MMP7, Regulated by c-Jun, is Involved in Oral Squamous Cell Carcinoma and Associated with Cancer-Related Fibroblasts Infiltration.

OBJECTIVE: This study aimed to analyze the expression of Matrix Metalloproteinase 7 (MMP7) and molecular mechanism at the Transcription Factor (TF) level in Oral Squamous Cell Carcinoma (OSCC). METHODS: MMP7 expression was preliminarily explored in Head and Neck Squamous Cell Car-cinoma (HNSCC) in the online database, followed by functional analysis and prediction of TF of MMP7. IHC was employed to detect MMP7 levels in OSCC samples. SCC9 and 293T cells were used to explore the transcriptional and regulatory effects of predicted TF on MMP7 by reporter double luciferase assay, RT-qPCR, western blotting, and cellular immunofluorescence. Transwell and TUNEL were employed to detect the migration and apoptosis. RESULTS: MMP7 was significantly up-regulated in HNSCC and OSCC tissues. Moreover, MMP7 was positively correlated with CAFs and significantly enriched in the signaling pathway of RNA degradation. The c-Jun pathway was also up-regulated in OSCC tissues, and predicted to be optimal TF of MMP7 with positive regulatory relationship. In OSCC, silencing and over-expression of c-Jun significantly decreased and increased the level of MMP7. Meanwhile, c-Jun affected the behavior of SCC9 cells, which showed that after c-Jun gene silencing, the ability of cell migration was weakened, while apoptosis was enhanced. When c-Jun gene was overexpressed, the migration ability was enhanced, but apoptosis was not significantly affected. CONCLUSION: MMP7 has been proven to be a key protein in the development of OSCC, and has the potential to become a biological marker and therapeutic target. It has been found that c-Jun could bind to the MMP7 promoter region, and the silencing or overexpression of c-Jun can positively regulate the expression of MMP7.

Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway.

Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.

Could aerobic exercise applied before constraint-induced movement therapy change circulating molecular biomarkers in chronic post-stroke?

BACKGROUND: Integrating aerobic exercise (AE) into rehabilitation programs for post-stroke individuals could enhance motor recovery and cardiovascular health by increasing brain-derived neurotrophic factor (BDNF) and the myokine irisin. Chronic stroke survivors typically exhibit elevated matrix metalloproteinase-9 (MMP-9) activity, which is negatively correlated with steps and time in medium cadence, although the impact of AE on this biomarker remains unclear. OBJECTIVE: To evaluate the effect of high-intensity AE training prior to modified constraint-induced movement therapy (mCIMT) on BDNF and irisin concentration, and on MMP-2 and MMP-9 activity in chronic post-stroke individuals and to associate these results with functional improvements. METHODS: Nine participants received AE combined with mCIMT for two weeks, while the control group (n = 7) received mCIMT alone. Manual dexterity and functional capacity were assessed before and after the intervention. Serum samples were analyzed for BDNF, irisin, MMP-2 and MMP-9. RESULTS: There were no significant main effects of assessment, group or interaction on molecular biomarkers. However, the AE group had a significant increase in MMP-9 activity post-intervention (p = .033; d = 0.67). For the Box and Block Test, there were significant main effects of assessment (F [1, 14] = 33.27, p = .000, ηp2 = 0.70) and group (F [1, 14] = 5.43, p = .035, ηp2 = .28). No correlations were found between biomarkers and clinical assessments. CONCLUSION: AE prior to mCIMT did not influence circulating BDNF and irisin levels but did induce an acute rise in MMP-9 activity, suggesting potential effects on cardiovascular remodeling in this population.

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

Maternal blood endometase level as a predictive biomarker for hypertensive disorders during pregnancy: a prospective cohort study.

