Extracellular Matrix Metalloproteinase Research Articles

Chronic cerebral hypoperfusion alters the CypA-EMMPRIN-gelatinase pathway: Implications for vascular dementia

Chronic cerebral hypoperfusion (CCH) is postulated to underlie multiple pathophysiological processes in vascular dementia (VaD), including extracellular matrix dysfunction. While several extracellular matrix proteins, namely cyclophilin A (CypA), extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases (matrix metalloproteinases, MMP-2 and -9) have been investigated in acute stroke, their involvement in CCH and VaD remains unclear. In this study, CypA-EMMPRIN-gelatinase proteins were analysed in a clinical cohort of 36 aged, cognitively unimpaired subjects and 48 VaD patients, as well as in a bilateral carotid artery stenosis mouse model of CCH. Lower CypA and higher EMMPRIN levels were found in both VaD serum and CCH mouse brain. Furthermore, gelatinases were differentially altered in CCH mice and VaD patients, with significant MMP-2 increase in CCH brain and serum, whilst serum MMP-9 was elevated in VaD but reduced in CCH, suggesting complex CypA-EMMPRIN-gelatinase regulatory mechanisms. Interestingly, subjects with cortical infarcts had higher serum MMP-2, while white matter hyperintensities, cortical infarcts and lacunes were associated with higher serum MMP-9. Taken together, our data indicate that perturbations of CypA-EMMPRIN signalling may be associated with gelatinase-mediated vascular sequelae, highlighting the potential utility of the CypA-EMMPRIN-gelatinase pathway as clinical biomarkers and therapeutic targets in VaD.

Elevated EMMPRIN Serum Levels Indicate Plaque Vulnerability in Patients With Asymptomatic High Grade Carotid Stenosis

Carotid atherosclerosis is an important cause of cerebral ischaemic stroke. Sonographic plaque characteristics are inappropriate for exact prediction of possible future ischaemic events. Additional markers are needed to predict the clinical outcome in high grade carotid stenosis. This study aimed to test extracellular matrix metalloproteinase inducer (EMMPRIN), due to its involvement in plaque formation and destabilisation, as a potential marker of high risk vulnerable plaques. EMMPRIN was analysed in pre-operative serum samples from patients with symptomatic and asymptomatic carotid artery stenosis by a specific ELISA. Pre-operative duplex sonography classified the atherosclerotic plaque due to echogenicity. Histopathological analysis of vulnerable and non-vulnerable plaques was based on the American Heart Association (AHA) classification. The study included 265 patients undergoing carotid endarterectomy: 90 (m:f, 69:21) patients with symptomatic and 175 (m:f, 118:57) with asymptomatic disease. Analysis of circulating EMMPRIN revealed significantly higher levels in patients with echolucent plaques (4 480; IQR 3 745, 6 144 pg/mL) compared with echogenic plaques (4 159; IQR 3 418, 5 402 pg/mL; p= .025). Asymptomatic patients with vulnerable plaques had significantly higher levels of EMMPRIN (4 875; IQR 3 850, 7 016 pg/mL) compared with non-vulnerable plaques (4 109; IQR 3 433, 5 402 pg/mL; p < .001). In logistic regression analysis, duplex sonography combined with age, gender, and clinical risk factors predicted vulnerable plaques in asymptomatic patients with an AUC of 0.71 (95% CI 0.61 - 0.80). EMMPRIN significantly improved the AUC in asymptomatic patients (AUC 0.79; 95% CI 0.71 - 0.87; p= .014). Patients with high risk plaques according to ultrasound and histopathological characteristics demonstrated increased serum EMMPRIN levels. EMMPRIN on top of clinical risk factors, including age, gender, and duplex sonography may be used for pre-operative risk stratification in asymptomatic patients.

Factors Associated with RANTES, EMMPIRIN, MMP2 and MMP9, and the Association of These Biomarkers with Cardiovascular Disease in a Multi-Ethnic Population.

