I Haku: matrix metalloprotease inhibitors. vastauksia 27 787.
II Haku human matrix metalloprotease inhibitors . Vastauksia 20 008
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Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.
JCI Insight. 2024 Mar 19:e173603. doi: 10.1172/jci.insight.173603. Online ahead of print.
PMID: 38502232
Free article.
Here we showed that the fibrinolytic pathway, which
includes plasminogen/plasmin, tissue plasminogen activator (tPA),
urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), were
dysregulated in human OA joints.
Pharmacological inhibition of plasmin attenuated OA progression in a
destabilization of the medial meniscus (DMM) mouse model, while genetic
deficiency of plasmin activator inhibitor (PAI-1), or injection of
plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in
mouse OA joints by microPET/CT imaging. In vitro studies identified that
plasmin promotes OA development through multiple mechanisms, including
the degradation of lubricin and cartilage proteoglycans, induction of
inflammatory and degradative mediators. We showed that uPA and uPAR
produced inflammatory and degradative mediators by activating the PI3K,
PDK1, AKT, and ERK signaling cascades, and activates matrix
metalloproteinases (pro-MMPs) to degrade proteoglycan. Together, we
demonstrated that fibrinolysis contributes to the development of OA
through multiple mechanisms and suggested that therapeutic targeting of
the fibrinolysis pathway can prevent or slow development of OA.
LOX-1 and MMP-9 Inhibition Attenuates the Detrimental
Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute
Ischemic Stroke.
Circ Res. 2024 Mar 19. doi: 10.1161/CIRCRESAHA.123.323371. Online ahead of print.
PMID: 38501247Acute ischemic stroke triggers endothelial activation that disrupts
vascular integrity and increases hemorrhagic transformation leading to
worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen
activator) is an effective treatment; however, its use is limited due to
a restricted time window and hemorrhagic transformation risk, which in
part may involve activation of MMPs (matrix metalloproteinases) mediated
through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein]
receptor 1). This study's overall aim was to evaluate the therapeutic
potential of novel MMP-9 (matrix metalloproteinase 9) and LOX-1
inhibitors in combination with rt-PA to improve stroke outcomes.
Results :Stroke and subsequent rt-PA treatment increased edema, hemorrhage,
MMP-9 activity, LOX-1 expression, and worsened neurological outcomes.
LOX-1 inhibition improved neurological function, reduced edema, and
improved endothelial barrier integrity. Elevated MMP-9 activity
correlated with increased edema, infarct volume, and decreased
neurological function. MMP-9 inhibition reduced MMP-9 activity and LOX-1
expression. In human brain microvascular endothelial cells, LOX-1/MMP-9
inhibition differentially attenuated MMP-9 levels, inflammation, and
activation following hypoxia plus glucose deprivation/R.
Multiple integrated computational approach to analyse wound healing potential of Symplocos racemosa bark as Matrix metalloproteinase inhibitors.
Nat Prod Res. 2024 Mar 18:1-10. doi: 10.1080/14786419.2024.2321488. Online ahead of print.
PMID: 38497294
The healing of wounds is the flagging concern in chronic
wound cases especially when accompanied by pathogenic, diabetic
comorbidities. Matrix metalloproteinases are associated with widespread pathological ailments, and the selective inhibitors for metallo …
Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.
Acta Pharm Sin B. 2024 Mar;14(3):1166-1186. doi: 10.1016/j.apsb.2023.12.009. Epub 2023 Dec 16.
PMID: 38487008
Free PMC article.
Cellular senescence is a hallmark of aging that
contributes greatly to aging and aging-related diseases. This study
demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. ..Proteomic analysis reveals that USC-EVs
are enriched with plasminogen activator urokinase (PLAU) and tissue
inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute
importantly to the anti-senescent effects of USC-EVs associated with
the inhibition of matrix metalloproteinases, cyclin-dependent kinase
inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1).
These findings suggest a great potential of autologous USC-EVs as a
promising anti-aging agent by transferring PLAU and TIMP1 proteins.
Relationship between the Expression of Matrix Metalloproteinases and Their Tissue Inhibitors in Patients with Brain Tumors.
Int J Mol Sci. 2024 Mar 1;25(5):2858. doi: 10.3390/ijms25052858.
