MMPs Research Articles

Fabrication and Characterization of Electrospun DegraPol® Tubes Releasing TIMP-1 Protein to Modulate Tendon Healing

Background: Tendon rupture repair can result from fibrotic scar formation through imbalanced ECM deposition during remodeling. The tissue inhibitors of matrix metalloprotease (TIMPs) not only decrease ECM degradation, regulated by matrix metalloproteases (MMPs), but also restrict TGF-β1 activation and thus diminish fibrosis. Methods: Rabbit tenocytes (rbTenocytes) and rabbit adipose-derived stem cells (rbASCs) were cultivated under different TIMP-1 concentrations. Proliferation and gene expression were assessed. TIMP-1 was incorporated into emulsion electrospun DegraPol® (DP) tubes that were characterized by SEM for fiber thickness, pore size, and wall thickness. Static and dynamic water contact angles, FTIR spectra, and TIMP-1 release kinetics were determined. Results: While the proliferation of rbTenocytes and rbACS was not affected by TIMP-1 supplementation in vitro, the gene expression of Col1A1 was increased in rbTenocytes, the gene expression of ki67 was increased in both cell types, the gene expression of tenomodulin was increased in both cell types at 100 ng/mL TIMP-1, and alkaline phosphatase expression ALP rose significantly in rbASCs. Electrospun TIMP-1/DP fibers had a ~5 μm diameter, a ~10 μm pore size, and a mesh thickness of ~200 μm. TIMP-1/DP meshes were more hydrophilic than pure DP meshes. TIMP-1 was released from the meshes with a sustained release of up to 7 days. Conclusions: TIMP-1/DP tubes may be used to modulate the fibrotic tissue reaction when applied around conventionally sutured tendon ruptures.

Inhibition of matrix metalloproteases by a chemical cross-linker to halt the corneal degradation in keratoconus.

The need for better and simpler alternative crosslinking strategies to treat keratoconus (KC) is becoming essential as there is only a single approved way to treat it. Recently, conventional UV-A Riboflavin crosslinking is proven to have some disadvantages such as causing damage to the corneal endothelium and inducing keratocyte apoptosis. A chemical cross-linker (CXL) using carbodiimide chemistry and an octanedioic acid spacer is found effective in stiffening the cornea and has the potential to be developed as an alternative therapy to halt KC progression. In order to investigate the molecular changes induced by the cross-linker, we have analyzed the effect of the cross-linker on the activity of matrix metalloproteases (MMPs) in epithelial and stromal layers of KC corneas and in in vitro cellular systems to determine its role in stiffening the KC cornea. At well-optimized concentration, KC corneal buttons were treated with the CXL and the stiffening of the cornea was measured. The collagen fibril assembly in the stroma was analyzed using transmission electron microscopy and the activity of MMPs 2 and 9 were visualized using gelatin zymography. KC corneal fibroblasts in culture and tumor necrosis factor-α (TNF-α) induced human corneal epithelial (HCE) cell line were treated with CXL and secretion of MMPs 1, 2, 3 and 9 were analyzed by enzyme-linked immunosorbent assay (ELISA). We found that the CXL stiffened the KC corneas comparable to the normal corneas, with very less cytotoxicity. The collagen fiber assembly was reorganized in an orderly fashion and fibril density and diameter increased after CXL treatment. The activity of MMPs and cathepsin G in the epithelial and stromal layers of KC tissues decreased post-treatment. Secretion and activity of MMPs from the corneal epithelial and stromal cells after CXL treatment were significantly reduced while the epithelial lysyl oxidase activity increased. The CXL, intended to stop the KC progression, modified the extracellular matrix collagen assembly in the stroma and decreased the secretion of a group of metalloproteases and their activity. We have demonstrated a set of molecular changes effected by the CXL, which might aid in the stiffening of the KC cornea.

The zinc-finger transcription factor Blimp1/Prdm1 is required for uterine remodelling and repair in the mouse.