The growing cardiovascular disease (CVD) epidemic calls for further research to identify novel biomarkers for earlier detection and as potential therapeutic targets. Biomarkers Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMP-2, and MMP-9) are linked to proatherogenic and proinflammatory pathways of CVD development, the majority of which are coronary artery disease (CAD) and stroke. We evaluated potential factors affecting these four biomarkers and established their association with CVD. This is a cross-sectional analysis using a nested case-control design involving 580 participants aged 21-75 years from the prospective multi-ethnic cohort study. A total of 290 CVD cases and 290 age-and sex-matched controls were identified. All participants underwent interviews, health screenings, and provided blood samples, including biomarkers RANTES, EMMPRIN, and MMPs. CVD was defined based on previous medical history. The average age of the participants was 55.7(SD = 10.3) years of age, and 34.6% were female. Arrhythmia history and low-density lipoprotein (LDL) levels were significant factors of logEMMPRIN (β = -0.124 [-0.245, -0.003] and β = 0.111 [0.0, 0.191], respectively). Only female sex (β = 0.189 [0.078, 0.300]) for logRANTES and age (β = 0.033 [0.010, 0.055]) for logMMP-2 and logMMP-9 were significant. The Indian ethnicity (β = 0.192 [0.048, 0.335]) and highly sensitive C-reactive protein (hs-CRP) levels (β = 0.063 [0.011, 0.116]) were statistically significant for logMMP-9. No association was detected between biomarkers and CVD. In this multi-ethnic study cohort, RANTES was associated with sex, EMMPRIN was associated with a history of arrhythmia and LDL levels, MMP-2 with age, and MMP-9 with ethnicity and hs-CRP levels. The biomarker serum levels were not associated with CVD.

Correlation between Extracellular Matrix Metalloproteinase Inducer in Peripheral Blood and Serum MMPs in patients with Acute Coronary Syndrome.

This research aimed to investigate the expression level of Extracellular matrix metalloproteinase inducer (EMMPRIN) in peripheral blood and matrix metalloproteinases (MMPs) in the serum of patients with acute coronary syndrome, and to clarify the relationship between them, so as to analyze the pathogenesis of the coronary syndrome. For this purpose, 232 patients (patient group) with the acute coronary syndrome (ACS) diagnosed in the cardiology department of our hospital from May 2020 to March 2021 were collected, and the coronary angiography results of 76 healthy people (healthy group) were collected at the same time, and the index differences between the two groups were compared. First, compare the EMMPRIN expression level of the two groups of subjects, including EMMPRIN on the surface of platelets and monocytes. Second, analyze the difference in MMPs expression level between the two groups, and compare the difference of EMMPRIN and MMPs expression levels in different types of patients according to the disease type. Finally, correlation analysis was used to evaluate the correlation between EMMPRIN and MMPs expression levels in patients, and the ability of mutual regulation between them was analyzed. Results showed that The expression levels of EMMPRIN and MMPs in patients were significantly different from those in healthy patients (P<0.05), and the expression levels of EMMPRIN and MMPs in different types of patients were significantly different (P<0.05). The distribution of coronary plaque in different types of patients was significantly different, and the expression levels of EMMPRIN and MMPs in patients with a different coronary plaque were significantly different (P<0.05). There was a positive correlation between EMMPRIN on the platelet surface and MMPs expression in serum, and a positive correlation between EMMPRIN on the monocyte surface and MMPs expression in serum. In conclusion, the peripheral blood EMMPRIN and serum MMPs in patients with acute coronary syndrome were significantly higher than those in healthy people, and the expression of EMMPRIN in patients with the acute coronary syndrome was positively correlated with serum MMPs.

Utility of Matrix Metalloproteinases in the Diagnosis, Monitoring and Prognosis of Ovarian Cancer Patients.

Ovarian cancer is one of the most common gynecologic malignancies. It is characterized by a high mortality rate, which is mainly due to the asymptomatic course of the disease. In light of the high mortality rate and increasing morbidity, new diagnostic methods are being explored to enable earlier detection, better monitoring, and improved prognosis. Such diagnostic methods include the assessment of tumor markers in various biological samples. Among the markers currently being investigated, extracellular matrix metalloproteinases (MMPs) are of particular interest. The objective of this article was to compile the existing knowledge of MMPs in ovarian cancer patients and to describe their potential diagnostic utility. Additionally, this article provides an overview of the symptoms, complications, and risk factors associated with ovarian cancer and the role of MMPs in physiology and pathology. Preliminary results indicate that tissue expression and blood and body fluid levels of MMPs may be different in ovarian cancer patients than in healthy women. The expression and concentration of individual MMPs have been shown to be correlated with cancer stage and disease severity. In addition, the preliminary value of some of these enzymes in predicting prognosis is discussed. However, as the amount of data is limited, more studies are needed to fully evaluate the potential function of individual MMPs in ovarian cancer patients. Based on the knowledge gathered for this article, it seems that MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, are tentatively the most useful. A thorough evaluation of their utility as modern biomarkers in ovarian cancer requires further investigation.

