Nanomedicines targeting matrix metalloproteinases for osteoarthritis treatment.

Limited involvement of MMP2, MMP9 and MMP14 in vasculogenic mimicry formation of human tumor cell lines.

Infection with Echinococcus multilocularis causes alveolar echinococcosis (AE), a severe parasitic disease characterised by progressive hepatic infiltration and fibrosis. Current treatment options remain limited, and the immune-mediated mechanisms underlying fibrosis are not fully understood. This study investigated the role of the IL-33/ST2 axis in AE-associated immunopathology and evaluated the effects of ST2 blockade in an experimental model. A murine model of AE was established in C57BL/6 mice, which were allocated to untreated infected, anti-ST2-treated infected and uninfected control groups. Liver pathology and fibrosis were assessed using haematoxylin and eosin staining, Masson's trichrome staining and transmission electron microscopy. Immune and fibrotic markers were analysed by immunohistochemistry and immunofluorescence. In parallel, liver samples from patients with AE were examined to evaluate translational relevance. Systemic cytokine profiles were quantified to assess immune modulation. Analysis of human AE liver samples showed an increased expression of IL-33/ST2 and associated immune and fibrotic markers, consistent with findings in the experimental mouse model. In infected mice, ST2 blockade significantly reduced metacestode lesion size and hepatic tissue invasion. This was accompanied by reduced fibrosis, as indicated by lower expression of α-smooth muscle actin, collagen I, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1. Anti-ST2 treatment was also associated with reduced hepatic infiltration of CD4⁺ T cells, B cells and M2 macrophages, along with decreased systemic levels of IFN-γ, TNF-α, IL-4, IL-13, IL-17 and IL-1β. ST2 blockade reduced metacestode growth and was associated with attenuated hepatic inflammation and fibrosis, supporting a role for IL-33/ST2 signalling in AE progression. Given the concurrent reduction in parasite burden, further studies are needed to determine whether the anti-fibrotic effects of ST2 inhibition are independent of parasite control.

Neuroinflammatory pathways activated by traumatic brain injury (TBI) are critical mediators of long-term neurological dysfunction and represent promising therapeutic targets. Toll-like receptor 4 (TLR4), an innate immune receptor, was previously shown to contribute to increased seizure susceptibility and cognitive deficits in rats after lateral fluid percussion injury (FPI). However, the cellular and molecular mechanisms underlying TLR4-mediated circuit dysfunction early after brain injury are not fully understood. In this study, we define a cell- and circuit- specific neuroimmune-enzyme effector signaling axis that mediates early post-TBI circuit dysfunction in the hippocampal Dentate Gyrus (DG). Using ex vivo electrophysiology in rat and mouse models one week after brain injury, we demonstrate that neuronal TLR4 signaling regulates both excitatory and inhibitory synaptic inputs to dentate granule cells (DGC). Collectively, pharmacological inhibition of TLR4 in rats and cell-type-specific deletion of TLR4 in mice show that neuronal TLR4 mediates injury-driven increase in DGC excitatory input frequency and relies on downstream activation of Matrix Metalloproteinase-9 (MMP-9). In contrast, TLR4 signaling contributed to a decrease in inhibitory current frequency after injury, but independent of MMP-9, revealing a mechanistic divergence. Systemic inhibition of either TLR4 signaling or MMP-9 activity in rats within 24h after injury reduced network hyperexcitability and improved long-term potentiation (LTP) in the DG measured in vivo one week after injury. Either TLR4 or MMP-9 inhibition early after injury effectively attenuated spatial memory deficits in a Barnes maze task one month post-injury. Paradoxically, in sham controls, inhibition of TLR4 increased the frequency of both excitatory and inhibitory inputs to DGCs and augmented network excitability, without altering MMP-9 levels, identifying context-dependent roles for TLR4 signaling. Together, these results identify a novel TLR4 -MMP-9 axis as a key driver of early post-TBI dentate gyrus circuit dysfunction and behavioral deficits.

Computational identification of potential MMP-2 inhibitors in cancer using machine learning, molecular docking, and dynamics simulations.

