Metalloproteinase Inhibitor Research Articles (Page 1)

Chitosan/mesoporous bioactive glass nanoparticles (MBGNs) composite coating deposited on silk suture: An initial in-vivo study.

In vitro inhibition of snake venom toxins by varespladib, marimastat, nafamostat and dimercaprol.

CRIP1 exacerbates osteoarthritis progression by recruiting UBE3A to induce the ubiquitination-mediated degradation of MFGE8.

Neuroprotective efficacy of royal jelly and propolis against cadmium-induced dysregulation of neurogenesis and neurotransmitters in the brain of rats: Molecular mechanisms and ultrastructure investigations.

Endometrial regeneration and the role of the extracellular matrix: mechanisms, challenges, and future perspectives.

Synaptic formation, the cornerstone of neurological function, underpins complex behaviors and cognitive processes, with structural/functional aberrations implicated in neurodevelopmental disorders and neurodegenerative pathologies. Synaptogenesis involves dynamic interplay between cell adhesion molecules (CAMs) and extracellular matrix (ECM) components, which collectively regulate neuronal connectivity and plasticity. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), emerge as critical regulators of these processes through ECM remodeling and modulation of cell surface receptor signaling. This review synthesizes current understanding of ECM-TIMP-MMP axes in synaptic development, highlighting their dual roles in physiological plasticity and pathological disruption across neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), neuro-oncological disorders, and neuroinflammatory conditions. By dissecting the context-dependent functions and therapeutic implications of TIMP family members in synaptic maintenance and disease progression, this work provides a conceptual framework for advancing TIMP-based neurotherapeutic strategies and a theoretical basis for future exploration of TIMP as a potential therapeutic target for neurological disorders.

Introduction: VS-041 is a novel drug candidate for HFpEF that inhibits key MMPs implicated in cardiac fibroinflammation, and diastolic dysfunction. VS-041 also inhibits formation of endotrophin, a collagen 6α–derived peptide, associated with increased risk of poor outcomes (heart failure hospitalization or death) in HFpEF. We conducted a phase 1 single- and multiple-ascending dose (SAD/MAD) safety, tolerability and pharmacokinetics (PK) study, and measured suppression of MMP9 activity in clinical plasma samples to estimate target engagement by VS-041. Methods: A randomized, double-blinded, placebo-controlled study enrolled 70 healthy participants. The study was comprised of two parts: both SAD and MAD were conducted with 8 participants (6 active, 2 placebo) per cohort. In the SAD, 5 cohorts received VS-041 orally as immediate release tablets at dosages ranging from 30 mg to 500 mg. In the MAD part, 4 cohorts received 50mg – 400mg once- or twice-daily dosing for 7 days. Safety evaluation included assessment of adverse events (AE), vital signs, ECGs, and clinical laboratory tests. Blood samples were collected for PK analysis. A novel ex-vivo MMP9 activity assay in human plasma was performed using fluorescein-labeled gelatin conjugate as a physiological and specific substrate for MMP9. Results: VS-041 was well tolerated across the dose range tested. No serious adverse events or dose-limiting toxicities were observed. There were few treatment-emergent AEs, all classified as mild and unrelated to test article administration. There were no ECG changes. VS-041 demonstrated dose-dependent increases in exposure up to 400mg, and steady state was achieved within 2 days with no accumulation. Terminal half-life ranged between 6-9 hrs. Serum levels achieved were within target range of the estimated minimally efficacious dose. In the ex-vivo assay, the gelatinolytic activity of MMP9 in plasma was inhibited by VS-041 in a concentration-dependent manner. The exposure of VS-041 modeled at a dose of 200mg BID is predicted to be continuously above or at the IC 50 for MMP9 (~90nM). Conclusions: VS-041 is safe and well tolerated at doses that effectively inhibit key MMPs implicated in cardiac pathophysiology, offering promising therapeutic potential for patients with HFpEF.