Low-dose telomerase is required for the expansion and migration of placental mesenchymal stem cells

Telomerase is activated in pluripotent stem cells and the majority of tumors and is postulated to be necessary for the acquisition of self-renewal and long-term proliferation. Placental mesenchymal stem cells (PMSCs) are very promising in regenerative medicine owing to their great capacity for self-renewal and differentiation potential. Although telomerase activity in the placenta is naturally low, it remains unclear whether telomerase activity is required for the properties of PMSCs. We herein isolated and identified a PMSC line carrying compound heterozygote variations in hTERT (DC-PMSCs) that lost telomerase activity, showed a typical surface phenotype of MSCs, and was able to differentiate into multiple cell lineages. DC-PMSCs showed accelerated telomere erosion, advanced senescence, and diminished migratory and invasive capabilities. RNA-seq identified 361 differentially expressed genes between DC-PMSCs and control groups, most of which were enriched in extracellular matrix, ECM, and related pathways. Knockdown of telomerase subunit genes in PMSCs confirmed the phenotype and attenuated the expression of extracellular matrix components and matrix metalloproteases. Our results suggest that low telomerase activity is not essential for the properties of MSCs, but that it is required for community maintenance and for the migration of PMSCs.

Differential proMMP-2 and proMMP-9 secretion in human pre-implantation embryos at day 5 of development.

Morphological development is the most common non-invasive criterion used to select in vitro human embryos for implantation. With this criterion, however, embryos in cellular arrest go unnoticed. A more accurate criterion is needed to improve the success rate of implantation. Extracellular matrix metalloproteases type 2 (MMP-2) and MMP-9 are key markers of embryonic development and the implantation process, according to various animal studies. The first objective of this study was to examine proMMP-2 and proMMP-9 activity in the culture media of human embryos with good morphological development. Secondly, the results of proMMP-2 and proMMP-9 activity in the culture medium were compared between pregnant and non-pregnant. Forty-two patients were approved by the Ethics and Research Committees of the Instituto Nacional de Perinatología in México City hospital, based on institutional inclusion criteria for in vitro fertilization. On day 5 of development, embryos were transferred to patients, and the culture media secretion profile of proMMP-2 and proMMP-9 activity was determined by substrate gel zymography. After analysis of embryo sac development, each patient was assigned to the pregnant (n=17) or non-pregnant (n=25) group. Our results demonstrate that proMMP-2 was active in the culture media corresponding to all 17 women achieving full-term pregnancy and proMMP-9 in the media corresponding to 11 of these women. Contrarily proMMP-2 and proMMP-9 were active in the culture media corresponding to 3 and 11 of the 25 non-pregnant patients, respectively. The clinical implications of this study suggest the activity evaluation of proMMP-2 and proMMP-9 in embryonic culture media on day 5 of development appears to be a reliable indicator of the quality of embryos and their capacity to establish a pregnancy.

Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage.

Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.

COVID-19 and oral cancer: Critical viewpoint.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has marked the beginning of a new pandemic named coronavirus disease 2019 (COVID-19). The World Health Organization has announced it as a health emergency that is of international concern. The disease has been reported to cause respiratory illness, pneumonia and even hinder the immunity of an individual. Individuals with disturbed immune responses have been found to be quite susceptible to this viral infection. Oral cancer patients are also at high risk in this pandemic situation and might encounter severe detrimental outcomes. Angiotensin receptors, documented in studies as the path of entry of this virus, are highly expressed in the epithelial cells of oral mucosa, making the group of individuals with oral cancers even more vulnerable. Extracellular matrix metalloproteinase inducer is another potential target for SARS-CoV-2. An exhaustion of angiotensin converting enzyme 2 cell receptors leads to protumoral effects, whereas a downregulation of extracellular matrix metalloproteinase inducer leads to antitumoral effects. Thus, it causes a variation of the biological behavior of the tumor. This article focusses on the molecular mechanisms, effects and patho-physiology of COVID-19 in oral squamous cell carcinoma patients. The different molecular changes in oral squamous cell carcinoma in the background of COVID-19 will modify various environmental factors for this pathology and have an effect on the carcinogenesis process. Understanding the behavior of the tumor will help plan advanced treatment strategies for oral squamous cell carcinoma patients in the background of COVID-19.