The zinc finger transcription factor Blimp1/PRDM1 regulates gene expression in diverse cell types. Its activity controls the maternal decidual response at early post-implantation stages of development. The present experiments demonstrate surprisingly that Blimp1 activity in the uterus is required for tissue remodelling at sites of embryonic failure. Moreover Blimp1 mutant females are refractory to RU486 induced decidual shedding. RNA-seq together with immunostaining experiments strongly suggest that the failure to up-regulate expression of the matrix metalloprotease Mmp10 in combination with insufficient suppression of BMP signalling, likely explain Blimp1-dependent phenotypic changes. In the post-partum uterus Blimp1 together with Mmp10 are highly upregulated at sites of tissue repair following placental detachment. Conditional Blimp1 removal significantly impairs the re-epithelization process and severely impacts involution of the endometrium and luminal epithelium. Overall these results identify Blimp1 as a master regulator of uterine tissue remodelling and repair.

MMP2 regulates proliferation and differentiation in chicken primary myoblasts, and RNA-seq screens for key genes.

The growth and development of chicken skeletal muscle directly affects chicken meat production, which is very important for broiler industry. Matrix metallopeptidase 2 (MMP2) exists in skeletal muscle. However, the underlying regulating of MMP2 remain unknown. In this study, MMP2 promoted cell proliferation and inhibited cell differentiation after overexpression in chicken primary myoblasts cells (CPMs). When MMP2 was knocked down, it inhibited CPMs proliferation and promoted cell differentiation. Subsequently, RNA sequencing (RNA-seq) and bioinformatics analysis were performed on overexpressing MMP2. We identified 265 up-regulated genes and 229 down-regulated genes. Based on the fragments per kilobase million (FPKM) ≥ 10, the retained data were analyzed by Pearson correlation analysis. MMP2 was positively correlated with carboxypeptidase M (CPM), MSTRG.14120 and aldehyde dehydrogenase 1 family member A3 (ALDH1A3), and the correlation coefficient was the highest (0.998). MMP2 was negatively correlated with hes family bHLH transcription factor 1 (HES1), and the correlation coefficient was the highest (0.998). Go term was enriched in cellular components or biogenesis, cellular processes, and cell aggregation. KEGG was significantly enriched to the cancer pathway. qRT-PCR analysis validated the transcriptomic results of RNA-seq. In conclusion, these results provided new insights into the molecular mechanisms by which MMP2 affected the proliferation and differentiation of chicken myoblasts.

Chronic high fat diet-induced cerebrovascular remodeling impairs recovery of blood flow after cerebral ischemia in mice.

Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9-/-) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9-/- mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO2) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO2. MMP-9-/- attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice.

Collagen turnover during cervical remodeling involves both intracellular and extracellular collagen degradation pathways.

Reproductive success requires accurately timed remodeling of the cervix to orchestrate the maintenance of pregnancy, the process of labor, and birth. Prior work in mice established that a combination of continuous turnover of fibrillar collagen and reduced formation of collagen cross-links allows for the gradual increase in tissue compliance and delivery of the fetus during labor. However, the mechanism for continuous collagen degradation to ensure turnover during cervical remodeling is still unknown. This study demonstrates the functional role of extracellular and intracellular collagen degradative pathways in two different settings of cervical remodeling: physiological term remodeling and inflammation-mediated premature remodeling. Extracellular collagen degradation is achieved by the activity of fibroblast-derived matrix metalloproteases MMP14, MMP2, and fibroblast activation protein (FAP). In parallel, we demonstrate the function of an intracellular collagen degradative pathway in fibroblast cells mediated by the collagen endocytic mannose receptor type-2 (MRC2). These pathways appear to be functionally redundant as loss of MRC2 does not obstruct collagen turnover or cervical function in pregnancy. While both extracellular and intracellular pathways are also utilized in inflammation-mediated premature cervical remodeling, the extracellular collagen degradation pathway uniquely employs fibroblast and immune-cell derived proteases. In sum, these findings identify the dual utilization of two distinct degradative pathways as a failsafe mechanism to achieve continuous collagen turnover in the cervix, thereby allowing dynamic shifts in cervical tissue mechanics and function.

Antioxidant and Anti-Inflammatory Impacts of Soft Tissue Crude Extract and Mucous of Snail Helix aspersa on an Excision Wound Model in Mice.

