Inhibition of matrix metalloproteinases to reduce blood brain barrier disruption and haemorrhagic transformation in ischaemic stroke: Go broad or go narrow?

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).

Hydrogen Sulfide Modulation of Matrix Metalloproteinases and CD147/EMMPRIN: Mechanistic Pathways and Impact on Atherosclerosis Progression.

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.

[MMPs/pH synergically responsive XTS-Prussian blue nanoparticles inhibiting proliferation and migration of RAFLS assisted with laser irradiation].

Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 ℃, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.

Development and validation of matrix metalloproteinase for predicting prognosis and tumour microenvironment immune profiles in uterine corpus endometrial carcinoma.

Background: Matrix metalloproteinases (MMPs) are involved in many processes of tumour progression and invasion. However, few studies have analysed the effects of MMP expression patterns on endometrial cancer (EC) development from the perspective of the tumour microenvironment (TME). we quantified MMP expression in individual by constructing an MMP score and found MMP score effectively predict the prognosis of EC patients. Methods: MMPs expression profiles were determined based on the differential expression of 12 MMP-related regulators. Principal component analysis (PCA) was used to construct an MMP scoring system which can quantify the MMPs expression patterns individually of EC patients. Kaplan-Meier analysis, the log-rank test, and time-dependent receiver operating characteristic (ROC) curve analysis were used to evaluate the value of MMPs expression in predicting prognosis. Single-cell RNA sequencing (scRNA-seq) dataset was used to verify correlation between MMPs and progression of EC. Gene Ontology (GO) analysis was used to investigate the pathways and functions underlying MMPs expression. Tumour immune dysfunction, exclusion prediction, and pharmacotherapy response analyses were performed to assess the potential response to pharmacotherapy based on MMPs patterns. Results: We downloaded the MMPs expression data, somatic mutation data and corresponding clinical information of EC patients from the TCGA website and ICGC portal. Based on the MMP-related differentially expressed genes (DEGs), the MMP score was constructed, and EC patients were divided into high and low MMP score groups. There was a positive correlation between MMP score and prognosis of EC patients. Patients with high MMP scores had better prognosis, more abundant immune cell infiltration and stronger antitumoor immunity. Although prognosis is worse with the lower group than the high, patients with low MMP score had better response to immunotherapy, which means they could prolong the survival time through Immunological checkpoint blockade (ICB) therapy. scRNA-seq analysis identified significant heterogeneity between MMP score and classical pathways in EC. Conclusion: Our work indicates that the MMP score could be a potential tool to evaluate MMP expression patterns, immune cell infiltration, response to pharmacotherapy, clinicopathological features, and survival outcomes in EC. This will provide the more effective guide to select immunotherapeutic strategies of EC in the future.

Effects of 10-MDP calcium salt on osteoblasts and fibroblasts.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: These results suggest that applying 10-MDP-containing adhesives to subgingival fillings may be safe and beneficial for the periodontal tissues.

Current evidence on the relationships among five polymorphisms in the matrix metalloproteinases genes and prostate cancer 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.

Dimethyl α-Ketoglutarate Promotes the Synthesis of Collagen and Inhibits Metalloproteinases in HaCaT Cells.

We observed that treatment with dimethyl α-ketoglutarate (DMK) increased the amount of intracellular α-ketoglutarate significantly more than that of α-ketoglutarate in HaCaT cells. DMK also increased the level of intracellular 4-hydroxyproline and promoted the production of collagen in HaCaT cells. In addition, DMK decreased the production of collagenase and elastase and down-regulated the expression of selected matrix metalloproteinases (MMPs), such as MMP-1, MMP-9, MMP-10, and MMP-12, via transcriptional inhibition. The inhibition of MMPs by DMK was mediated by the suppression of the IL-1 signaling cascade, leading to the attenuation of ERK1/2 phosphorylation and AP-1 transactivation. Our study results illustrate that DMK, an alkylated derivative of α-ketoglutarate, increased the level of 4-hydroxyproline, promoted the production of collagen, and inhibited the expression of selected MMPs by affecting the IL-1 cascade and AP-1 transactivation in HaCaT cells. The results suggest that DMK might be useful as an anti-wrinkle ingredient.

Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma.