Molecularly Imprinted Nanoparticles towards MMP9 for Controlling Cardiac ECM after Myocardial Infarction: A Predictive Experimental-Computational Chemistry Investigation

The recent advances in nanotechnology are revolutionizing preventive and therapeutic approaches to treating cardiovascular diseases. Controlling the extracellular matrix metalloproteinase (MMP) activation and expression in the failing human left ventricular myocardium represents a significant therapeutic target for heart disease. In this study, we used molecularly imprinting polymers (MIPs) to restore the correct balance between MMPs and their tissue inhibitors (TIMPs), and explored the potential of this technique exhaustively through chemical synthesis, physicochemical and biological characterizations, and computational chemistry methods. By molecular dynamics simulations based on classical force fields, we simulated the early stages of the imprinting process in solution disclosing the pivotal interaction established between the monomers and the MMP9 protein template. The average interaction energies of methacrylic acid (MAA) and poly (ethylene glycol) ethyl ether methacrylate (PEG) units were in the ranges 17–22 and 30–37 kcal/mol, respectively. At low coverage, the PEG monomers seemed firmly anchored to the protein surface and were not displaced by water, while only about 20% of MAA was replaced by water. The synthesis of MIPs was successfully with a monomer conversion higher than 99% and the production of spherical particles with average diameter of 344 ± 33 nm. HPLC analysis showed a specific recognition factor of MMP9 on MIPs of about 1.3. FT-IR Chemical Imaging confirmed the mechanisms necessary to generate a “selective memory” of the MIPs towards the enzyme. HPLC results indicated that the rebound amount of both TIMP1 and MMP2 to MIPs is lower than that of the template, showing a selectivity factor of 2.1 and 2.3, respectively. Preliminary tests on the effect of MIPs on H9C2 cells revealed that this treatment has no cytotoxic effects.

CURRENT INSIGHTS INTO TUMOR MICROENVIRONMENT OF MUCOEPIDERMOID CARCINOMAS OF SALIVARY GLAND

Objectives Mucoepidermoid carcinoma (MEC) is the most common salivary gland tumor in both adults and children. The aim was to review the current insights and components of the tumor microenvironment (TME) of MEC, its molecular alterations concomitant with its cellular interactions, and the clinical implications of these findings. Study Design A database search was performed retrieving studies that evaluated the pathophysiology of TME in salivary gland MEC. Results MEC consists of a diversity of immune cells (lymphocytes T and NK) and their immune checkpoints (especially PD1 and PD-L1), cancer-associated fibroblasts, cytokines (IL-6), chemokines (CCR4 and CCR7), growth factors (FGF-1 and FGF-2), extracellular matrix proteins and metalloproteinases (MMP-1 and MMP-13), and tumor associated macrophages. These TME components form complex interactions that mainly prevent effective antitumor immunity and promote cancer progression. Conclusions Although most studies showed that TAM in MEC are associated to tumor progression, the presence of T cells and immune checkpoints in the tumor microenvironment varied across studies. The complexity and heterogeneity of the tumor microenvironment at various stages of MEC tumorigenesis remain to be characterized in greater detail for development of efficient therapeutic strategies to treat patients. Mucoepidermoid carcinoma (MEC) is the most common salivary gland tumor in both adults and children. The aim was to review the current insights and components of the tumor microenvironment (TME) of MEC, its molecular alterations concomitant with its cellular interactions, and the clinical implications of these findings. A database search was performed retrieving studies that evaluated the pathophysiology of TME in salivary gland MEC. MEC consists of a diversity of immune cells (lymphocytes T and NK) and their immune checkpoints (especially PD1 and PD-L1), cancer-associated fibroblasts, cytokines (IL-6), chemokines (CCR4 and CCR7), growth factors (FGF-1 and FGF-2), extracellular matrix proteins and metalloproteinases (MMP-1 and MMP-13), and tumor associated macrophages. These TME components form complex interactions that mainly prevent effective antitumor immunity and promote cancer progression. Although most studies showed that TAM in MEC are associated to tumor progression, the presence of T cells and immune checkpoints in the tumor microenvironment varied across studies. The complexity and heterogeneity of the tumor microenvironment at various stages of MEC tumorigenesis remain to be characterized in greater detail for development of efficient therapeutic strategies to treat patients.

