum levels of MMP-9, TIMP-1, TIMP-2 and MMP-2/TIMP-2 complex were determined by enzyme-linked immunosorbent assay (ELISA). Using the same method, we have shown that serum MMPs are elevated in spontaneous early pregnancy failure as compared to normal pregnancy. Results The serum levels of MMP-9 and TIMP-1 were stable throughout pregnancy. The level of MMP-2/TIMP-2 complex was slightly increased after week 15 without statistical significance. For our best knowledge, this is a first study of the serum levels of MMP-9, MMP-2/TIMP-2 and TIMP-1 on different time points during normal pregnancy. Further measurements with the correlation to the outcome of the pregnancy are needed.