Wound healing is a complex natural process in which tissue requires recovering injured tissue cells. Helix aspersa has a high nutritional value and is considered a rich natural source of antioxidants and anti-inflammatory agents. So, this study aimed to assess the effect of soft tissue crude extract and mucous of H. aspersa topically applied as a gel for 12 days. The wounds were observed and photographed twice a week. The inflammatory, oxidative stress markers and matrix metalloproteinases were evaluated in skin tissue homogenate and CD3+ and CD69+ T lymphocytes were detected in wound tissue. Data showed that a comparison of applying soft tissue crude extract and mucous of H. aspersa to skin wounds enhanced the healing process, resulting in a significant decrease in dermal inflammation compared to untreated mice. Also, they significantly increased the antioxidant enzyme activities with reduced malondialdehyde (MDA) levels in wound tissues. The levels of matrix metalloproteases-2 and -9 were significantly decreased and the immune status was enhanced in the wound environment by increasing proportions of CD3+ and CD69+ T lymphocytes. H. aspersa mucous and soft tissue crude extract are viable substitutes for synthetic topical wound therapies with anti-inflammatory, antioxidant, and immunomodulatory potencies, with a preference for the crude soft tissue extract based on the outcomes.

Regulation of TGF-β1, PI3K/PIP3/Akt, Nrf-2/Keap-1 and NF-κB signaling pathways to avert bifenthrin induced hepatic injury: A palliative role of daidzein.

Bifenthrin (BFN) is a noxious insecticide which is reported to damage various body organs. Daidzein (DZN) is a natural flavone with excellent pharmacological properties. This research was conducted to evaluate the alleviative strength of DZN to counteract BFN prompted liver toxicity in male albino rats. Thirty-two rats were divided into 4 groups i.e., the control, BFN (7 mg /kg), BFN (7 mg/kg) + DZN (20 mg/kg) and DZN (20 mg/kg) alone group. The biochemical assessment was performed by using qRT PCR as well as standard ELISA protocols. The findings are validated by applying pharmacodynamic techniques including molecular simulation. It was observed that BFN reduced the gene expressions of phosphoinositide 3-kinase (PI3K), phosphatidylinositol-3, 4, 5-triphosphate (PIP3), Protein kinase B (Akt), nuclear factor erythroid 2-related factor 2 (Nrf-2) while promoting the gene expressions of Kelch-like ECH-associated protein 1 (Keap-1). Moreover, BFN notably reduced the activities of glutathione reductase (GSR), heme-oxygenase-1 (HO-1), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) while elevating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). BFN promoted the levels of matrix metallopeptidase 2 (MMP-2), Procollagen III N-terminal Pro-peptide (PIIINP), alkaline phosphatase (ALP), transforming growth factor-beta-1 (TGF-β1), aspartate aminotransferase (AST), tissue inhibitor of matrix metalloproteinases 1 (TIMP1), and alanine aminotransferase (ALT). The levels of nuclear factor- kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) were increased following the BFN intoxication. BFN enhanced the expressions of cysteine-aspartic acid protease-3 (Caspase-3) and Bcl-2-associated X protein (Bax) while suppressing the gene expression of B-cell lymphoma-2 (Bcl-2). Moreover, BFN disrupted the normal histology of liver tissues. Nonetheless, DZN treatment remarkably alleviated hepatic damages owing to its antioxidative, anti-apoptotic as well as anti-inflammatory abilities. However, DZN supplementation remarkably safeguarded which is further confirmed by in-silico assessment.

Functional Characteristics of the Crosstalk Between Vocal Fold Fibroblasts and Macrophages-The Role of Vibration in Vocal Fold Inflammation.

This in vitro study investigated the interaction between human vocal fold fibroblasts (hVFF) and macrophages under the influence of cigarette smoke extract (CSE) and vibration as potential regulators of vocal fold (VF) inflammation. Experimental in vitro pilot study. Immortalized hVFF were cultured in flexible-bottomed cell culture plates, treated with CSE, and subjected to static or dynamic conditions in a phonomimetic bioreactor. For coculture, unstimulated orlipopolysaccharide/IFNγ-stimulated THP-1 (human leukemia monocytic cell line) macrophages were added in inserts for a final 24hours of vibration period. We measured messenger ribonucleic acid (mRNA) (quantitative polymerase chain reaction [qPCR]) and protein levels (Western Blot, ELISA, and LUMINEX®) of hVFF and analyzed the results using two- and three-way ANOVA with post hoc tests. Under inflammatory stimulation, we observed a reduction of collagen (COL) type 1A1, 1A2, and 3A1, and increased gene expression of COL4A1, matrix metallopeptidase 2, and vascular endothelial growth factor A in hVFF. Additionally, the pro-inflammatory markers cyclooxygenase (COX) 1 and 2, interleukin (IL) 1β, IL-6, and IL-8 were upregulated. CSE increased COX1 and COX2 levels, whereas vibration reduced CSE-induced increases of COL4A1 and COX2 in pro-inflammatory stimulated hVFF. This study indicates that vibration may mitigate CSE-induced inflammatory damage in the hVFF, thereby offering new insights into the cellular crosstalk that underlies the pathophysiology of VF inflammation in smoking-related voice disorders.

