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Journal of Immunology (Baltimore, Md. :... Jan 2024Staphylococcus aureus is a significant cause of morbidity and mortality in pulmonary infections. Patients with autosomal-dominant hyper-IgE syndrome due to STAT3...
Staphylococcus aureus is a significant cause of morbidity and mortality in pulmonary infections. Patients with autosomal-dominant hyper-IgE syndrome due to STAT3 deficiency are particularly susceptible to acquiring staphylococcal pneumonia associated with lung tissue destruction. Because macrophages are involved in both pathogen defense and inflammation, we investigated the impact of murine myeloid STAT3 deficiency on the macrophage phenotype in vitro and on pathogen clearance and inflammation during murine staphylococcal pneumonia. Murine bone marrow-derived macrophages (BMDM) from STAT3 LysMCre+ knockout or Cre- wild-type littermate controls were challenged with S. aureus, LPS, IL-4, or vehicle control in vitro. Pro- and anti-inflammatory responses as well as polarization and activation markers were analyzed. Mice were infected intratracheally with S. aureus, bronchoalveolar lavage and lungs were harvested, and immunohistofluorescence was performed on lung sections. S. aureus infection of STAT3-deficient BMDM led to an increased proinflammatory cytokine release and to enhanced upregulation of costimulatory MHC class II and CD86. Murine myeloid STAT3 deficiency did not affect pathogen clearance in vitro or in vivo. Matrix metalloproteinase 9 was upregulated in Staphylococcus-treated STAT3-deficient BMDM and in lung tissues of STAT3 knockout mice infected with S. aureus. Moreover, the expression of miR-155 was increased. The enhanced inflammatory responses and upregulation of matrix metalloproteinase 9 and miR-155 expression in murine STAT3-deficient as compared with wild-type macrophages during S. aureus infections may contribute to tissue damage as observed in STAT3-deficient patients during staphylococcal pneumonia.
Topics: Humans; Mice; Animals; Pneumonia, Staphylococcal; Job Syndrome; Staphylococcus aureus; Macrophage Activation; Matrix Metalloproteinase 9; Inflammation; Staphylococcal Infections; Mice, Knockout; MicroRNAs; Mice, Inbred C57BL; STAT3 Transcription Factor
PubMed: 37982695
DOI: 10.4049/jimmunol.2300151 -
Journal of Pineal Research Aug 2023Chondrosarcoma has a high propensity to metastasize and responds poorly to chemotherapy and radiation treatment. The enzymatic activity of matrix metalloproteinases...
Chondrosarcoma has a high propensity to metastasize and responds poorly to chemotherapy and radiation treatment. The enzymatic activity of matrix metalloproteinases (MMPs) is very important in chondrosarcoma metastasis. Melatonin exhibits anticarcinogenic activity in many types of cancers by suppressing the expression of certain MMP family members, but this has not yet been clearly determined in chondrosarcoma. Our study demonstrates that MMP7 plays an essential role in chondrosarcoma cell proliferation, migration, and anoikis resistance. We also found that MMP7 is highly expressed in chondrosarcomas. Our in vitro and in vivo investigations show that melatonin strongly inhibits chondrosarcoma cell proliferation, migration, and anoikis resistance by directly suppressing MMP7 expression. Melatonin reduced MMP7 synthesis by promoting levels of miR-520f-3p expression, which were downregulated in human chondrosarcoma tissue samples. Pharmacological inhibition of miR-520f-3p markedly reversed the effects of melatonin upon chondrosarcoma proliferation and metastasis. Thus, our study suggests that melatonin has therapeutic potential for reducing the tumorigenesis and metastatic potential of chondrosarcoma via the miR-520f-3p/MMP7 axis.
Topics: Humans; MicroRNAs; Cell Line, Tumor; Melatonin; Matrix Metalloproteinase 7; Cell Proliferation; Chondrosarcoma; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 37057370
DOI: 10.1111/jpi.12872 -
Scientific Reports Sep 2023Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack...
Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin α. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.