Background: Chronic kidney disease (CKD) has been linked to elevated inflammatory biomarkers, yet few studies have evaluated these associations using iothalamate-based measures of kidney function, highlighting the need for further research. Research question: Is CKD associated with elevated inflammatory markers when defined by measured glomerular filtration rate (mGFR) and urinary albumin-to-creatinine ratio (UACR)? Methods: Participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort were included if they had data available for at least one inflammatory marker at visit 2. 17 inflammatory markers were assessed, including C-reactive protein (CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), serum amyloid A, intercellular and vascular adhesion molecules (ICAM, VCAM), E-selectin, P-selectin, monocyte chemoattractant protein (MCP), myeloperoxidase (MPO), receptor for advanced glycation end products (RAGE), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Kindey function was assessed using the urinary clearance of iothalamate. CKD was defined as mGFR < 60 mL/min/1.73 m 2 or UACR ≥ 30 mg/g. To further assess whether associations persisted without albuminuria, we also defined CKD solely by mGFR < 60 mL/min/1.73 m 2 . Generalized estimating equations (GEE) were used to assess associations between CKD status and inflammatory markers, accounting for familial clustering. Exponentiated beta coefficients from GEE models were used to present geometric mean (GM) ratios of each biomarker by CKD status, adjusted for demographics, lifestyle factors, cardiovascular risk factors, and medication use. Results: Among 1,010 participants (mean age 61 ± 10 years; 67% women; 48% Black adults), 207 were classified as having CKD. After adjusting for potential confounders, individuals with CKD had significantly higher levels of hsCRP, VCAM, TNFR1, and TNFR2 compared to those without CKD (GM ratios > 1; p < 0.05), while the remaining inflammatory markers showed no significant differences ( Figure 1 ). Importantly, these elevations remained significant when CKD was defined by mGFR alone ( Figure 2 ). Conclusion: Our findings suggest that CKD, defined by mGFR, is associated with specific inflammatory biomarkers, underscoring the need for mechanistic studies to investigate these associations.

IntroductionMatrix metalloproteinases (MMPs) are enzymes participating in tumorigenesis and tumor progression through their proteolytic and cell-signaling properties. They are regulated mostly by endogenous tissue inhibitors of metalloproteinases (TIMPs). The expression of both MMPs and TIMPs is often altered in cancers. Many studies investigated their potential as circulating cancer biomarkers, with confounding results, which might be induced by preanalytical issues, particularly by using serum instead of plasma. The study aims to investigate plasma levels of selected MMPs and TIMPs in association with the diagnosis and prognosis of colorectal cancer.MethodsThe clinico-pathological data of 148 patients operated for colorectal cancer were collected from the medical records system at the University Hospital Pilsen. Sixty-eight age-matched healthy subjects were included as controls. Plasma levels of MMP-2, -7, -8, -9, -10, and TIMP-1, -2, -3, and -4 were assessed with multiplex immunoassays with the technology xMAP.ResultsMMP-8 and -9 levels were significantly elevated in patients (P= 0.0002 and 0.0009, respectively), TIMP-2 levels were significantly decreased in colorectal cancer patients (P = 0.0016). When comparing the early colorectal cancer (stage I and II) with advanced colorectal cancer (stage III and IV), MMP-8 and TIMP-1 were significantly increased in advanced colorectal cancer (P = 0.0173 and <0.0001, respectively). The area under the curve and the receiver operating characteristic were between 0.680 and 0.530 for all studied biomarkers. In univariate analysis, overall survival was significantly elevated in patients with MMP-7, -8, or TIMP-1, which was higher than cut-offs (hazard ratio = 4.57, 2.03, and 7.64, respectively).ConclusionThese findings suggest that plasma MMP-7, MMP-8, and TIMP-1 are potential prognostic biomarkers for colorectal cancer . None of the investigated biomarkers revealed diagnostic potential.

The Potential Role of Serum Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) as a Biomarker of Fibrosis in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

TIMP1: A novel immune-related signature associated with invasiveness and inhibition of pituitary adenoma.

