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International Journal of Molecular... Feb 2024Asthma is a complex chronic respiratory disease characterized by airway hyperresponsiveness, inflammation, and obstruction. Many genes have been identified as associated... (Review)
Review
Asthma is a complex chronic respiratory disease characterized by airway hyperresponsiveness, inflammation, and obstruction. Many genes have been identified as associated with asthma but none with such substantial significance as the ADAM33 gene due to its role in airway remodeling and bronchial hyperresponsiveness. This review summarizes the current knowledge on the genetic and functional aspects of ADAM33 in asthma pathogenesis. We highlight its genetic variants associated with asthma susceptibility and severity, as well as the functional effects of ADAM33 on airway remodeling, smooth muscle cell proliferation, and its interplay with environmental factors. Additionally, we discuss the potential clinical implications of ADAM33 as a therapeutic target for asthma management.
Topics: Humans; Airway Remodeling; Asthma; Bronchial Hyperreactivity; Genetic Predisposition to Disease; ADAM Proteins
PubMed: 38396994
DOI: 10.3390/ijms25042318 -
Advanced Science (Weinheim,... Sep 2023High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing...
High altitude exposure leads to various cognitive impairments. The cerebral vasculature system plays an integral role in hypoxia-induced cognitive defects by reducing oxygen and nutrition supply to the brain. RNA N6-methyladenosine (m6A) is susceptible to modification and regulates gene expression in response to environmental changes, including hypoxia. However, the biological significance of m6A in endothelial cell performance under hypoxic conditions is unknown. Using m6A-seq, RNA immunoprcipitation-seq, and transcriptomic co-analysis, the molecular mechanism of vascular system remodeling under acute hypoxia is investigated. A novel m6A reader protein, proline-rich coiled-coil 2B (PRRC2B), exists in endothelial cells. PRRC2B knockdown promoted hypoxia-induced endothelial cell migration by regulating alternative splicing of the alpha 1 chain of collagen type XII in an m6A-dependent manner and the decay of matrix metallopeptidase domain 14 and ADAM metallopeptidase domain 19 mRNA in an m6A-independent manner. In addition, conditional knockout of PRRC2B in endothelial cells promotes hypoxia-induced vascular remodeling and cerebral blood flow redistribution, thus alleviating hypoxia-induced cognitive decline. Therefore, PRRC2B is integral in the hypoxia-induced vascular remodeling process as a novel RNA-binding protein. These findings provide a new potential therapeutic target for hypoxia-induced cognitive decline.
Topics: Mice; Animals; Endothelial Cells; Vascular Remodeling; RNA; Hypoxia; Metalloproteases
PubMed: 37395402
DOI: 10.1002/advs.202300892 -
ELife Sep 2023The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been...
The amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic strain that expresses and secretes human Aβ. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease a disintegrin and metalloprotease 2 (ADM-2), an ortholog of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.
Topics: Animals; Humans; Amyloid beta-Peptides; Caenorhabditis elegans; Peptide Hydrolases; Disintegrins; Alzheimer Disease; Endopeptidases; Plaque, Amyloid; Metalloproteases; Membrane Proteins; ADAM Proteins
PubMed: 37728486
DOI: 10.7554/eLife.83465 -
Cardiovascular Research Aug 2023Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such...
AIMS
Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis.
METHODS AND RESULTS
The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding, rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30% reduction in E/e' and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a down-regulation of transforming growth factor (TGF)-β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent-binding protein of TGF-β and extra domain A-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity.
CONCLUSION
Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular, in heart failure with fibrosis and diastolic dysfunction.
Topics: Rats; Humans; Animals; Disintegrins; Myocardium; Heart Failure; Cardiomyopathies; Collagen; Fibroblasts; Transforming Growth Factor beta; Thrombospondins; Metalloproteases; Fibrosis
PubMed: 37216909
DOI: 10.1093/cvr/cvad078 -
Brain Research Bulletin Nov 2023The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders...
BACKGROUND
The inhibition of matrix metalloproteinases (MMPs) has shown potential in the treatment of various neurodegenerative diseases, and perioperative neurocognitive disorders (PND) is accompanied by the increased expression of MMP-2 and MMP-9 in the hippocampus. However, the effect of inhibiting MMP-2 and MMP-9 on PND is not clear. In this study we aimed to evaluate the effects of inhibiting MMP-2 and MMP-9 on cognitive function in the aged mice after surgery, in order to find a possible target for the prevention and treatment of PND METHODS: In this study, 14-month-old C57BL/6 mice were used to establish a PND model by tibial fracture surgery and sevoflurane anesthesia. Three days later, part of the mice were subjected to cognitive assessment and the other was sacrificed for biochemical analysis. We used the Novel object recognition test and Fear conditioning test to evaluate the postoperative cognitive function of mice. The expression of mmp-2 and MMP-9 was detected by western blotting. We also examined the expression of claudin-5 and occludin using Western blotting, and the activation of microglia and astrocytes using immunofluorescence.