PMID: 38474106
Free PMC article.Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play
critical roles in regulating processes associated with malignant
behavior. These endopeptidases selectively degrade components of the
extracellular matrix (ECM), growth factors, and their receptors,
contributing to cancer cell invasiveness and migratory characteristics
by disrupting the basal membrane. However, the expression profile and
role of various matrix metalloproteinases remain unclear, and only a few
studies have focused on differences between diagnoses of brain tumors. However, the expression profile and role of various matrix
metalloproteinases remain unclear, and only a few studies have focused
on differences between diagnoses of brain tumors. Using quantitative
real-time PCR analysis, we identified the expression pattern of ECM
modulators (n = 10) in biopsies from glioblastoma (GBM; n = 20), astrocytoma (AST; n = 9), and meningioma (MNG; n = 19) patients. We found eight deregulated genes in the glioblastoma group compared to the benign meningioma group, with only MMP9 (FC = 2.55; p = 0.09) and TIMP4 (7.28; p
< 0.0001) upregulated in an aggressive form. The most substantial
positive change in fold regulation for all tumors was detected in matrix metalloproteinase 2 (MNG = 30.9, AST = 4.28, and GBM = 4.12). Notably, we observed an influence of TIMP1, demonstrating a positive correlation with MMP8, MMP9, and MMP10 in tumor samples. Subsequently, we examined the protein levels of the investigated MMPs (n = 7) and TIMPs (n
= 3) via immunodetection. We confirmed elevated levels of MMPs and
TIMPs in GBM patients compared to meningiomas and astrocytomas. Even
when correlating glioblastomas versus astrocytomas, we showed a
significantly increased level of MMP1, MMP3, MMP13, and TIMP1. The
identified metalloproteases may play a key role in the process of
gliomagenesis and may represent potential targets for personalized
therapy. However, as we have not confirmed the relationship between mRNA
expression and protein levels in individual samples, it is therefore
natural that the regulation of metalloproteases will be subject to
several factors.
Matrix Metalloproteinases in the Periodontium-Vital in Tissue Turnover and Unfortunate in Periodontitis.
Int J Mol Sci. 2024 Feb 27;25(5):2763. doi: 10.3390/ijms25052763.
PMID: 38474009
Free PMC article.
Review.The extracellular matrix (ECM) is a complex non-cellular
three-dimensional macromolecular network present within all tissues and
organs, forming the foundation on which cells sit, and composed of
proteins (such as collagen), glycosaminoglycans, proteoglycans,
minerals, and water. The ECM provides a fundamental framework for the
cellular constituents of tissue and biochemical support to surrounding
cells.
The ECM is a highly dynamic structure that is constantly being remodeled. Matrix metalloproteinases
(MMPs) are among the most important proteolytic enzymes of the ECM and
are capable of degrading all ECM molecules. MMPs play a relevant role in physiological as well as pathological
processes; MMPs participate in embryogenesis, morphogenesis, wound
healing, and tissue remodeling, and therefore, their impaired activity
may result in several problems. MMP activity is also associated with
chronic inflammation, tissue breakdown, fibrosis, and cancer invasion
and metastasis. The periodontium is a unique anatomical site, composed
of a variety of connective tissues, created by the ECM. During
periodontitis, a chronic inflammation affecting the periodontium,
increased presence and activity of MMPs is observed, resulting in
irreversible losses of periodontal tissues. MMP expression and activity
may be controlled in various ways, one of which is the inhibition of
their activity by an endogenous group of tissue inhibitors of
metalloproteinases (TIMPs), as well as reversion-inducing cysteine-rich
protein with Kazal motifs (RECK).
Matrix metalloproteinases are associated with severity of disease among COVID-19 patients: A possible pharmacological target.
Basic Clin Pharmacol Toxicol. 2024 Mar 11. doi: 10.1111/bcpt.14001. Online ahead of print.
PMID: 38468413
COVID-19 is a devastating disease and imbalanced matrix
metalloproteinase (MMP) activity may contribute to its pathophysiology. This exploratory study examined whether increased circulating
concentrations of MMP-2 and MMP-9, and their endogenous inhibitors, the
tissue inhibitors of MMP (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4 are
persistently found in patients 2 weeks after their recovery from severe
or critical COVID-19 as compared with those in healthy controls.