Extracellular Vesicles Derived from Human Umbilical Mesenchymal Stem Cells Transfected with miR-7704 Improved Damaged Cartilage and Reduced Matrix Metallopeptidase 13.

We aimed to explore the therapeutic efficacy of miR-7704-modified extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HUCMSCs) for osteoarthritis (OA) treatment. In vitro experiments demonstrated the successful transfection of miR-7704 into HUCMSCs and the isolation of EVs from these cells. In vivo experiments used an OA mouse model to assess the effects of the injection of miR-7704-modified EVs intra-articularly. Walking capacity (rotarod test), cartilage morphology, histological scores, and the expression of type II collagen, aggrecan, interleukin-1 beta, and matrix metalloproteinase 13 (MMP13) in the cartilage were evaluated. The EVs were characterized to confirm their suitability for therapeutic use. IL-1beta-treated chondrocytes increased type II collagen and decreased MMP13 after treatment with miR-7704-overexpressed EVs. In vivo experiments revealed that an intra-articular injection of miR-7704-overexpressed EVs significantly improved walking capacity, preserved cartilage morphology, and resulted in higher histological scores compared to in the controls. Furthermore, the decreased expression of MMP13 in the cartilage post treatment suggests a potential mechanism for the observed therapeutic effects. Therefore, miR-7704-overexpressed EVs derived from HUCMSCs showed potential as an innovative therapeutic strategy for treating OA. Further investigations should focus on optimizing dosage, understanding mechanisms, ensuring safety and efficacy, developing advanced delivery systems, and conducting early-phase clinical trials to establish the therapeutic potential of HUCMSC-derived EVs for OA management.

Matrix Metallopeptidase 9 Promotes Contraction in Human Uterine Myometrium.

Matrix metallopeptidase 9 (MMP9) is a secreted zinc-dependent peptidase known for extracellular remodeling. MMP9 is elevated in tissues from women experiencing preterm labor, and previous research has shown that the addition of combined matrix metallopeptidases 2 and 9 (MMP2/9) enhances uterine contractions. We hypothesized that adding MMP9 alone would enhance myometrial contractions and that specific MMP9 inhibition would suppress uterine contractions. In myometrial tissue from women undergoing term Caesarean sections, we observed an increased contractile response as measured by area under the curve over time in tissues treated with MMP9 compared to vehicle-treated controls (p = 0.0003). This effect was primarily due to increased contraction frequency in MMP9-treated tissues compared to controls (p < 0.0001). Specific inhibition of MMP9 with the highly selective MMP9 inhibitor 1 (AG-L-66085) reduced contractile responses in myometrial tissues from pregnant women. We observed a reduction in the oxytocin-induced contractile response as measured by area under the curve over time (p < 0.0001) and contraction amplitude (p < 0.0068) in AG-L-66085-treated tissues compared to vehicle-treated controls. To determine the effects of MMP9 inhibition in the absence of exogenous oxytocin, we tested the effects of AG-L-66085 on spontaneous contractions. The area under the curve (p = 0.0415) and amplitude (p = 0.0354) of spontaneous contractions were reduced in response to 1μM AG-L-66085, and the inhibitory effects increased as the AG-L-66085 concentration increased. Together, these data support the hypothesis that elevated MMP9 promotes myometrial contractions and labor, while its inhibition promotes relaxation.