RESULTS
The results showed that surgery increased the expression of MMP-2 and MMP-9 in the hippocampus of mice, accompanied by cognitive impairment, decreased expression of claudin-5 and occludin, and increased activation of microglia and astrocytes. However, inhibition of MMP-2 and MMP-9 expression by SB-3CT reversed these changes.
CONCLUSIONS
Our study shows that inhibition of MMP-2 and MMP-9 alleviates anesthesia/surgery-induced cognitive decline by increasing BBB integrity and inhibiting glial cell activation.
Topics: Animals; Mice; Blood-Brain Barrier; Claudin-5; Cognitive Dysfunction; Hippocampus; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Occludin
PubMed: 37939860
DOI: 10.1016/j.brainresbull.2023.110810 -
Circulation Jul 2023
Topics: Humans; Neprilysin; Myocardium; Cardiomyopathy, Hypertrophic
PubMed: 37428831
DOI: 10.1161/CIRCULATIONAHA.123.064153 -
Cells Aug 2023Membrane type1-matrix metalloproteinase (MT1-MMP) is a member of metalloproteinases that is tethered to the transmembrane. Its major function in cancer progression is to... (Review)
Review
Membrane type1-matrix metalloproteinase (MT1-MMP) is a member of metalloproteinases that is tethered to the transmembrane. Its major function in cancer progression is to directly degrade the extracellular matrix components, which are mainly type I-III collagen or indirectly type IV collagen through the activation of MMP-2 with a cooperative function of the tissue inhibitor of metalloproteinase-2 (TIMP-2). MT1-MMP is expressed as an inactive form (zymogen) within the endoplasmic reticulum (ER) and receives truncation processing via furin for its activation. Upon the appropriate trafficking of MT1-MMP from the ER, the Golgi apparatus to the cell surface membrane, MT1-MMP exhibits proteolytic activities to the surrounding molecules such as extracellular matrix components and cell surface molecules. MT1-MMP also retains a non-proteolytic ability to activate hypoxia-inducible factor 1 alpha (HIF-1A) via factors inhibiting the HIF-1 (FIH-1)-Mint3-HIF-1 axis, resulting in the upregulation of glucose metabolism and oxygen-independent ATP production. Through various functions of MT1-MMP, cancer cells gain motility on migration/invasion, thus causing metastasis. Despite the long-time efforts spent on the development of MT1-MMP interventions, none have been accomplished yet due to the side effects caused by off-target effects. Recently, MT1-MMP-specific small molecule inhibitors or an antibody have been reported and these inhibitors could potentially be novel agents for cancer treatment.
Topics: Matrix Metalloproteinase 14; Tissue Inhibitor of Metalloproteinase-2; Cell Membrane; Antibodies; Collagen Type I; Collagen Type III
PubMed: 37681919
DOI: 10.3390/cells12172187 -
Journal of Neuroinflammation Jul 2023Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies....
BACKGROUND
Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known.
FINDINGS
In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031).
CONCLUSION
Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.
Topics: Humans; Blood-Brain Barrier; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Matrix Metalloproteinase 9; Microglia; Biomarkers
PubMed: 37481571
DOI: 10.1186/s12974-023-02841-7 -
Immunological Investigations Apr 2024Psoriasis is a chronic inflammatory disease characterized by squamous and erythematous plaques on the skin and the involvement of the immune system. Global prevalence... (Review)
Review
Psoriasis is a chronic inflammatory disease characterized by squamous and erythematous plaques on the skin and the involvement of the immune system. Global prevalence for psoriasis has been reported around 1-3% with a higher incidence in adults and similar proportions between men and women. The risk factors associated with psoriasis are both extrinsic and intrinsic, out of which a polygenic predisposition is a highlight out of the latter. Psoriasis etiology is not yet fully described, but several hypothesis have been proposed: 1) the autoimmunity hypothesis is based on the over-expression of antimicrobial peptides such as LL-37, the proteins ADAMTSL5, K17, and hsp27, or lipids synthesized by the PLA2G4D enzyme, all of which may serve as autoantigens to promote the differentiation of autoreactive lymphocytes T and unleash a chronic inflammatory response; 2) dysbiosis of skin microbiota hypothesis in psoriasis has gained relevance due to the observations of a loss of diversity and the participation of pathogenic bacteria such as spp. or spp. the fungi spp. or . and the virus HPV, HCV, or HIV in psoriatic plaques; 3) the oxidative stress hypothesis, the most recent one, describes that the cell injury and the release of proinflammatory mediators and antimicrobial peptides that leads to activate of the Th1/Th17 axis observed in psoriasis is caused by a higher release of reactive oxygen species and the imbalance between oxidant and antioxidant mechanisms. This review aims to describe the mechanisms involved in the three hypotheses on the etiopathogeneses of psoriasis.
Topics: Male; Adult; Female; Humans; Psoriasis; Skin; Autoimmunity; Autoantigens; Antimicrobial Peptides; ADAMTS Proteins
PubMed: 38240030
DOI: 10.1080/08820139.2024.2302823 -
Aktuelle Urologie Feb 2024
Topics: Humans; Botulinum Toxins, Type A; Urinary Bladder, Overactive
PubMed: 38330951
DOI: 10.1055/a-2056-2793