Despite the enormous health importance of cerebral small vessel disease (cSVD) there are few treatments available. A major limitation in screening new therapies is a lack of clinically relevant disease models. Induced pluripotent stem cell (iPSC) technology allows creation of in vitro models of the vascular unit, which is found to be affected in cSVD. Here we derived iPSC from skin biopsies obtained from patients with two of the most common monogenic forms of cSVD, HTRA1 mutations and COL4A1/2 mutations. iPSCs were differentiated into brain endothelial-like cells and mural cells and co-cultured in a transwell system to replicate the vascular unit. iPSC models derived from the two distinctive forms of monogenic cSVD demonstrated a common molecular phenotype characterised by tight junction defects, elevated actin stress fiber expression and mural cell loss, increased blood-brain barrier (BBB) permeability and elevated matrix metalloproteinase (MMP) levels. Moreover, the model was successfully optimised to a 96-well format to screen 13 MMP inhibitors, three of which effectively restored permeability to control levels. Our findings provide evidence that MMP inhibition could serve as a potential therapeutic strategy for cSVD as well as present a robust model to screen drugs in cSVD.

Host-directed therapy for tuberculosis: Repurposed drugs toward global tuberculosis elimination.

Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac changes during pregnancy. It is clear that during pregnancy, the heart adapts to increased ventricular preload through the development of a reversible, pregnancy-induced cardiac hypertrophy. Cardiomyocyte growth must be supported by changes in the cardiac extracellular matrix (ECM), an extremely diverse and dynamic set of components, whose composition and regulation affect cardiac biomechanics. The ECM undergoes extensive remodeling during periods of cardiac stress, such as those experienced during pregnancy and the postpartum period. The full extent of ECM changes and their contributions to biomechanical changes and maternal heart plasticity, however, remain vastly understudied. Recent studies suggest that alterations in the expression of several fibrillar collagens, such as collagens I and III, and regulatory proteins, such as matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases, occur during a healthy pregnancy. On the contrary, in the setting of pregnancy-associated cardiovascular diseases, such as preeclampsia and peripartum cardiomyopathy, adverse changes in ECM remodeling have been reported. This review aims to summarize the current state of the field, highlighting changes in the cardiac ECM and its components during healthy pregnancies, how perturbations in ECM remodeling can lead to the development of pregnancy-related cardiovascular pathologies, and discuss the notable gaps in knowledge that need to be addressed if we are to fully understand ventricular remodeling in the context of pregnancy and reduce maternal cardiovascular disease burden.

Effect of TU-100 on Colorectal Liver Metastasis in Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis.

To evaluate the role of matrix metalloproteinases (MMPs) and cathepsins in dentin erosion and assess the efficacy of synthetic and natural inhibitors in preventing collagen matrix degradation and preserving dentin integrity. A systematic literature search was conducted and updated in January 2025 across PubMed, Scopus, and Web of Science, targeting studies that investigated the role of matrix metalloproteinases (MMPs) and/or cysteine cathepsins in dentin erosion or erosion-abrasion models. In vitro, in situ, and in vivo experimental studies evaluating the effects of synthetic and natural protease inhibitors were included. Study selection, data extraction, and risk of bias assessment were performed following PRISMA 2020 guidelines. A total of 22 studies met the inclusion criteria, comprising predominantly in vitro designs, alongside in situ and combined experimental models. Across studies, MMP-2, MMP-8, and MMP-9, together with cathepsin K, were consistently identified as key enzymes involved in collagen degradation following acidic challenges. Erosive protocols varied in pH, exposure time, and cycling frequency, but uniformly promoted demineralization and enzymatic activation. Synthetic inhibitors (e.g., ferrous sulfate, stannous fluoride) and natural compounds (e.g., green tea catechins, theaflavins) demonstrated significant reductions in enzymatic activity and dentin loss. Importantly, studies assessing combined inhibition of MMPs and cathepsins reported the greatest protective effects, supporting a multimodal strategy to limit erosive dentin degradation. Acidic challenges promote the activation of matrix metalloproteinases and cysteine cathepsins, thereby accelerating dentin erosion through progressive collagen degradation. Both synthetic and natural inhibitors were shown to attenuate proteolytic activity and reduce dentin loss under experimental conditions. Notably, strategies targeting multiple enzymatic pathways consistently demonstrated greater protective effects than single-agent approaches. Nevertheless, the predominance of in vitro and in situ evidence highlights the need for well-designed clinical studies to confirm the long-term efficacy and translational relevance of these interventions. The incorporation of MMP and cathepsin inhibitors into preventive and therapeutic oral care strategies represents a promising adjunct for enhancing dentin resistance to erosive challenges. However, clinical implementation requires standardized experimental protocols, clearer dose-response characterization, and validation in long-term clinical settings. Advancing dual-targeted inhibitory approaches may contribute to more effective and durable dentin preservation in patients at risk of erosive tooth wear.