Preeclampsia (PE) occurs due to inadequate spiral artery/trophoblast remodeling in early pregnancy. Endometases are involved in the remodeling of spiral arteries and placental trophoblasts. This study aimed to investigate differences in blood endometase levels between pregnant women with hypertensive disorders (PE and gestational hypertension [GHT]) and healthy pregnant women and to evaluate whether plasma endometase values ​​could play a predictive role in PE or GHT diagnosis. A total of 90 pregnant women (n(PE) = 30, n(GHT) = 30, n(healthy pregnant) = 30) who presented at the hospital between December 2023 and May 2024 and were 26-32 years of age and > 20 weeks pregnant were included in the study. The endometase levels in all pregnant women were determined in maternal blood plasma via enzyme-linked immunosorbent assay. The endometase values were recalculated according to albumin values, and corrected endometase (cEndo) values were determined. No significant differences in blood endometase levels were observed between the groups (p > 0.05). The cEndo value was significantly lower in the PE and GHT groups than in the control group (p < 0.05). There was no statistically significant difference in the cEndo values between the PE and GHT groups (p > 0.05). A statistically significant negative linear relationship was detected between cEndo values and mean systolic blood pressure and mean diastolic blood pressure (p < 0.05). The cEndo values in the PE and GHT groups at early (≤ 32 weeks 3 days) and late pregnancy were compared, and no statistically significant difference was detected (p > 0.05). Maternal blood cEndo values may play a successful role in distinguishing hypertensive diseases of pregnancy (PE + GHT) from healthy pregnant women. cEndo does not play an effective role in the differential diagnosis between pregnant women with PE and those with GHT. Studies with larger patient populations are needed.

Protein Kinase C and Matrix Metalloproteinases Expression Using Phorbol Myristate Acetate in Degenerative Intervertebral Disc Cells.

Background: Degeneration of nucleus pulposus (NP) cells involves multiple factors. The relationship between the canonical Wnt/ß-catenin signaling pathway and matrix metalloproteinases (MMPs) is important in cellular senescence. Protein kinase C (PKC), an intermediate of the non-canonical Wnt pathway stimulated by phorbol myristate acetate (PMA), possibly prevents NP cell senescence, although not yet demonstrated in human-based studies. This study aimed to investigate the effect of PMA stimulation on the non-canonical and canonical Wnt pathways and MMP expression in human NP cells to ascertain its inhibitory effects on the senescence of NP cells. Methods: Human disc tissues of Pfirrmann grades 1 and 2 were collected from patients during spinal surgery and subsequently cultured. Protein and ribonucleic acid (RNA) were isolated from NP cells treated with PMA (400 nM) for 24 hours. Expression of MMP1, MMP13, tissue inhibitor of matrix metalloproteinase 1 (TIMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), transient receptor potential vanilloid 4 (TRPV4), interleukin-6 (IL-6), and ß-catenin were detected using western blot analysis. Messenger RNA (mRNA) expression of type II collagen and glycosaminoglycan (GAG) were analyzed using reverse transcription polymerase chain reaction. IL-6 and prostaglandin E2 (PGE2) levels were measured using enzyme-linked immunosorbent assay. Results: Expression of PKC-δ (intermediate of the non-canonical Wnt pathway) and ß-catenin (intermediate of the canonical Wnt pathway) was increased by PMA treatment. The mRNA levels of type II collagen and GAG increased; however, their protein levels were not altered. PMA treatment increased the expression of MMP1, TIMP1, ADAMTS5, IL-6, PGE2, and TRPV4; however, the expression of MMP13 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was unaltered. Conclusions: PMA activated PKC-δ, affecting the non-canonical Wnt pathway; however, its effect on ß-catenin in the canonical Wnt pathway was limited. ß-catenin activation through the TRPV4 channel led to increased expression of MMP1 and ADAMTS5 and that of IL-6 and PGE2 owing to NF-κB expression. Consequently, the degeneration of NP cells was not prevented.

Degradation of pathogenic amyloids induced by matrix metalloproteinase-9.

Over the past decade, the greatest promise for treating severe and currently incurable systemic and neurodegenerative diseases has turned to agents capable of effectively degrading pathological amyloid deposits without causing side effects. Specifically, amyloid destruction observed in immunotherapy is hypothesized to occur through activation of proteolytic enzymes. This study examines poorly understood effects of an immune enzyme, extracellular matrix metalloproteinase-9 (MMP9), on amyloids associated with Alzheimer's and Parkinson's diseases, lysozyme, insulin, and dialysis-related amyloidoses. The study establishes the universality of MMP9's effect on various amyloids, with its efficacy largely depending on the fibrillar cluster size. Irreversible amyloid degradation by MMP9 is attributed to the destruction of intramolecular interactions rather than intermolecular hydrogen bonds in the fibril backbone. This process results in the loss of ordered fiber structure without reducing aggregate size or increasing cytotoxicity. Thus, MMP9 can mitigate side effects of anti-amyloid therapy associated with the formation of low-molecular-weight degradation products that may accelerate fibrillogenesis and amyloid propagation between tissues and organs. MMP9 shows promise as a component of safe anti-amyloid drugs by enhancing the accessibility of binding sites through "loosening" amyloid clusters, which facilitates subsequent fragmentation and monomerization by other enzymes.