Subjects who had severe (n = 26) or critical (n = 25) PCR-confirmed
COVID-19 and healthy controls (n = 21) had blood samples drawn 2 weeks
after recovery and serum MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4
were determined using two Human Luminex® Discovery Assays. Circulating
MMP activity was also determined by gel zymography. Patients who had
severe or critical COVID-19 had increased circulating MMP-9 and MMP-2
concentrations, with increased MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios
indicating increased MMP activity, confirmed by gel zymography (all p
< 0.05). Higher circulating MMP-9 (but not MMP-2) concentrations were
found in critical versus severe COVID-19 (p < 0.05). We found
increased circulating MMP-9 and MMP-2 concentrations and activity many
days after recovery from the acute disease, with MMP-9 levels associated
with disease severity. These biochemical alterations suggest that MMP-2
and MMP-9 may be important pharmacological targets in COVID-19.
Serum levels of matrix metalloproteinases 1, 2, and 7, and their tissue inhibitors 1, 2, 3, and 4 in polytraumatized patients: Time trajectories, correlations, and their ability to predict mortality.
PLoS One. 2024 Mar 8;19(3):e0300258. doi: 10.1371/journal.pone.0300258. eCollection 2024.
PMID: 38457458
Free PMC article.
There has been limited research on assessing metalloproteinases (MMPs)
1, 2, and 7, as well as their tissue inhibitors (TIMPs) 1, 2, 3, and 4
in the context of polytrauma. These proteins play crucial roles in
various physiological and pathological processes and could be a reliable
tool in polytrauma care. We aimed to determine their clinical
relevance. We assessed 24 blunt polytrauma survivors and 12 fatalities
(mean age, 44.2 years, mean ISS, 45) who were directly admitted to our
Level I trauma center and spent at least one night in the intensive care
unit. We measured serum levels of the selected proteins on admission
(day 0) and days 1, 3, 5, 7, and 10. The serum levels of the seven
proteins varied considerably among individuals, resulting in similar
median trend curves for TIMP1 and TIMP4 and for MMP1, MMP2, TIMP2, and
TIMP3. We also found a significant interrelationship between the MMP2,
TIMP2, and TIMP3 levels at the same measurement points. Furthermore, we
calculated significant cross-correlations between MMP7 and MMP1, TIMP1
and MMP7, TIMP3 and MMP1, TIMP3 and MMP2, and TIMP4 and TIMP3 and an
almost significant correlation between MMP7 and TIMP1 for a two-day-lag.
The autocorrelation coefficient reached statistical significance for
MMP1 and TIMP3. Finally, lower TIMP1 serum levels were associated with
in-hospital mortality upon admission. The causal effects and
interrelationships between selected proteins might provide new insights
into the interactions of MMPs and TIMPs. Identifying the underlying
causes might help develop personalized therapies for patients with
multiple injuries. Administering recombinant TIMP1 or increasing
endogenous production could improve outcomes for those with multiple
injuries. However, before justifying further investigations into basic
research and clinical relevance, our findings must be validated in a
multicenter study using independent cohorts to account for clinical and
biological variability.
Resistance training modifies of serum levels of matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases in multiple sclerosis women - a randomized controlled trail.
BMC Neurosci. 2024 Mar 4;25(1):13. doi: 10.1186/s12868-024-00856-1.
PMID: 38438999
Free PMC article.
Clinical Trial.
Fifteen healthy aged-matched women participated as a control group (HCON). The serum level of matrix metalloproteinase-2 (MMP-2), matrix metallopeptidase-9 (MMP-9), tissue metalloproteinase inhibitors-1 (TIMP-1), tissue metalloproteinase inhibitors-2 ( …
BMC Cancer. 2024 Mar 4;24(1):296. doi: 10.1186/s12885-024-12030-1.
PMID: 38438882
Free PMC article.
The expression of E-cadherin was upregulated and those of
MMP9, Ezrin, Bcl-2, p-c-RAF (S338) and p-ERK1/2 (T202/Y204) were
downregulated after DOCK1 knockout, while DOCK1 overexpression played
the opposite effect. Additionally, Raf inhibitor LY3009120 reversed the function … '
- Vielä 11-29 artikkelit ovat tältä vuodelta 2024. Niistätä otan vain otsikot. no 30 on joulukuulta 2023.
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