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International Journal of Molecular... Jun 2024The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early... (Review)
Review
The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early identification of at-risk pregnancies could significantly improve the management, therapy and prognosis of these pregnancies, especially if these at-risk pregnancies are identified in the first trimester. The aim of this review was to summarize the possible biomarkers that can be used to diagnose early placental dysfunction and, consequently, at-risk pregnancies. We divided the biomarkers into proteins and non-proteins. Among the protein biomarkers, some are already used in clinical practice, such as the sFLT1/PLGF ratio or PAPP-A; others are not yet validated, such as HTRA1, Gal-3 and CD93. In the literature, many studies analyzed the role of several protein biomarkers, but their results are contrasting. On the other hand, some non-protein biomarkers, such as miR-125b, miR-518b and miR-628-3p, seem to be linked to an increased risk of complicated pregnancy. Thus, a first trimester heterogeneous biomarkers panel containing protein and non-protein biomarkers may be more appropriate to identify and discriminate several complications that can affect pregnancies.
Topics: Humans; Pregnancy; Female; Biomarkers; Pregnancy Trimester, First; Placenta; Pregnancy Outcome; Pre-Eclampsia; MicroRNAs; Pregnancy-Associated Plasma Protein-A; Diabetes, Gestational
PubMed: 38892323
DOI: 10.3390/ijms25116136 -
International Journal of Molecular... Jun 2024Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of...
Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.
Topics: Matrix Metalloproteinase 9; Humans; Triple Negative Breast Neoplasms; Cell Movement; Female; Cell Line, Tumor; Animals; Mice; Apoptosis; Cell Proliferation; Neoplasm Invasiveness; Xenograft Model Antitumor Assays; Gene Expression Regulation, Neoplastic; Antineoplastic Agents; Lung Neoplasms; Mice, Nude
PubMed: 38892310
DOI: 10.3390/ijms25116123 -
International Journal of Molecular... May 2024The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2)...
The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in OE, OSNs expressing ORs that are enriched in OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.
Topics: Animals; Receptors, Odorant; Mice; Olfactory Receptor Neurons; Smell; ADAM17 Protein; Mice, Knockout; Carrier Proteins; Olfactory Mucosa; Gene Expression Regulation; Membrane Proteins; Mice, Inbred C57BL; Humans
PubMed: 38892263
DOI: 10.3390/ijms25116079 -
International Journal of Molecular... May 2024Synthetic deer antler peptides (TSKYR, TSK, and YR) stimulate the proliferation of human chondrocytes and osteoblasts and increase the chondrocyte content of collagen...
Synthetic deer antler peptides (TSKYR, TSK, and YR) stimulate the proliferation of human chondrocytes and osteoblasts and increase the chondrocyte content of collagen and glycosamino-glycan in vitro. This study investigated the peptide mixture's pain relief and chondroprotective effect in a rat model of collagenase-induced osteoarthritis. Thirty-six adult male Sprague-Dawley rats were divided into three groups: control (saline), positive control (hyaluronic acid), and ex-perimental (peptides). Intra-articular collagenase injections were administered on days 1 and 4 to induce osteoarthritis in the left knees of the rats. Two injections of saline, hyaluronic acid, or the peptides were injected into the same knees of each corresponding group at the beginning of week one and two, respectively. Joint swelling, arthritic pain, and histopathological changes were evaluated. Injection of the peptides significantly reduced arthritic pain compared to the control group, as evidenced by the closer-to-normal weight-bearing and paw withdrawal threshold test results. Histological analyses showed reduced cartilage matrix loss and improved total cartilage degeneration score in the experimental versus the control group. Our findings suggest that intra-articular injection of synthetic deer antler peptides is a promising treatment for osteoarthritis.
Topics: Animals; Injections, Intra-Articular; Antlers; Osteoarthritis, Knee; Male; Deer; Rats; Rats, Sprague-Dawley; Peptides; Disease Models, Animal; Hyaluronic Acid; Cartilage, Articular; Collagenases
PubMed: 38892229
DOI: 10.3390/ijms25116041 -
International Journal of Molecular... May 2024There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with...
There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate and gene expressions by age and sex in ages between 20-80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity ( = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance ( = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of to gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin-angiotensin system (RAS) and immune signaling. Additionally, differences in and gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.
Topics: Humans; COVID-19; ADAM17 Protein; Angiotensin-Converting Enzyme 2; Middle Aged; Female; Male; Aged; Adult; SARS-CoV-2; Severity of Illness Index; Aged, 80 and over; Young Adult; Biomarkers
PubMed: 38892098
DOI: 10.3390/ijms25115911 -
International Journal of Molecular... May 2024Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane...
Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds β1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and β1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12-mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFβ signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.