Changes in PEDF, MMP-2, and TGF-ß2 levels in the aqueous humor of cataract patients and their correlation with disease severity.

OBJECTIVE: To explore the changes of Pigment Epithelium-Derived Factor (PEDF), Matrix Metalloproteinase-2 (MMP-2), and Transforming Growth Factor-ß2 (TGF-ß2) levels in the aqueous humor of cataract patients and their correlation with disease severity. METHODS: 93 cataract patients and 56 healthy subjects were study objects. PEDF, MMP-2, and TGF-ß2 levels of aqueous humor were compared, and the correlation between each index and Lens Opacity Classification System (LOCS) III classification was analyzed. ROC curve was used to analyze the evaluation value of the combined detection of each index on cataract development, and logistic regression to analyze the influence of the changes of each index on cataract development. RESULTS: PEDF levels were lower and MMP-2 and TGF-ß2 levels were higher in the aqueous humor of cataract patients than in healthy subjects. PEDF levels in the aqueous humor were negatively correlated with LOCS III classification, while MMP-2 and TGF-ß2 levels were positively correlated with LOCS III classification. The AUC value of combined detection was higher than that of PEDF, MMP-2, and TGF-ß2 in the aqueous humor alone. MMP-2 ≥ 15.13 pg/mL, TGF-ß2 ≥ 385.91 pg/mL and PEDF < 198.85 ng/mL were risk factors for cataract development. CONCLUSION: The changes in PEDF, MMP-2, and TGF-ß2 levels in the aqueous humor of cataract patients are related to LOCS III classification. The combined detection is valuable in evaluating cataract development.

Circulating Matrix Metalloproteinases for Prediction of Aortic Dilatation in Children with Bicuspid Aortic Valve: A Single-Center, Observational Study.

Circulating biomarkers have been proposed for early identification of aortic dilatation progression associated with bicuspid aortic valve (BAV), but matrix metalloproteinases (MMPs) are distinguished as signatures of increased extracellular matrix degradation, a landmark of aneurysm formation. The current study aims to identify the role of MMP-1, MMP-2, MMP-9, and the MMP inhibitor, TIMP-1, in identifying aortic dilation in children with BAV. We conducted a study on 73 children divided into two study groups, depending on the presence of aortic dilatation (group 1-43 BAV controls and group 2-30 children with BAV and aortic dilatation). Each patient underwent a cardiac ultrasound and, in each case, serum MMP-1, MMP-2, MMP-9, and TIMP-1 were quantified using xMAP technology. Comparison of the MMPs between the two study groups revealed significantly higher values only in the case of TIMP-1, among BAV controls. Moreover, the same TIMP-1 inversely correlated with aortic annulus absolute size and z score, as well as with ascending aorta z score. No particular correlation between the aortic phenotype and the presence of aortic dilatation was found. Future longitudinal research starting at pediatric ages could show the significance of MMPs screening in BAV individuals as predictors of aortic aneurysm formation.

Exploring the Bioactive Potential of Taraxacum officinale F.H. Wigg Aerial Parts on MDA Breast Cancer Cells: Insights into Phytochemical Composition, Antioxidant Efficacy, and Gelatinase Inhibition within 3D Cellular Models.