Failures in oral implant installation may be associated with elevated concentrations of matrix metalloproteinases (MMPs). The overexpression of these enzymes leads to extensive extracellular matrix degradation, delaying or impairing tissue repair. Moreover, their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), are often insufficient to counteract pathologically elevated MMP levels. To address this, various MMP-regulating strategies have been explored, including the use of flavonoids such as naringenin (NA), a citrus-derived compound with promising anti-inflammatory effects and MMP downregulation. Additionally, surface modifications of titanium (Ti) implants can enhance tissue response and improve osseointegration. This study aimed to characterize and evaluate the effects of Ti surface modification through alkali treatment and NA-laden gelatin methacryloyl (GelMA) coating on osteoblast (Ob) functions related to peri-implant repair invitro. Ti discs were alkalinized using 5 M sodium hydroxide (NaOH) at 60°C for 24 h. GelMA hydrogel (15% w/v) containing 0% (control) or 1% NA (w/w) was prepared and applied as a coating. The coatings were characterized for morphology, swelling, degradation, and NA release profile. SAOS-2 osteoblasts (HTB-85) were then cultured on the coated discs, and cell adhesion, viability, and synthesis of MMP-2, MMP-9, TIMP-1, and TIMP-2 were assessed. Data were analyzed by one- or two-way ANOVA and Student's t-test/post hoc tests (α = 0.05). Scanning electron microscopy confirmed successful coating, with the GelMA+NA 1% group showing a more uniform and porous surface compared to GelMA alone. Both formulations displayed similar swelling capacity and degradation profiles over 21 days (p > 0.05). NA release was sustained for 14 days, peaking at 15 h. Cell viability and adhesion were comparable between groups (p > 0.05). Osteoblasts cultured on GelMA and exposed to the inflammatory stimulus tumor necrosis factor-alpha (TNF-α) showed increased synthesis of MMP-2, MMP-9, TIMP-1, and TIMP-2. However, cells cultured on GelMA+NA 1% exhibited significantly reduced MMP-2 and MMP-9 levels compared to GelMA under TNF-α stimulation (p < 0.05), with no significant changes in TIMP-1 or TIMP-2. In summary, Ti surface modification through alkali treatment followed by GelMA/NA coating was cytocompatible, showed controlled degradability, sustained NA release, and downregulated MMP synthesis in osteoblasts. These results suggest its potential as a promising strategy to modulate MMPs, which may help mitigate excessive matrix degradation and favor peri-implant tissue repair.

Integrin β5-positive cancer-associated fibroblasts promoting lung adenocarcinoma invasion leading to poor prognosis.

The effects of TRPC6 activation for various periods of time on three classes of functional outputs were examined in cultured podocytes: albumin permeation across a confluent layer; changes in nephrin dynamics; and cell death. Albumin permeation in transwell assays was significantly increased within 1 h in response to the activation of formyl peptide receptors (FPR), but the TRPC6 inhibitor SAR‐7334 had no effect on this response, and 1 h or 24 h exposures to the TRPC6 activator PPZ2 did not increase albumin permeation. Direct TRPC6 activation for 24 h evoked an increase in shedding of nephrin ectodomains into the surrounding media, accompanied by an increase in matrix metalloprotease‐7 (MMP‐7). These effects were blocked by the calcineurin inhibitor cyclosporin A (CsA), as well as by Batimastat, a broad‐spectrum inhibitor of metalloproteinases including MMP‐7. TRPC6 activation for 24 h also evoked an increase in occludin abundance but had no effect on the abundance of podocin. Finally, TRPC6 activation for 72 h, but not for 24 h, evoked an increase in apoptotic cell death based on increases in cleaved caspase‐3. This effect was blocked by both SAR‐7334 and CsA. TRPC6 activation did not induce pyroptosis based on the measurement of cleaved gasdermin D.

Digital dermatitis (DD) is a painful hoof disease in cattle, closely linked to Treponema spp., for which the pathogenesis remains poorly understood and effective treatments are lacking. This study identifies a persistent pro-inflammatory proteomic signature in untreated, non-healing active DD lesions in the foot skin of cattle, characterized by increased immune cell infiltration and elevated matrix metalloproteinase (MMP) activity. Treatment of active DD lesions with CMC2.24, a non-antibiotic MMP inhibitor, maintains the lesions in an M2 stage in most cases; however, it reduces histological dermatitis, lowering reactive oxygen species (ROS) levels and downregulating proteomic keratinization pathways. Mechanistically, CMC2.24 dampens inflammatory IL-1β cell responses in bovine macrophages exposed to DD-associated T. phagedenis. Active DD lesions treated with oxytetracycline (OTC) antibiotics remain clinically similar to CMC2.24; however, they progress to chronic M4 stages, becoming keratinized and maintaining inflammatory features, including increased S100A8 expression and reactive oxygen species (ROS) production. These findings integrate clinical and histological observations from treatments with conventional antibiotics and antibiotic-free protease inhibitors, highlighting novel therapies for managing DD and mitigating the exaggerated inflammatory response.