Topics: Humans; Animals; ADAM12 Protein; Mice; Extracellular Matrix Proteins; Basigin; Protein Binding; Mice, Nude; Protein Domains; Cell Movement; MCF-7 Cells; Gene Expression Regulation, Neoplastic; Neoplasms; Female; Cell Line, Tumor; Extracellular Matrix
PubMed: 38892056
DOI: 10.3390/ijms25115871 -
International Journal of Molecular... May 2024Keloids, marked by abnormal cellular proliferation and excessive extracellular matrix (ECM) accumulation, pose significant therapeutic challenges. Ethyl pyruvate (EP),...
Keloids, marked by abnormal cellular proliferation and excessive extracellular matrix (ECM) accumulation, pose significant therapeutic challenges. Ethyl pyruvate (EP), an inhibitor of the high-mobility group box 1 (HMGB1) and TGF-β1 pathways, has emerged as a potential anti-fibrotic agent. Our research evaluated EP's effects on keloid fibroblast (KF) proliferation and ECM production, employing both in vitro cell cultures and ex vivo patient-derived keloid spheroids. We also analyzed the expression levels of ECM components in keloid tissue spheroids treated with EP through immunohistochemistry. Findings revealed that EP treatment impedes the nuclear translocation of HMGB1 and diminishes KF proliferation. Additionally, EP significantly lowered mRNA and protein levels of collagen I and III by attenuating TGF-β1 and pSmad2/3 complex expression in both human dermal fibroblasts and KFs. Moreover, metalloproteinase I (MMP-1) and MMP-3 mRNA levels saw a notable increase following EP administration. In keloid spheroids, EP induced a dose-dependent reduction in ECM component expression. Immunohistochemical and western blot analyses confirmed significant declines in collagen I, collagen III, fibronectin, elastin, TGF-β, AKT, and ERK 1/2 expression levels. These outcomes underscore EP's antifibrotic potential, suggesting its viability as a therapeutic approach for keloids.
Topics: Humans; Keloid; Fibroblasts; Pyruvates; Spheroids, Cellular; Matrix Metalloproteinase 1; Transforming Growth Factor beta1; HMGB1 Protein; Collagen; Cell Proliferation; Cells, Cultured; Matrix Metalloproteinase 3; Extracellular Matrix; Collagen Type I; Smad2 Protein; Smad3 Protein; Up-Regulation; Male
PubMed: 38892032
DOI: 10.3390/ijms25115844 -
International Journal of Molecular... May 2024Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation...
Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
Topics: Animals; Aortic Aneurysm, Abdominal; Angiotensin II; Matrix Metalloproteinase 12; Mice; Apolipoproteins E; Humans; Matrix Metalloproteinase Inhibitors; Male; Disease Models, Animal; Mice, Knockout; Mice, Inbred C57BL; Elastin; Proteomics
PubMed: 38891996
DOI: 10.3390/ijms25115809 -
International Journal of Molecular... May 2024Tetanus disease, caused by , starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic...
Tetanus disease, caused by , starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic treatment in case of accidents. The incidence of tetanus is high in underdeveloped countries, requiring the administration of antitetanus antibodies, usually derived from immunized horses or humans. Heterologous sera represent risks such as serum sickness. Human sera can carry unknown viruses. In the search for human monoclonal antibodies (mAbs) against TeNT (Tetanus Neurotoxin), we previously identified a panel of mAbs derived from B-cell sorting, selecting two nonrelated ones that binded to the C-terminal domain of TeNT (HCR/T), inhibiting its interaction with the cellular receptor ganglioside GT1b. Here, we present the results of cellular assays and molecular docking tools. TeNT internalization in neurons is prevented by more than 50% in neonatal rat spinal cord cells, determined by quantitative analysis of immunofluorescence punctate staining of Alexa Fluor 647 conjugated to TeNT. We also confirmed the mediator role of the Synaptic Vesicle Glycoprotein II (SV2) in TeNT endocytosis. The molecular docking assays to predict potential TeNT epitopes showed the binding of both antibodies to the HCR/T domain. A higher incidence was found between N1153 and W1297 when evaluating candidate residues for conformational epitope.
Topics: Animals; Rats; Neurons; Humans; Antibodies, Monoclonal; Endocytosis; Tetanus Toxin; Molecular Docking Simulation; Tetanus; Epitopes; Gangliosides; Cells, Cultured; Computer Simulation; Metalloendopeptidases
PubMed: 38891974
DOI: 10.3390/ijms25115788 -
International Journal of Molecular... May 2024Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual...
Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including and , compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of and zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.
Topics: Humans; Animals; Zebrafish; Glaucoma; Child; Male; Female; Child, Preschool; HEK293 Cells; Genetic Predisposition to Disease; Mutation; Matrix Metalloproteinases; ADAMTS Proteins; Adolescent; Infant; Zebrafish Proteins; Endoplasmic Reticulum Stress
PubMed: 38891949
DOI: 10.3390/ijms25115757