Synergistic effect of Cortex Moutan and Poria in protecting myocardium against ischemic injury based on network pharmacology

Objective: To explore the potential mechanisms of Cortex Moutan-Poria synergistic effect in anti-myocardial ischemic injury based on network pharmacology. Methods: Active components from Cortex Moutan-Poria were identified using the TCMSP database, and their potential targets were predicted with the UniProt database. Gene targets related to myocardial ischemic injury were sourced from the TTD database. An analysis map linking the “herbal pair-active components-targets-disease” and corresponding protein networks were constructed using Cytoscape 3.10.1 software and the STRING platform, respectively. Enrichment analyses refer to the Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analyses and Gene Ontology (GO) databases for corresponding biological pathways and signalling pathway information for further exploration of the possible involvement of drug targets in downstream signalling. Results: A total of 17 active components of the Cortex Moutan-Poria herbal pair and 243 predicted targets were identified, among which 133 targets interacted with the active components in myocardial ischemic injury. Key genes associated with myocardial ischemic injury included B-cell lymphoma-2 (BCL-2), Jun N-terminal Kinase (JUN), Matrix Metallopeptidase 9 (MMP9), cysteine-dependent aspartate-specific proteases-3 (Caspase-3), Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Interleukin-1β (IL-1β), Tumor Necrosis Factor (TNF), IL-6, Protein Kinase B (AKT1), and Stylonychia lemnae macronuclear development protein 6 (MDP6). Conclusion: The anti-myocardial ischemic injury effect of the Cortex Moutan-Poria combination is attributed to its multi-component, multi-target, and multi-pathway pharmacological properties. The pathways, core proteins, and major genes identified in this study for treating myocardial ischemic injury provide a theoretical foundation for subsequent experimental research.

TFDP1 overexpression promotes apoptosis of nucleus pulposus cells in intervertebral disc degeneration through regulating ADAM15/MMP9 axis.

Intervertebral disc degeneration (IVDD) is a common contributor for low back pain, which is featured by loss of extracellular matrix and nucleus pulposus cells (NPCs). Hence, our current study is undertaken to explore the potential mechanism of NPC apoptosis during IVDD. Transcription factor Dp-1 (TFDP1) expression in degenerative and non-degenerative intervertebral disc tissues was analyzed by bioinformatics. After transfection as needed, viability and apoptosis of NPCs were evaluated by cell counting kit-8 assay and flow cytometry, respectively. Western blot or quantitative real-time reverse transcription polymerase chain reaction was applied to assess expressions of TFDP1, matrix metallopeptidase 9 (MMP9), a disintegrin and metalloproteinase 15 (ADAM15), and apoptosis-associated proteins. TFDP1 expression was upregulated in degenerative intervertebral disc tissues. TFDP1 overexpression repressed viability, promoted apoptosis, increased expressions of Bax, Cleaved caspase 3, MMP9 and ADAM15, and decreased Bcl-2 expression in NPCs, while TFDP1 silencing did conversely. ADAM15 silencing promoted viability, inhibited apoptosis, increased Bcl-2 expression, and decreased Bax, Cleaved caspase 3, and MMP9 expressions in NPCs, which were reversed by TFDP1 overexpression. TFDP1 overexpression promotes apoptosis of NPCs in IVDD through regulating ADAM15/MMP9 axis, highlighting its role as a molecular target for the treatment of low back pain.

Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment.

We present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, n = 17), muscle-invasive bladder cancer (MIBC, n = 51), and neoadjuvant-treated MIBC (n = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and analyzed using data-independent acquisition, yielding >8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell-cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid/DNA metabolism. Treatment-naïve MIBC presents three proteomic subgroups with resemblance to the basal-squamous, stroma-rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune-depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP-14. Genomic panel sequencing yielded the prototypical profile of prevalent FGRF3 alterations in NMIBC and TP53 alterations in MIBC. Tumor-stroma interactions of MIBC were investigated by proteomic analysis of patient-derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor-induced stromal proteome phenotypes. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Silencing of Epidermal Growth Factor-like Domain 8 Promotes Proliferation and Cancer Aggressiveness in Human Ovarian Cancer Cells by Activating ERK/MAPK Signaling Cascades.