BackgroundInfluenza A virus (IAV) is a major respiratory pathogen with the potential to invade the central nervous system (CNS), leading to neurological complications. However, the mechanisms underlying IAV neurotropism and its impact on neuronal cells remain poorly understood. This study is aimed at establishing a reliable in vitro model using differentiated SH‐SY5Y human neuroblastoma cells to investigate IAV infection in the CNS, with a specific focus on oxidative stress and matrix metalloproteinases (MMPs) production.MethodsDifferentiated SH‐SY5Y cells were infected with Influenza A/NWS/33 (H1N1) strain. Redox state was assessed by measuring intracellular glutathione (GSH) levels, Glutaredoxin 1 (Grx1) expression, and Prdx1 release. The activation of oxidative stress‐responsive MMPs (MMP‐2, MMP‐9) was analyzed via western blot, gelatin zymography, and qRT‐PCR. The effect of MMPs inhibition on viral replication was evaluated using Batimastat (BB‐94) and siRNA‐mediated downmodulation.ResultsIAV efficiently infects and replicates in differentiated SH‐SY5Y cells, inducing oxidative stress, as evidenced by decreased GSH levels, increased glutathionylated proteins and Grx1 expression, and Prdx1 release. Additionally, IAV infection enhances the production and activation of MMP‐2 and MMP‐9, a process regulated by redox balance, as demonstrated by the inhibitory effects of redox modulators. Finally, postinfection treatment with BB‐94, an MMPs inhibitor, and siRNA‐mediated downmodulation significantly reduces viral replication and infectivity.ConclusionsThese findings demonstrate that IAV infection modulates neuronal redox balance and promotes MMPs activation, fostering a cellular environment that enhances viral replication and spread within neuronal‐like cells.

Introduction: Maternal infection (MI) can result in significant neurodevelopmental abnormalities and long-term neurological sequelae in offspring. This study was designed to investigate MI-induced alterations in synaptic protein expression, axonal morphology, dendritic, and spine morphology, and behaviour in a neonatal rat model of bacterial meningitis. Methods: On gestational day 10, pregnant rats were randomly assigned to the following groups: (1) control (Ctrl), (2) MI (pregnant rats were infected with Cronobacter sakazakii by rectovaginal colonization), (3) MI +matrix metalloproteinase inhibitor (MI+MMPI) (C. sakazakii infected pregnant rats received a MMP-9 inhibitor). Male offspring from experimental groups were examined in the novel odor recognition (NOR) test on postnatal day (PND) 15 and the tail suspension test (TST) on PND-60. Results: Offspring from the MI group were impaired in NOR and exhibited depressive behaviour during TST, whereas MI+MMPI group responses were comparable to the Ctrl group. In addition, MI upregulated the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), MMP-9, and nuclear factor erythroid 2-related factor 2 (Nrf2) in their offspring. In turn, MI downregulating Na+/K+-ATPase activity, postsynaptic density protein (PSD)-95, and multiple ankyrin repeat domain protein (SHANK3) altered the conversion of mature brain-derived neurotrophic factor precursor to mature (mBDNF). Further, MI induced bending and shortening of pyramidal neuronal axon length, reduced dendritic branching complexity, and alerted dendritic and spine morphology. Treatment with MMPI minimized these MI-induced effects. Conclusion: MI can cause microstructural rearrangements in the developing brain and behavioural deficits. Our experimental model mimics the neurological sequelae of neonatal meningitis and could be useful for developing therapeutic strategies.

Nitrate treatment decreases circulating matrix metalloproteinases concentrations in overweight women.

Skin aging, pigmentation disorders and skin barrier dysfunction are strongly associated with oxidative stress, chronic inflammation and extracellular matrix degradation. In this context, plant sprouts have gained popularity as a rich source of bioactive compounds and are becoming promising candidates for dermatological applications. The aim of this review was to summarize current scientific research on the potential of sprout extracts in skin care and to identify the biological mechanisms underlying their dermatological activity. A comprehensive literature search was conducted in Medline, Scopus, and Google Scholar databases up to February 2026. Studies assessing the effects of topical sprout extracts on skin structure, inflammation, pigmentation, and hair growth were included. A total of 31 studies met the inclusion criteria and were subjected to qualitative analysis. Available evidence indicates that sprout extracts have multifaceted effects relevant to skin health, including stimulation of collagen synthesis, inhibition of matrix metalloproteinases, improvement of epidermal hydration, melanogenesis, and suppression of inflammatory signaling pathways. These effects are largely attributed to bioactive compounds such as phenolic acids, flavonoids, isothiocyanates, and other antioxidant phytochemicals, which exhibit antioxidant, anti-inflammatory, and anti-aging properties. Preliminary clinical studies suggest that ingredients derived from sprouts may improve skin elasticity, hydration, and photoprotection. Although most of the evidence comes from in vitro and animal studies, it preliminarily supports the emerging concept of “food for skin” and highlights the potential of sprouted plant materials as multifunctional ingredients in dermatology.