BACKGROUND: Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS: 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS: Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated ß-catenin signaling pathway in LCSCs. CONCLUSIONS: LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.

Mmp17-deficient mice exhibit heightened goblet cell effector expression in the colon and increased resistance to chronic Trichuris muris infection.

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-ß, 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.

Hydrogen sulfide inhibits the rupture of fetal membranes throngh anti-aging pathways.

INTRODUCTION: To investigate the relationship between hydrogen sulfide(H2S) and the senescence level of the fetal membranes, and to elucidate how H2S affects the integrity of the fetal membranes. METHODS: The H2S and the senescence levels of fetal membranes, and the expressions of H2S synthase CBS and CSE were detected in the preterm (PT) group and the preterm premature ruptured membranes (pPROM) group. The effects of H2S 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. RESULTS: The level of H2S in the fetal membranes in the pPROM group is significantly lower than that in the PT group matched for gestational age. The level of H2S is negatively correlated with the senescence level of fetal membranes. Treatment with H2S 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. DISCUSSION: Our study suggests that H2S, through its anti-aging effect, can influence the expression of MMPs and EMT, thereby contributing to the maintenance of fetal membrane integrity.

TIMP-1 Protects Tight Junctions of Brain Endothelial Cells From MMP-Mediated Degradation.

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.

S-nitrosylation of EMMPRIN influences the migration of HSCs and MMP activity in liver fibrosis.

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.

A review of current status of cell-based therapies for aortic aneurysms.

An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023).

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.

Stage-Dependent Levels of Brain-Derived Neurotrophic Factor and Matrix Metalloproteinase 9 in the Prognosis of Colorectal Cancer.

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.

Matrix disequilibrium in Alzheimer's disease and conditions that increase Alzheimer's disease risk.

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.

Actin cytoskeleton depolymerization increases matrix metalloproteinase gene expression in breast cancer cells by promoting translocation of cysteine-rich protein 2 to the nucleus.

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.

Antitumor Properties of Matrikines of Different Origins: Prospects and Problems of Their Application.

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.

Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

BACKGROUND: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. OBJECTIVE: In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. METHODS: The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. RESULTS: The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. CONCLUSION: Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

A self-etch bonding system with potential to eliminate selective etching and resist proteolytic degradation.

OBJECTIVES: Bonded restorations using self-etch (SE) systems exhibit a limited lifespan due to their susceptibility to hydrolytic, enzymatic or fatigue degradation and poor performance on enamel. This study was conducted to develop and assess the performance of a two-step SE system using a functional monomer bis[2-(methacryloyloxy)ethyl]phosphate (BMEP) and demonstrate a strategy to enhance stability of bonded resin composite restorations to both enamel and dentine. METHODS: A two-step SE system was formulated with a primer containing BMEP, with an adhesive with or without BMEP, and compared to a commercial 10-MDP-containing system, ClearfilTM SE Bond 2 (CFSE). The systems were evaluated on enamel for surface roughness and microshear bond strength (µSBS) and on dentine for microtensile bond strength (µTBS), nanoleakage, MMP inhibition and cyclic flexural fatigue. RESULTS: Whilst all bonding systems resulted in statistically similar µSBS, BMEP-based primers yielded greater enamel surface roughness than the CFSE primer. The BMEP-free adhesives resulted in statistically similar or higher µTBS and lower nanoleakage compared to CFSE. In situ zymography revealed minimal to no MMP activity within the hybrid layer of BMEP-based systems. The BMEP-free adhesive exhibited flexural strength and fatigue resistance statistically similar to CFSE. CONCLUSIONS: Incorporation of BMEP in the primer led to satisfactory bond strengths with both enamel and dentine, potentially eliminating the need for selective enamel etching. Combined with an adhesive formulation that is solvent-free and hydrophobic, and confining the acidic functional monomer in the primer resulted in minimal interfacial leakage, and resistance to proteolytic degradation and the cyclic nature of chewing. CLINICAL SIGNIFICANCE: The SE bonding system containing BMEP combines the potent etching of phosphoric acid with the therapeutic function of the phosphate-based monomer in creating a homogenous hybrid layer with protection against endogenous proteolytic enzymes. This strategy may overcome current challenges that arise during selective enamel etching.