Modulation of Fibroblast Phenotype by Colorectal Cancer Cell-Secreted Factors Is Mostly Independent of Oncogenic KRAS.

KRAS mutations have been shown to extend their oncogenic effects beyond the cancer cell, influencing the tumor microenvironment. Herein, we studied the impact of mutant KRAS on the modulation of the pro-tumorigenic properties of cancer-associated fibroblasts (CAFs), including α-SMA expression, TGFβ1 and HGF production, extracellular matrix components and metalloproteinases expression as well as collagen contraction and migration capacities. To do so, CCD-18Co normal-like colon fibroblasts were challenged with conditioned media from control and KRAS silenced colorectal cancer (CRC) cells. Our results showed that the mutant KRAS CRC cell-secreted factors were capable of turning normal-like fibroblasts into CAF-like by modulating the α-SMA expression, TGFβ1 and HGF production and migration capacity. Oncogenic KRAS played a secondary role as its silencing did not completely impair the capacity of CRC cells to modulate most of the fibroblast properties analyzed. In summary, our work suggests that mutant KRAS does not play a major role in controlling the CRC cell-secreted factors that modulate the behavior of fibroblasts. The fact that CRC cells retain the capacity to modulate the pro-tumorigenic features of fibroblasts independently of KRAS silencing is likely to negatively impact their response to KRAS inhibitors, thus standing as a putative mechanism of resistance to KRAS inhibition with potential therapeutical relevance.

Theories and Molecular Basis of Vascular Aging: A Review of the Literature from VascAgeNet Group on Pathophysiological Mechanisms of Vascular Aging.

Vascular aging, characterized by structural and functional alterations of the vascular wall, is a hallmark of aging and is tightly related to the development of cardiovascular mortality and age-associated vascular pathologies. Over the last years, extensive and ongoing research has highlighted several sophisticated molecular mechanisms that are involved in the pathophysiology of vascular aging. A more thorough understanding of these mechanisms could help to provide a new insight into the complex biology of this non-reversible vascular process and direct future interventions to improve longevity. In this review, we discuss the role of the most important molecular pathways involved in vascular ageing including oxidative stress, vascular inflammation, extracellular matrix metalloproteinases activity, epigenetic regulation, telomere shortening, senescence and autophagy.

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

Cluster of differentiation (CD)147, also termed extracellular matrix metalloprotease inducer or basigin, is a glycoprotein ubiquitously expressed throughout the human body, the oral cavity included. CD147 actively participates in physiological tissue development or growth and has important roles in reactive processes such as inflammation, immunity, and tissue repair. It is worth noting that deregulated expression and/or activity of CD147 is observed in chronic inflammatory or degenerative diseases, as well as in neoplasms. Among the latter, oral squamous cell carcinoma (OSCC) is characterized by an upregulation of CD147 in both the neoplastic and normal cells constituting the tumor mass. Most interestingly, the expression and/or activity of CD147 gradually increase as healthy oral mucosa becomes inflamed; hyperplastic/dysplastic lesions are then set on, and, eventually, OSCC develops. Based on these findings, here we summarize published studies which evaluate whether CD147 could be employed as a marker to monitor OSCC development and progression. Moreover, we describe CD147-promoted cellular and molecular events which are relevant to oral carcinogenesis, with the aim to provide useful information for assessing whether CD147 may be the target of novel therapeutic approaches directed against OSCC.