In this work, aerial parts of Taraxacum officinale F.H. Wigg. produced in Umbria, Italy, were chemically investigated by solid-phase microextraction/gas chromatography-mass spectrometry (SPME/GC-MS) to describe their volatile profile. The results obtained showed the preponderant presence of monoterpenes, with limonene and 1,8-cineole as the main components. Further analyses by GC/MS after derivatization reaction were performed to characterize the non-volatile fraction highlighting the presence of fatty acids and di- and triterpenic compounds. T. officinale methanol and dichloromethane extracts, first analyzed by HRGC/MS, were investigated to evaluate the antioxidant activity, cytotoxicity, and antiproliferative properties of MDA cells on the breast cancer cell line and MCF 10A normal epithelial cells as well as the antioxidant activity by colorimetric assays. The impact on matrix metalloproteinases MMP-9 and MMP-2 was also explored in 3D cell systems to investigate the extracts' efficacy in reducing cell invasiveness. The extracts tested showed no cytotoxic activity with EC50 > 250 µg/mL on both cell lines. The DPPH assay revealed higher antioxidant activity in the MeOH extract compared with the DCM extract, while the FRAP assay showed a contrasting result, with the DCM extract exhibiting slightly greater antioxidant capacity. After treatment for 24 h with a non-cytotoxic concentration of 500 µg/mL of the tested extracts, gelatin zymography and Western blot analyses demonstrated that both MeOH and DCM extracts influenced the expression of MMP-9 and MMP-2 in MDA cells within the 3D cell model, leading to a significant decrease in the levels of these gelatinases, which are crucial markers of tumor invasiveness.

Targeting Matrix Metalloproteinase-3 for Dental Caries Prevention Using Herbal Isolates: MMP3 Inhibition by Cinnamic Acids.

Objectives: Dental caries, a prevalent infectious disease affecting teeth, ranks highest among 328 diseases, according to a 2017 Lancet study. In demineralized human dentin, matrix metalloproteinase-3 (MMP3) functions as a proteoglycanase, contributing to the degradation of proteoglycan components. This process exposes collagen fibrils, thereby facilitating the demineralization of the dentin matrix. Inhibiting MMP3 shows potential for preventing dental caries. Methods: The binding affinity of 20 cinnamic acid derivatives, namely cynarin, chlorogenic acid, rosmarinic acid, cinnamyl caffeate, phenethyl caffeate, N-p-coumaroyltyramine, caffeic acid 3-glucoside, caffeic acid phenethyl ester, roscovitine, benzyl caffeate, o-coumaric acid, artepillin C, caffeic acid, methyl caffeate, 2-methylcinnamic acid, ferulic acid, drupanin, p-coumaric acid, cinnamic acid, and sinapinic acid, to the MMP3 catalytic cleft, was assessed utilizing AutoDock 4.0. Molecular dynamics simulation was then employed to analyze the stability of backbone atoms in free MMP3, MMP3-positive control inhibitor, and MMP3 complexed with the top-ranked cinnamic acid over a 100 ns computer simulation. Results: Four cinnamic acids demonstrated ΔG binding scores below -10 kcal/mol, with cynarin emerging as the most potent MMP3 inhibitor, featuring a ΔG binding score and inhibition constant value of -15.57 kcal/mol and 3.83 pM, respectively. The MMP3-cynarin complex exhibited stability after a 50 ns computer simulation, showing a root-mean-square deviation of 8 Å. Conclusions: The inhibition of MMP3 by cynarin, chlorogenic acid, rosmarinic acid, and cinnamyl caffeate holds promise as a potential preventive strategy for dental caries.

Cannabiorcol as a novel inhibitor of the p38/MSK-1/NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis.

BACKGROUND: The bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear. METHODS: In silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1ß and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol's effects on OA and its fundamental mechanisms. RESULTS: Cannabiorcol inhibits the expression of IL-1ß-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa ß (NF-κß) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats. CONCLUSION: Cannabiorcol inhibits IL-1ß-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.

Impacts of Matrix Metalloproteinase-8 Genotypes, Smoking, Alcohol Drinking, and Helicobacter Pylori Infection on Gastric Cancer.

