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International Journal of Molecular... Jul 2023Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of... (Review)
Review
Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.
Topics: Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasms; Matrix Metalloproteinases; Proteolysis; Extracellular Matrix
PubMed: 37569509
DOI: 10.3390/ijms241512133 -
Dermatologie (Heidelberg, Germany) Aug 2023The basic anatomical understanding of aesthetic medicine has changed fundamentally since the turn of the millennium. With the advent of modern minimally invasive...
The basic anatomical understanding of aesthetic medicine has changed fundamentally since the turn of the millennium. With the advent of modern minimally invasive injection procedures using botulinum toxin and hyaluronic acid fillers, anatomical structures that had previously received little attention and were not considered relevant have steadily gained in importance and moved into the scientific focus. Understanding the three-dimensional arrangement of the face with its defined anatomical layers and compartments serves the procedural dermatologist in the sense of a navigation system to optimize treatment success and patient safety when performing aesthetic injections in the facial region. The principles of the biomechanical interaction of the structures are of elementary importance in the creation of individual treatment plans for the implementation of natural and balanced therapeutic results. Modern injection anatomy as an interdisciplinary subject of the three fields of anatomy, dermatology and plastic surgery makes a decisive contribution here.
Topics: Humans; Cosmetic Techniques; Botulinum Toxins, Type A; Face; Hyaluronic Acid; Esthetics
PubMed: 37460865
DOI: 10.1007/s00105-023-05185-8 -
Nature Communications Oct 2023Peptidoglycan, a gigadalton polymer, functions as the scaffold for bacterial cell walls and provides cell integrity. Peptidoglycan is remodelled by a large and diverse...
Peptidoglycan, a gigadalton polymer, functions as the scaffold for bacterial cell walls and provides cell integrity. Peptidoglycan is remodelled by a large and diverse group of peptidoglycan hydrolases, which control bacterial cell growth and division. Over the years, many studies have focused on these enzymes, but knowledge on their action within peptidoglycan mesh from a molecular basis is scarce. Here, we provide structural insights into the interaction between short peptidoglycan fragments and the entire sacculus with two evolutionarily related peptidases of the M23 family, lysostaphin and LytM. Through nuclear magnetic resonance, mass spectrometry, information-driven modelling, site-directed mutagenesis and biochemical approaches, we propose a model in which peptidoglycan cross-linking affects the activity, selectivity and specificity of these two structurally related enzymes differently.
Topics: Humans; Staphylococcus aureus; Peptidoglycan; Hydrolases; Lysostaphin; Mass Spectrometry; Staphylococcal Infections; Cell Wall
PubMed: 37872144
DOI: 10.1038/s41467-023-42506-w -
Drug Design, Development and Therapy 2023The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro....
PURPOSE
The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro. Excessively activated microglia produce pro-inflammatory mediators such as matrix metalloproteinases [MMPs] and their specific inhibitors, tissue inhibitors of metalloproteinases [TIMPs], causing neuronal damage. Ursolic acid (UA) acts as a neuroprotective agent in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model keeping the MMP/TIMP balance with underlying mechanisms unclear. Our study used OGDR model to determine whether and how UA reduces neuronal damage by reversing MMP/TIMP imbalance caused by microglia in I/R injury in vitro.
METHODS
SH-SY5Y cells were first cultured with 95% N and 5% CO and then cultivated regularly for OGDR model. Cell viability was tested for a proper UA dose. We established a co-culture system with SH-SY5Y cells and microglia-conditioned medium (MCM) stimulated by lipopolysaccharide (LPS) and interferon-gamma (IFNγ). MMP9 and TIMP1 levels were measured with ELISA assay to confirm the UA effect. We added recombinant MMP9 (rMMP9) and TIMP1 neutralizing antibody (anti-TIMP1) for reconfirmation. Transmission electron microscopy was used to observe cell morphology, and flow cytometry and Annexin V-FITC and PI labeling for apoptotic conditions. We further measured the calcium fluorescence intensity in SH-SY5Y cells.
RESULTS
The MCM significantly reduced cell viability of SH-SY5Y cells after OGDR (0.01), which was restored by UA (0.25 µM) (<0.05), whereas lactate dehydrogenase activity, intraneuronal Ca concentration, and apoptosis-related indexes were showed significant improvement after UA treatment (<0.01). UA corrected the MMP/TIMP imbalance by decreasing MMP9 expression and increasing TIMP1 expression in the co-culture system (<0.01) and the effects of UA on SH-SY5Y cells were mitigated by the administration of rMMP9 and anti-TIMP1 (<0.01).
CONCLUSION
We demonstrated that UA inhibited microglia-induced neuronal cell death in an OGDR model of ischemic reperfusion injury by stabilizing the MMP9/TIMP1 imbalance.
Topics: Humans; Glucose; Macrophages; Matrix Metalloproteinase 9; Microglia; Neuroblastoma; Ursolic Acid
PubMed: 37637267
DOI: 10.2147/DDDT.S411408 -
Nucleus (Austin, Tex.) Dec 2023As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders.... (Review)
Review
As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes and is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. encodes the lamin A precursor, prelamin A and encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse () that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.
Topics: Humans; Animals; Mice; Lamin Type A; Metalloendopeptidases; Health Promotion; Progeria; Aging; Membrane Proteins
PubMed: 37885131
DOI: 10.1080/19491034.2023.2270345 -
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 -
Shock (Augusta, Ga.) Feb 2024Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths.... (Review)
Review
Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the intensive care unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation, which is characterized by microvascular thrombosis. Von Willebrand factor (VWF) and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of VWF and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their use as markers of severe illness, and potential targets for new therapeutic development.
Topics: Humans; von Willebrand Factor; Sepsis; Shock, Septic; Disseminated Intravascular Coagulation; Thrombosis; ADAMTS13 Protein
PubMed: 38150358
DOI: 10.1097/SHK.0000000000002291 -
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