Ovarian cancer (OC) is the second most common female reproductive cancer and the most lethal gynecological malignancy worldwide. Most human OCs are characterized by high rates of drug resistance and metastasis, leading to poor prognosis. Improving the outcomes of patients with relapsed and treatment-resistant OC remains a challenge. This study aimed to investigate the role of epidermal growth factor-like domain 8 (EGFL8) in human OC by examining the effects of siRNA-mediated EGFL8 knockdown on cancer progression. EGFL8 knockdown in human OC cells promoted aggressive traits associated with cancer progression, including enhanced proliferation, colony formation, migration, invasion, chemoresistance, and reduced apoptosis. Additionally, knockdown upregulated the expression of epithelial-mesenchymal transition (EMT) markers (Snail, Twist1, Zeb1, Zeb2, and vimentin) and cancer stem cell biomarkers (Oct4, Sox2, Nanog, KLF4, and ALDH1A1), and increased the expression of matrix metallopeptidases (MMP-2 and MMP-9), drug resistance genes (MDR1 and MRP1), and Notch1. Low EGFL8 expression also correlated with poor prognosis in human OC. Overall, this study provides crucial evidence that EGFL8 inhibits the proliferation and cancer aggressiveness of human OC cells by suppressing ERK/MAPK signaling. Therefore, EGFL8 may serve as a valuable prognostic biomarker and a potential target for developing novel human OC therapies.

Matrix Metalloproteinase 9 as Biomarker for Malignant Mammary Tumors in Dogs

Canine mammary tumors (CMTs) are frequently occurring types of tumor in female dogs. Matrix metallopeptidase 9 (MMP-9) plays a role in dismantling the extracellular matrix during normal bodily functions and diseases, including cancer. The goal of this research was to evaluate the serum levels of MMP-9 as a potential diagnostic indicator for CMTs using the ELISA method. We collected tissue samples from mammary glands and blood specimens from 50 dogs suspected of having CMTs and 30 healthy control dogs. Histological examination was used to diagnose the mammary tumors, with findings indicating that 88% of the cases were malignant CMT and 12% were benign. According to ELISA results, there was a statistically considerable elevation in the mean serum level of MMP-9 in malignant cases (199.09 ng/ml) compared to benign cases (56.721 ng/ml) and controls (36.055 ng/ml). MMP-9 serum levels were significantly correlated with dogs aged 10–15 years, as well as with female dogs. In terms of stage and grade of the disease, the mean levels of MMP-9 increased as the disease progressed (Stage IV: 343.235 ng/ml). However, there was no correlation with the grade of the disease, and in regard to MMP-9 serum levels, it was not feasible to distinguish between newly diagnosed cases and recurring cases. In conclusion, measuring serum MMP-9 levels may aid in assessing the presence of malignancies in dogs with mammary tumors‎‎‎.

Association of MMP9, HsCRP, and ESR with 5-ASA Treatment Duration and Disease Activity Based on Truelove and Witts Criteria in Patients With Diagnosed Ulcerative Colitis

Background: The American College of Gastroenterology (ACG) currently recommends the Truelove and Witts scoring system for evaluating Ulcerative Colitis (UC) disease activity. Inflammatory markers such as Matrix Metallopeptidase 9 (MMP-9), High-sensitivity C-Reactive Protein (HsCRP), and Erythrocyte Sedimentation Rate (ESR) have previously been shown to correlate with intestinal inflammation. To evaluate the association of MMP-9, HsCRP, and LED with disease activity and treatment duration in UC according to the Truelove and Witts criteria.Methods: An observational analytic study with a cross-sectional design was conducted involving subjects with UC diagnosed pathologically and receiving 5-ASA therapy at the Gastroenterohepatology Outpatient Department of Dr. Soetomo Hospital. MMP-9, HsCRP, and ESR serum levels were measured. The disease activity was determined based on the Truelove and Witts criteria. Analysis was done by spearman's correlation. P-values and correlation coefficients (r) were presented.Results: Among the 31 subjects, the majority were female (67.7%) with an average age of 46.84 years. Approximately 35.5% subjects had been treated for more than 6 months. The MMP-9 and HsCRP serum levels were above normal range (71% and 93.5% subjects, respectively). The majority (74.2%) of the subjects had normal ESR levels. Among the investigated inflammatory markers, only ESR levels significantly had a very weak positive correlation (p=0.010; r=0.004).Conclusion: ESR serves as an effective biomarker for UC disease activity compared to MMP-9 and HsCRP. Further study is warranted to explore the role of these biomarkers in UC management.Keywords: ESR, HsCRP, MMP-9, Truelove and Witts, ulcerative colitis

Prolonged Cardiopulmonary Bypass Time-Induced Endothelial Dysfunction via Glypican-1 Shedding, Inflammation, and Matrix Metalloproteinase 9 in Patients Undergoing Cardiac Surgery.