The venom of hazardous jellyfish contains harmful substances to human health, such as metalloproteinases, which are challenging to purify. Therefore, identifying substrate sequences using crude venom is crucial for the development of peptide inhibitors. This study utilized a designed peptide library and an abundance-based hydrolysis product analysis approach to identify the substrate sequences of toxin metalloproteinases from Nemopilema nomurai nematocyst venom (NnNV) and further modified these sequences into peptide inhibitors. Specifically, a peptide library comprising 41 potential substrate sequences was constructed and incubated with NnNV. 12 substrate sequences and 14 cleavage sites were identified from the hydrolysis products. In the design of peptide inhibitors, thiol (-SH) and phosphate groups (-PO3H2) were used as zinc-binding groups, and sixty derived peptides were obtained. 15 peptide inhibitors were selected for their efficacy in inhibiting toxin metalloproteinase activity, with CPRGQPIIQDV demonstrating the most potent effect. CPRGQPIIQDV mainly presented β-sheet and random coil structures, and significantly reduced the cytotoxicity and pro-inflammatory effects of NnNV on RAW264.7 cells. This study established a method for identifying metalloproteinase substrate sequences using crude jellyfish venom and provided an initial design and screening of peptide inhibitors, offering new insights into the management of jellyfish stings.

Aim: This study aimed to evaluate the effect of various matrix metalloproteinase (MMP) inhibitors on the shear bond strength (SBS) of composite resin to dentin in permanent teeth using an etch-and-rinse adhesive system and the pairwise comparative analysis between each MMP inhibitor group and the control group.Materials and methods: Dentin blocks were prepared from 60 permanently extracted molars and were randomly distributed into four groups (each group, n = 15). The dentinal blocks were pretreated with 0.01M phosphate-buffered saline (PBS) (pH 7.2) in the control group (Group I), 2% chlorhexidine (CHX) (Group II), Gluma desensitizer (Kulzer, Germany) (Group III), and 6.5% proanthocyanidin (Group IV) before applying the etch and rinse adhesive system (Ivoclar, Switzerland). After the adhesive application, composite resin (Kulzer, Germany) was applied, and after seven days, the SBS values were determined with a Universal Testing Machine (Zwick/Roell Z020, ZwickRoell Group, Germany).Results: There was a significant difference in the SBS values of Gluma desensitizer, 2% CHX, 6.5% proanthocyanidin, and the control group (P < 0.05). The Gluma desensitizer group showed the highest bond strength values (mean 12.98 MPa), which were significantly greater than those of all the other groups.Conclusions: Under the experimental conditions of this study, pretreatment with MMP inhibitors was advantageous in improving the SBS of the composite attached to permanent teeth dentin, with Gluma being most effective.

Effects of hormonal treatment on the expression of collagen type I, matrix metalloproteinase-1, and tissue inhibitor of metalloproteinases-1 in endometriosis.

Proteomic polygenic risk scores of age-related plasma protein levels reveal a role for Metalloproteinase inhibitor 2 (TIMP2) in cognitive performance.

Cancer remains a significant global health challenge, affecting populations in both developed and developing countries. Increasing attention is being directed toward the potential of natural compounds as promising candidates in the search for effective cancer treatments. Dieckol, a marine-derived phlorotannin isolated from the brown algae Ecklonia cava, has garnered attention for its broad-spectrum bioactivities, particularly its anticancer potential. Dieckol demonstrates potent antioxidant and anti-inflammatory properties that help reduce oxidative stress and persistent inflammation, both of which are key contributors to tumor progression. It influences critical cellular processes such as apoptosis and autophagy, often triggering mitochondrial dysfunction and lysosomal impairment to induce cancer cell death. Dieckol has been shown to influence biotransformation enzymes and to restrict tumor invasion and metastasis by modulating matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and tissue inhibitors of metalloproteinases (TIMPs). In addition, it disrupts multiple oncogenic signaling cascades such as PI3K/Akt/mTOR, NF-κB, JAK/STAT3, and FAK which collectively hinder cancer cell growth, survival, motility, and angiogenesis. The aim of this review is to provide an in-depth analysis of existing studies on dieckol, emphasizing its diverse mechanisms and potential in suppressing cancer progression. It further highlights current evidence, clarifies its molecular targets, and evaluates its prospects as a promising candidate for cancer prevention and therapy.