Enhanced susceptibility of SARS-CoV-2 spike RBD protein assay targeted by cellular receptors ACE2 and CD147: Multivariate data analysis of multisine impedimetric response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cells through the binding of spike protein to the host cell surface-expressing angiotensin-converting enzyme 2 (ACE2) or by endocytosis mediated by extracellular matrix metalloproteinase inducer (CD147). We present extended statistical studies of the multisine dynamic electrochemical impedance spectroscopy (DEIS) revealing interactions between Spike RBD and cellular receptors ACE2 and CD147, and a reference anti-RBD antibody (IgG2B) based on a functionalised boron-doped diamond (BDD) electrode. The DEIS was supported by a multivariate data analysis of a SARS-CoV-2 Spike RBD assay and cross-correlated with the atomic-level information revealed by molecular dynamics simulations. This approach allowed us to study and detect subtle changes in the electrical properties responsible for the susceptibility of cellular receptors to SARS-CoV-2, revealing their interactions. Changes in electrical homogeneity in the function of the RBD concentration led to the conclusion that the ACE2 receptor delivers the most homogeneous surface, delivered by the high electrostatic potential of the relevant docking regions. For higher RBD concentrations, the differences in electrical homogeneity between electrodes with different receptors vanish. Collectively, this study reveals interdependent virus entry pathways involving separately ACE2, CD147, and spike protein, as assessed using a biosensing platform for the rapid screening of cellular interactions (i.e. testing various mutations of SARS-CoV-2 or screening of therapeutic drugs).

Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure.

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.

Neuroprotective Effects of Chlorogenic Acid in a Mouse Model of Intracerebral Hemorrhage Associated with Reduced Extracellular Matrix Metalloproteinase Inducer.

Chlorogenic acid (CGA) has been reported to have various biological activities, such as anti-inflammatory, anti-oxidant and anti-apoptosis effects. However, the role of CGA in intracerebral hemorrhage (ICH) and the underlying mechanisms remain undiscovered. The current study aims to investigate the effect of CGA on neuroinflammation and neuronal apoptosis after inhibition of EMMPRIN in a collagenase-induced ICH mouse model. Dose optimization data showed that intraperitoneal administration of CGA (30 mg/kg) significantly attenuated neurological impairments and reduced brain water content at 24 h and 72 h compared with ICH mice given vehicle. Western blot and immunofluorescence analyses revealed that CGA remarkably decreased the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in perihematomal areas at 72 h after ICH. CGA also reduced the expression of matrix metalloproteinases-2/9 (MMP-2/9) at 72 h after ICH. CGA diminished Evans blue dye extravasation and reduced the loss of zonula occludens-1 (ZO-1) and occludin. CGA-treated mice had fewer activated Iba-1-positive microglia and MPO-positive neutrophils. Finally, CGA suppressed cell death around the hematoma and reduced overall brain injury. These outcomes highlight that CGA treatment confers neuroprotection in ICH likely by inhibiting expression of EMMPRIN and MMP-2/9, and alleviating neuroinflammation, blood–brain barrier (BBB) disruption, cell death and brain injury.

The utility of metalloprotienase 9 (MMP-9) in diagnostics of ovarian cancer

Ovarian cancer is characterized by increasing morbidity and high mortality, which translates into the necessity of searching and implementing new methods enabling early detection and effective treatment of this cancer. Such methods may include the determination of tumour markers, such as extracellular matrix metalloproteinases. In the diagnosis of ovarian cancer, metalloproteinase 9 (MMP-9) is of particular interest. MMP-9 is important in the process of carcinogenesis through its involvement in, among other things, tumour cell migration and invasion, metastasis formation, and angiogenesis. Preliminary results showed that tissue expression and serum levels of MMP-9 increase in patients with ovarian cancer, further correlating with stage and presence of metastases. However, more studies are needed to assess the usefulness of MMP-9, but the results already obtained show that it can be a useful parameter also in a combined analysis with markers standardly determined in the diagnosis of ovarian cancer, i.e. CA 125 and HE-4. The aim of this study is to present, based on literature data, the potential usefulness of MMP-9 in the diagnosis and monitoring of ovarian cancer.

Theranostic Contribution of Extracellular Matrix Metalloprotease Inducer-Paramagnetic Nanoparticles Against Acute Myocardial Infarction in a Pig Model of Coronary Ischemia-Reperfusion.

Background:Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion.Methods:In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion.Results:After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation.Conclusions:Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.