A prolonged cardiopulmonary bypass (CPB) time of over 180 min is linked to poorer outcomes and higher mortality in cardiac surgery. This study examines how glypican-1 shedding, matrix metallopeptidase 9 (MMP9), and the pro-inflammatory cytokine IL-1β may contribute to endothelial dysfunction in patients undergoing on-pump surgery with an extended CPB. Fifty-one patients undergoing cardiac surgical procedures were divided into two groups based on the intraoperative CPB duration: (i) normal CPB (<180 min, n = 23) and (ii) prolonged CPB (>180 min, n = 28). The preoperative, intraoperative, and postoperative plasma levels of glypican-1, MMP9, and IL-1β were measured. Before surgery, the plasma levels of glypican-1, MMP9, and IL-1β were comparable between the normal CPB and the prolonged CPB groups. However, after the end of the CPB, all three markers showed significant elevation in the prolonged CPB group compared to the normal CPB group. Significant correlations were observed between the intraoperative and postoperative levels of MMP9, IL-1β, and glypican-1. A strong positive correlation was also observed between the intraoperative and postoperative levels of glypican-1 and the duration of the CPB. A prolonged CPB triggers a systemic inflammatory response and activates MMP9, leading to glypican-1 shedding and endothelial dysfunction.

Metalloproteases and their inhibitors in the postpartum endometrial remodeling in dairy cows: their relationship with days to conception after parturition.

In dairy herds, it is expected that cows will be cycling and the uterus will be ready for a new conception before the fourth week postpartum. However, an alteration in the endometrial remodeling can delay conception, increasing the parturition-to-conception interval, and consequently decreasing the reproductive performance. The endometrial matrix has a relevant participation in the processes of postpartum uterine remodeling. In this sense, the matrix metalloprotease (MMP) system and its inhibitors (TIMPs) are directly involved in the proteolytic degradation of the matrix and their action is related to the concentration of steroid hormones. The aim of this study was to evaluate the protein expression of MMP2, MMP14, MMP9, and their inhibitors, TIMP1 and TIMP2, in the luminal epithelium, glandular epithelium and stroma of endometrial biopsies from dairy cows, at 60 days in milk. Together, the results obtained provide evidence about the expression of MMP2, MMP14 and MMP9, and their inhibitors, TIMP1 and TIMP2, in the postpartum uterus of dairy cows, and about how the balance in their expression could be associated with the achievement of pregnancy. The high protein expression of MMP2, MMP14 and TIMP1 in dairy cows with short parturition-to-conception interval could be important for uterine remodeling and early conception in dairy cows. In addition, the imbalance observed in the MMP9/TIMP1 ratio could be generating an excess of gelatinase activity in the endometrium, causing a delayed conception.

From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment.

Ductal carcinoma in situ (DCIS) is a noninvasive breast disease that variably progresses to invasive breast cancer (IBC). Given the unpredictability of this progression, most DCIS patients are aggressively managed similar to IBC patients. Undoubtedly, this treatment paradigm places many DCIS patients at risk of overtreatment and its significant consequences. Historically, prognostic modeling has included the assessment of clinicopathological features and genomic markers. Although these provide valuable insights into tumor biology, they remain insufficient to predict which DCIS patients will progress to IBC. Contemporary work has begun to focus on the microenvironment surrounding the ductal cells for molecular patterns that might predict progression. In this review, extracellular microenvironment alterations occurring with the malignant transformation from DCIS to IBC are detailed. Not only do changes in collagen abundance, organization, and localization mediate the transition to IBC, but also the discrete post-translational regulation of collagen fibers is understood to promote invasion. Other extracellular matrix proteins, such as matrix metalloproteases, decorin, and tenascin C, have been characterized for their role in invasive transformation and further demonstrate the prognostic value of the extracellular matrix. Importantly, these extracellular matrix proteins influence immune cells and fibroblasts toward pro-tumorigenic phenotypes. Thus, the progressive changes in the extracellular microenvironment play a key role in invasion and provide promise for prognostic development.