Topics: Animals; Humans; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms; Proteolysis; Biological Transport; Matrix Metalloproteinases
PubMed: 37726363
DOI: 10.1038/s41598-023-42659-0 -
Mediators of Inflammation 2023Coronary artery disease (CAD) is a caused by atherosclerotic plaque buildup in the coronary arteries that supply blood and oxygen to the heart. Matrix metalloproteinase... (Review)
Review
Coronary artery disease (CAD) is a caused by atherosclerotic plaque buildup in the coronary arteries that supply blood and oxygen to the heart. Matrix metalloproteinase (MMP) is a family of zinc-dependent endopeptidase that is involved in various stages of atherosclerosis as demonstrated in and studies. MMP-2 is associated with both stable and unstable atherosclerotic plaque formation. The current review aimed to identify the role of MMP-2 in atherosclerosis development among CAD patients. Literature search was conducted through four online databases and only studies that were published from 2018 until February 2023 were included. The risk of bias was assessed by using the Newcastle-Ottawa Scale. A total of 10,622 articles were initially identified, and only eight studies that fulfilled the selection criteria were included in this review. The results showed that MMP-2 levels and activity were higher in patients with unstable CAD than those with stable CAD and healthy subjects. There was a significant association between MMP-2 levels and cardiovascular disease with MMP-14 levels, which is a pro-MMP-2 activator. In addition, two single nucleotide polymorphisms of the MMP-2 gene (rs243865 and rs243866) were significantly associated with the development of atherosclerosis. In conclusion, MMP-2 plays a crucial role in the development of atherosclerosis among patients with CAD and could be a potential target for CAD therapy.
Topics: Humans; Coronary Artery Disease; Matrix Metalloproteinase 2; Plaque, Atherosclerotic; Atherosclerosis; Polymorphism, Single Nucleotide; Matrix Metalloproteinase 3
PubMed: 37457745
DOI: 10.1155/2023/9715114 -
European Journal of Histochemistry : EJH Jun 2024Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its...
Effects of artificial light with different spectral compositions on refractive development and matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2 expression in the sclerae of juvenile guinea pigs.
Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its remodeling, while tissue inhibitor of matrix MMP-2 (TIMP-2) inhibits active MMP-2. The present study aimed to look into how refractive development and the expression of MMP-2 and TIMP-2 in the guinea pigs' remodeled sclerae are affected by artificial light with varying spectral compositions. Three weeks old guinea pigs were randomly assigned to groups exposed to five different types of light: natural light, LED light with a low color temperature, three full spectrum artificial lights, i.e. E light (continuous spectrum in the range of ~390-780 nm), G light (a blue peak at 450 nm and a small valley 480 nm) and F light (continuous spectrum and wavelength of 400 nm below filtered). A-scan ultrasonography was used to measure the axial lengths of their eyes, every two weeks throughout the experiment. Following twelve weeks of exposure to light, the sclerae were observed by optical and transmission electron microscopy. Immunohistochemistry, Western blot and RT-qPCR were used to detect the MMP-2 and TIMP-2 protein and mRNA expression levels in the sclerae. After four, six, eight, ten, and twelve weeks of illumination, the guinea pigs in the LED and G light groups had axial lengths that were considerably longer than the animals in the natural light group while the guinea pigs in the E and F light groups had considerably shorter axial lengths than those in the LED group. Following twelve weeks of exposure to light, the expression of the scleral MMP-2 protein and mRNA were, from low to high, N group, E group, F group, G group, LED group; however, the expression of the scleral TIMP-2 protein and mRNA were, from high to low, N group, E group, F group, G group, LED group. The comparison between groups was statistically significant (p<0.01). Continuous, peaks-free or valleys-free artificial light with full-spectrum preserves remodeling of scleral extracellular matrix in guinea pigs by downregulating MMP-2 and upregulating TIMP-2, controlling eye axis elongation, and inhibiting the onset and progression of myopia.
Topics: Animals; Guinea Pigs; Matrix Metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-2; Sclera; Light; Myopia; Refraction, Ocular
PubMed: 38934084
DOI: 10.4081/ejh.2024.3982 -
Nature Communications Nov 2023Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the...
Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.
Topics: Animals; Dogs; Humans; NF-kappa B; Madin Darby Canine Kidney Cells; Cell Competition; Signal Transduction; Carcinogenesis; Matrix Metalloproteinases, Secreted
PubMed: 37923722
DOI: 10.1038/s41467-023-42774-6 -
International Journal of Molecular... Dec 2023Bone tissue is a dynamic structure that is involved in maintaining the homeostasis of the body due to its multidirectional functions, such as its protective, endocrine,... (Review)
Review
Bone tissue is a dynamic structure that is involved in maintaining the homeostasis of the body due to its multidirectional functions, such as its protective, endocrine, or immunological role. Specialized cells and the extracellular matrix (ECM) are responsible for the remodeling of specific bone structures, which alters the biomechanical properties of the tissue. Imbalances in bone-forming elements lead to the formation and progression of bone diseases. The most important family of enzymes responsible for bone ECM remodeling are matrix metalloproteinases (MMPs)-enzymes physiologically present in the body's tissues and cells. The activity of MMPs is maintained in a state of balance; disruption of their activity is associated with the progression of many groups of diseases, including those of the skeletal system. This review summarizes the current understanding of the role of MMPs in bone physiology and the pathophysiology of bone tissue and describes their role in specific skeletal disorders. Additionally, this work collects data on the potential of MMPs as bio-markers for specific skeletal diseases.