Introduction: Chlorhexidine (CHX) has been most commonly used as an antimicrobial component as well as for disinfection before the placement of restorations. CHX has demonstrated successful inhibition of dentin Matrix Metalloproteinase (MMP) collagenolytic activity when used in concentrations of 0.2% and 2%, however this may influence the bond strength of composite resin to Biodentine when applied before adhesive procedures. The present study endeavours to evaluate a bonding strategy that would best suit the preconditioning with CHX. Aim: To evaluate the effect of two different concentration of CHX on Shear Bond Strength (SBS) between resin composite and Biodentine, using self-etch and etch-rinse bonding strategies. Materials and Methods: The present in-vitro study was carried out in the Department of Conservative Dentistry and Endodontics in Mahatma Gandhi Mission Dental College and Hospital, Navi Mumbai, Maharashtra, India, from January 2022 to May 2022 on 108 acrylic blocks. A central cavity was prepared in the acrylic block and randomly divided into six main groups. Group 1 (control) Biodentine placement; selfetch adhesive application followed by resin composite. Group 2 (control) Biodentine placement; etch and rinse adhesive application followed by resin composite. Since two different bonding strategies, self- etch and etch-and-rinse were used, two control groups were included. Each of these bonding methods has different application protocols and bonding mechanisms, which could independently affect the SBS between resin composite and Biodentine, therefore two control groups were included. Including both controls allows for a fair and unbiased comparison with the experimental groups where CHX (at 0.2% or 2%) was used. This ensures that any observed differences in bond strength can be accurately attributed to the effect of CHX, rather than differences between the bonding strategies themselves. Group 3 Biodentine placement; application of 0.2% CHX prior to application of self-etch adhesive followed by resin composite placement. Group 4 Biodentine placement; application of 2% CHX prior to application of self-etch adhesive followed by resin composite placement. Group 5 Biodentine placement; for etch and rinse adhesive system application 0.2% CHX after acid etching prior to application of adhesive followed by resin composite placement. Group 6 Biodentine placement; for etch and rinse adhesive system application 2% CHX after acid etching prior to application of adhesive followed by resin composite placement. Thereafter the samples were subjected to the shear bond testing in a universal testing machine. The obtained data was tabulated and statistically analysed for normality using Shapiro-wilk test. Further statistical analysis was done using One-way Analysis of Variance and Two-way ANOVA followed by Tukey–Kramer Test for pair-wise comparisons. Post-hoc test was done to compare control group compared with CHX treated group irrespective of bonding technique. Results: Surface treatment of Biodentine with 0.2% or 2% CHX reduced the bond strength of composite resin to Biodentine irrespective of bonding strategies. The One-way ANOVA test showed there was statistically significant difference in SBS of the resin composite bonded to Biodentine when the different bonding strategies and surface treatment are applied( p<0.001 ). Two-way ANOVA test showed statistically significant difference in SBS between etching technique and different concentrations of CHX with p<0.001. A higher SBS was observed when the Biodentine was pretreated with 0.2% CHX (Group 3 and Group 5) compared to 2% CHX (Group 4 and Group 6) (p<0.001). Posthoc test statistically significant difference found in SBS when control groups when compared to groups treated with CHX, irrespective of bonding technique (p<0.001). Conclusion: Application of 2% and 0.2% CHX on Biodentin reduced the SBS with resin composite, irrespective of the bonding strategy. Between the self-etch and etch-rinse adhesive system used in this study, etch-rinse showed higher SBS for 0.2% CHX compared to self-etch adhesive system.

Multi-specific targeting of CD44 and the catalytic and hemopexin domains of MMP9 as a therapeutic strategy for osteoclast inhibition.

Thromboembolic ischemic stroke induces neutrophil recruitment and matrix metalloproteinase-9 release to enhance ischemic brain injury.