BACKGROUND/AIM: In gastric cancer (GCa) tissues, mRNA expression of matrix metalloproteinase-8 (MMP-8) is notably reduced compared to healthy tissues. Furthermore, abnormally low or elevated serum levels of MMP-8 have been linked to a significantly poor prognosis. The involvement of MMP-8 genotypes in susceptibility to GCa remains underexplored. We aimed to assess the influence of MMP-8 genotypes on GCa susceptibility and their potential interactions with smoking, alcohol consumption, and Helicobacter pylori (H. pylori) infection. PATIENTS AND METHODS: The study utilized polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) to analyze MMP-8 rs11225395, rs34009635, and rs35866072 genotypes in 161 GCa patients and 483 controls. RESULTS: No statistically significant difference was detected in the distribution of genotypic (p for trend=0.3635) or allelic (p=0.1954) frequencies of MMP-8 rs11225395. Under a dominant model, combined CT+TT genotypes showed no association with GCa risk [odds ratio (OR)=0.77, 95% confidence interval (95%CI)=0.54-1.10, p=0.1852]. Similarly, no association was observed for MMP-8 rs34009635 or rs35866072. Importantly, individuals with the MMP-8 rs11225395 CC genotype demonstrated a significant increase in GCa risk when exposed to smoking (OR=4.04, 95%CI=2.28-7.16, p=0.0001), alcohol consumption (OR=2.83, 95%CI=1.64-4.89, p=0.0002), and H. pylori infection (OR=3.53, 95%CI=2.12-5.90, p=0.0001). CONCLUSION: The findings indicate that individuals carrying the MMP-8 rs11225395 CC genotype have increased susceptibility to GCa, especially when combined with risk factors, such as smoking, alcohol consumption, and H. pylori infection. These results suggest that MMP-8 genotype-based preventive strategies, including lifestyle alterations and targeted infection treatments, may be valuable in mitigating GCa development.

Evaluation of the effect of taurine on the matrix metalloproteinase-9 and the expression changes of miRNA-21 and miRNA-146a in SH-SY5Y cell line.

OBJECTIVES: Alzheimer's disease (AD), a brain disorder, is the leading cause of dementia among older adults. Taurine, an amino acid abundantly present in the brain, and shows potential neuroprotective properties. Therefore, we investigated the effects of taurine on Matrix Metalloproteinase-9 (MMP-9) levels and the expression changes of miRNA-21 and miRNA-146a in the SH-SY5Y cell line. METHODS: Taurine's impact on the SH-SY5Y cell line was evaluated via the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. MMP-9 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while the expression of miRNA-21 and miRNA-146a genes was assessed through Real-Time PCR analysis. RESULTS: The MTT assay revealed no toxic effects on SH-SY5Y cells with increasing concentrations of taurine. Analysis of gene expression indicated a rise in miRNA-21 expression and a decline in miRNA-146 expression with increasing taurine concentration, with the most notable change observed at 1 mg/mL taurine (p<0.001). ELISA results demonstrated a significant increase in MMP-9 levels in the SH-SY5Y cell line treated with 1 mg/mL taurine compared to the untreated group (p<0.001). CONCLUSIONS: Our study revealed that taurine can alter the expression of miRNA-146a and miRNA-21. In conclusion, taurine therapy presents promising therapeutic avenues for treating AD or mitigating severe symptoms. Nonetheless, further research is necessary to comprehensively grasp the precise mechanisms at play.

Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Cyclic adenosine monophosphate critically modulates cardiac GLP-1 receptor's anti-inflammatory effects.

BACKGROUND: Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. They also have anti-inflammatory actions through both central and peripheral mechanisms. GLP1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3`-5`-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various anti-apoptotic and anti-inflammatory effects via its effectors protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). However, the precise role and importance of cAMP in mediating GLP1R`s anti-inflammatory actions, at least in the heart, remains to be determined. To this end, we tested the effects of the GLP1R agonist liraglutide on lipopolysaccharide (LPS)-induced acute inflammatory injury in H9c2 cardiac cells, either in the absence of cAMP production (AC inhibition) or upon enhancement of cAMP levels via phosphodiesterase (PDE)-4 inhibition with roflumilast. METHODS & RESULTS: Liraglutide dose-dependently inhibited LPS-induced apoptosis and increased cAMP levels in H9c2 cells, with roflumilast but also PDE8 inhibition further enhancing cAMP production by liraglutide. GLP1R-stimulated cAMP markedly suppressed the LPS-dependent induction of pro-inflammatory tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6 cytokine expression, of inducible nitric oxide synthase (iNOS) expression and nuclear factor (NF)-kB activity, of matrix metalloproteinases (MMP)-2 and MMP-9 levels and activities, and of myocardial injury markers in H9c2 cardiac cells. The effects of liraglutide were mediated by the GLP1R since they were abolished by the GLP1R antagonist exendin(9-39). Importantly, AC inhibition completely abrogated liraglutide`s suppression of LPS-dependent inflammatory injury, whereas roflumilast significantly enhanced the protective effects of liraglutide against LPS-induced inflammation. Finally, PKA inhibition or Epac1/2 inhibition alone only partially blocked liraglutide`s suppression of LPS-induced inflammation in H9c2 cardiac cells, but, together, PKA and Epac1/2 inhibition fully prevented liraglutide from reducing LPS-dependent inflammation. CONCLUSIONS: cAMP, via activation of both PKA and Epac, is essential for GLP1R`s anti-inflammatory signaling in cardiac cells and that cAMP levels crucially regulate the anti-inflammatory efficacy of GLP1R agonists in the heart. Strategies that elevate cardiac cAMP levels, such as PDE4 inhibition, may potentiate the cardiovascular, including anti-inflammatory, benefits of GLP1R agonist drugs.