Topics: Humans; Matrix Metalloproteinases; Bone Remodeling; Extracellular Matrix; Musculoskeletal Diseases; Bone and Bones
PubMed: 38138968
DOI: 10.3390/ijms242417139 -
Clinical & Translational Oncology :... Mar 2024Matrix metalloproteinases (MMP) are important proteases that degrade the extracellular matrix (ECM) and thus essentially mediate tumor vascularization, metastasis, and...
BACKGROUND
Matrix metalloproteinases (MMP) are important proteases that degrade the extracellular matrix (ECM) and thus essentially mediate tumor vascularization, metastasis, and invasion. However, their potential roles in uterine corpus endometrial carcinoma (UCEC) are not fully understood.
PATIENTS AND METHODS
The expression, prognostic value, and correlation of UCEC patients with MMP were investigated using data from The Cancer Genome Atlas (TCGA) and other databases. Furthermore, differentially expressed genes (DEGs) were identified and their biological functions and correlations with infiltrating immune cells were analyzed.
RESULTS
A total of 22 MMPs were found to be abnormally expressed in UCEC tumor tissues, and high expression of MMP11 and MMP17 were associated with a better UCEC prognosis. MMP11 and MMP17 were observed to be significantly enriched in tumor tissue ECM and were associated with pathways involving degradation, glycolytic metabolism, and PI3K-Akt signaling. Infiltration of natural killer (NK), mast, and NK CD56bright cells was enhanced in tumor tissues with high MMP11 and MMP17 expression.
CONCLUSION
MMP11 and MMP17 may affect UCEC prognosis by influencing immune cell infiltration and may be potential UCEC biomarkers.
Topics: Humans; Female; Matrix Metalloproteinase 17; Matrix Metalloproteinase 11; Phosphatidylinositol 3-Kinases; Prognosis; Biomarkers; Carcinoma, Endometrioid; Endometrial Neoplasms
PubMed: 37523078
DOI: 10.1007/s12094-023-03284-5 -
Journal of the American Heart... Oct 2023Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying...
Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A () and cluster of differentiation 36 () genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (, ), and matrix metalloproteinase 8, 9 () appeared in multiple canonical pathways. -knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of and genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors and and matrix metalloproteinases, and indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.
Topics: Humans; Child; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Anthracyclines; Cancer Survivors; Case-Control Studies; Neoplasms; Cardiomyopathies; Antibiotics, Antineoplastic; Myocytes, Cardiac; RNA, Messenger; Gene Expression
PubMed: 37750583
DOI: 10.1161/JAHA.123.029954 -
Current Eye Research Aug 2023To investigate the biochemical characteristics in experimental keratomycosis.
PURPOSE
To investigate the biochemical characteristics in experimental keratomycosis.
METHODS
Experimental mice were injected with solution Controls mice received liposomes containing phosphate-buffered saline (PBS-LIP). Raman spectroscopy was used to analyze the biochemical characteristics. The infiltration of inflammatory cells was analyzed by histopathology. Cytokine mRNA levels were detected by real-time polymerase chain reaction.
RESULTS
Raman Spectroscopy: In the experimental group, collagen, lipids, amide I and III were decreased, amide II, hyper proline amino acids, and arginine were increased, and proline and phenylalanine were significantly increased on day 3. Histopathology: more severe keratomycosis developed in the experimental group than in the control group. Statistically significant mRNA expression of Collagen4\MMP2\MMP9\TIMP1.MMP9 was negatively correlated with the secretion of Collagen4.
CONCLUSIONS
Matrix metalloproteinases are involved in biochemical changes in keratomycosis.
Topics: Mice; Animals; Matrix Metalloproteinase 9; Corneal Ulcer; Eye Infections, Fungal; RNA, Messenger; Amides; Proline
PubMed: 37027008
DOI: 10.1080/02713683.2023.2199448