Lymphatic malformations are lesions that can be due to inherited or somatic mutations, and they lead to a defective lymphatic vasculature. Activating KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations have been identified recently in patients with lymphatic malformation with lymphedema, chylous ascites, or life-threatening chylothorax. In a lymphatic malformation mouse model, KRAS mutations are associated with a loss of lymphatic valves, which has been proposed to cause chylothorax via retrograde lymph flow into the pleural space. However, the mechanisms underlying the loss of lymphatic valves are unknown. To investigate the mechanisms leading to valve loss, we combined the lymphatic-specific and tamoxifen-inducible Flt4CreERT2 with Kras-loxP-stop-loxP-G12D (Kras+/G12D) mice and Prox1GFP reporter mice to induce the restricted expression of KRAS-G12D and enable valve quantification in postnatal pups. Human dermal lymphatic endothelial cells expressing KRAS-G12D were probed for changes in mRNA and protein expression with quantitative real-time polymerase chain reaction, Western blot, and gel zymography, and mechanistic studies were performed using 3-dimensional cell culture in collagen matrices. Our data showed that lymphatic-specific expression of KRAS-G12D significantly attenuated valve development in the mesentery, diaphragm, and ear skin. Quantitative real-time polymerase chain reaction, Western blot, and gel zymography using human dermal lymphatic endothelial cells expressing KRAS-G12D revealed the upregulation of the PA (plasminogen activator) pathway and MMPs (matrix metalloproteinases). The MMPs were sufficiently activated by plasmin, the product of the PA pathway, in human dermal lymphatic endothelial cells grown in a 3-dimensional collagen matrix, indicating a role for MMPs in the degradation of valve ECM (extracellular matrix) core. Furthermore, a broad-spectrum MMP inhibitor given to Flt4CreERT2;Kras+/G12D mice rescued lymphatic valve development. We conclude that hyperactive KRAS signaling upregulates MMPs that become excessively activated by the upregulation of the PA pathway. MMPs then degrade the lymphatic valve ECM core, preventing valve formation.

Oxytetracycline has been successfully used to treat flexural limb deformities in foals. However, its antimicrobial properties and potential adverse side effects warrant the investigation of alternatives. Inhibition of matrix metalloproteinases (MMPs) or collagen cross-linking have been suggested as possible mechanisms of action. This study assessed the influence of potential alternative substances lacking antimicrobial properties on collagen gel contraction by juvenile equine myofibroblasts in vitro. Myofibroblasts were isolated from forelimb SDFTs and inferior check ligaments from foals euthanised for reasons unrelated to this study, and seeded in collagen gels containing oxytetracycline, MMP-inhibitors incyclinide, ilomastat, aprotinin, and pentoxifylline, β-aminopropionitrile fumarate (BAPN), and control medium. The gels were measured in photographs up to 96h after release, and differences in contraction were evaluated. Compared to control, BAPN and incyclinide induced significant inhibition (p < 0.05) of collagen gel contraction by myofibroblasts at all time points, and the inhibition was more potent than that observed with oxytetracycline. Consequently, the inhibitory capacity of BAPN and incyclinide on myofibroblast-mediated collagen gel contraction, which demonstrates their effect on tractional structuring of collagen, makes them promising candidates as potential substitutes for oxytetracycline. Further investigations into their side effects, pharmacodynamics, pharmacokinetics, and application methods in juvenile equine patients are needed.

Maternal infection (MI) can increase the risk of neurodevelopmental and behavioural changes. This study examined MI-induced changes in motor coordination through the inflammatory-pathway-mediated epigenetic status of Reln. On gestational day (GD) 10, rats were assigned as (i) Control (Ctrl); (ii) Cronobacter sakazakii (CS) infection on GD-10 through recto-vaginal colonization; (iii) Negative Control (NC) [infected with C. sakazakii and treated with dimethyl sulfoxide (DMSO) 1 h before and 24 h after infection]; and (iv) C. sakazakii-infected rats treated with matrix metalloproteinase inhibitor (MMPI), 1 h before and 24 h after infection (CS + MMPI). Offspring were subjected to footprint analysis and the ladder rung walking test, which revealed that MI caused significant deficits in motor coordination. In addition, MI activated complement components—a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1, C5a)—as well as proinflammatory cytokines such as interleukin-6 (IL-6) and matrix metalloproteinases (MMP-2, MMP-3, and MMP-9). Furthermore, the levels of DNA methyltransferase 3 alpha (DNMT3A), methyl-CpG-binding protein 2 (MeCP2), and histone H3 lysine 4 trimethylation (H3K4me3) were elevated in the CS and NC groups. Concurrently, the level of Reln promoter methylation increased; as a result, mRNA and protein, as well as postsynaptic density protein-95 (PSD-95), levels were decreased. Overall, the findings suggest that MI altered MMP-2/3/9 activity, H3K4me3, and the methylation of Reln, thereby affecting reelin, synaptic protein expression, and motor coordination in an experimental meningitis rat model.