Matrix Metalloproteinases on Skin Photoaging.

BACKGROUND: Skin aging is characterized by an imbalance between the generation and degradation of extracellular matrix molecules (ECM). Matrix metalloproteinases (MMPs) are the primary enzymes responsible for ECM breakdown. Intrinsic and extrinsic stimuli can induce different MMPs. However, there is limited literature especially on the summary of skin MMPs and potential inhibitors. OBJECTIVE: We aim to focus on the upregulation of MMP expression or activity in skin cells following exposure to UV radiation. We also would like to offer valuable insights into potential clinical applications of MMP inhibitors for mitigating skin aging. METHODS: This article presents the summary of prior research, which involved an extensive literature search across diverse academic databases including Web of Science and PubMed. RESULTS: Our findings offer a comprehensive insight into the effects of MMPs on skin aging after UV irradiation, including their substrate preferences and distinct roles in this process. Additionally, a comprehensive list of natural plant and animal extracts, proteins, polypeptides, amino acids, as well as natural and synthetic compounds that serve as inhibitors for MMPs is compiled. CONCLUSION: Skin aging is a complex process influenced by environmental factors and MMPs. Research focuses on UV-induced skin damage and the formation of Advanced Glycosylation End Products (AGEs), leading to wrinkles and impaired functionality. Inhibiting MMPs is crucial for maintaining youthful skin. Natural sources of MMP inhibitor substances, such as extracts from plants and animals, offer a safer approach to obtain inhibitors through dietary supplements. Studying isolated active ingredients can contribute to developing targeted MMP inhibitors.

Elevated Plasma Matrix Metalloproteinases Are Associated With Mycobacterium tuberculosis Bloodstream Infection and Mortality in Human Immunodeficiency Virus-Associated Tuberculosis.

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

At2-MMP is required for attenuation of cell proliferation during wound healing in incised Arabidopsis inflorescence stems.

Wound healing of partially incised Arabidopsis inflorescence stems constitutes cell proliferation that initiates mainly in pith tissues about three days after incision, and that the healing process completes in about seven days. Although the initiation mechanisms of cell proliferation have been well documented, the suppression mechanisms remain elusive. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases well-known as proteolytic enzymes in animal systems functioning in extracellular matrix remodeling during physiological and pathological processes, including tissue differentiation, growth, defense, wound healing, and control of cancer growth. In this study, we report At2-MMP might contribute to the suppression mechanism of cell proliferation during tissue-repair process of incised inflorescence stems. At2-MMP transcript was gradually upregulated from day 0 to 5 after incision, and slightly decreased on day 7. Morphological analysis of incised stem of defected mutant at2-mmp revealed significantly enhanced cell proliferation around the incision site. Consistent with this, semi-quantitative analysis of dividing cells displayed a significant increment in the number of dividing cells in at2-mmp as compared to WT. These results showed that the upregulation of At2-MMP at the later stage of wound-healing process is likely to be involved in the completion of the process by attenuating the cell proliferation.

Significance of Fibrillin-1, Filamin A, MMP2 and SOX9 in Mitral Valve Pathology.

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ-relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1-2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets.