Matrix Metalloproteinase Inhibitor Research Articles

Uncovering the Impact of MMP-9 and TIMPs in Diabetic Nephropathy: A Review on Bioflavonoids in Disease Management

This article provides a thorough analysis of the complex roles played by tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinase-9 (MMP-9) in the development and progression of diabetic nephropathy (DN). Diabetic nephropathy, a notable complication of diabetes, is characterized by a progressive decline in kidney function, prompting a thorough examination of its fundamental molecular pathways. This article pre-sents a comprehensive overview of the function played by MMP-9, a key enzyme in the re-modeling of extracellular matrix, in developing tubulointerstitial and glomerular fibrosis, which are critical aspects of renal dysfunction in DN. Simultaneously, the review delves into the regulatory functions of TIMPs, emphasizing their crucial role in maintaining the delicate balance between matrix degradation and repair. The abnormal regulation of the MMP-9/TIMP axis is explored as a pivotal factor contributing to increased vascular permeability, inflammation, and structural alterations within the renal microenvironment. By synthesizing current research findings, the purpose of this review was to unravel the complex molecular interplay between MMP-9 and TIMPs in diabetic nephropathy. The insights derived from this comprehensive analysis hold promise for identifying potential therapeutic targets that could mitigate renal damage, arrest disease progression, and enhance clinical outcomes for individuals grappling with diabetic nephropathy. Finally, it concludes by emphasizing the necessity for additional research to validate these findings and facilitate the translation of this knowledge into targeted therapeutic interventions for improved management of diabetic nephropathy.

Exploring the link between genetic disorders and early-onset periodontal disease

Periodontal disease is a complex, multifactorial condition characterized by chronic inflammation and progressive destruction of the tooth-supporting structures. Among its various forms, early-onset periodontitis is particularly aggressive and often associated with genetic predispositions. Genetic and epigenetic factors play pivotal roles in shaping host susceptibility to this disease by influencing immune responses, inflammatory regulation, and tissue homeostasis. Single-nucleotide polymorphisms (SNPs) in genes encoding cytokines, such as interleukin-1β and tumor necrosis factor-alpha, are linked to heightened inflammatory responses, amplifying tissue damage and accelerating disease progression. Additionally, polymorphisms in genes like TLR2 and TLR4 impair microbial recognition, promoting chronic inflammation and dysbiosis. Epigenetic modifications, including DNA methylation and histone acetylation, further modulate gene expression, contributing to the dynamic interplay between genetic predispositions and environmental factors like smoking or poor oral hygiene. Emerging research has also highlighted genetic markers such as human leukocyte antigen (HLA) alleles and matrix metalloproteinase (MMP) variants as predictors of disease severity and therapeutic outcomes. These insights have driven the development of targeted therapies, including inhibitors of pro-inflammatory mediators, MMP inhibitors, and potential miRNA-based interventions. High-throughput technologies, such as genome-wide association studies (GWAS), have expanded the understanding of genetic pathways involved in periodontal disease. These advances enable earlier disease detection and personalized treatment strategies, offering the potential to mitigate progression and reduce the burden of severe periodontitis. The integration of genetic and epigenetic research into clinical practice marks a significant step toward precision medicine, providing a framework for tailored prevention and therapeutic interventions aimed at improving patient outcomes. Future research must continue to explore these genetic mechanisms to uncover novel biomarkers and refine targeted treatment approaches for periodontal disease.

Hepatoprotective potential of Chrysin in a rat model of isoniazid- and rifampicin-induced hepatic injury: suppression of matrix metalloproteinase and transforming growth factor β

BackgroundThe ability of Chrysin (CHY) to scavenge free radicals has been widely explored. The scope of the research was to show that CHY protects the rat liver against damage caused by the drugs isoniazid (INH) and rifampicin (RFM).ResultsRats were divided into 6 groups, each of which had six rats. Isoniazid (100 mg/kg, p.o.) and rifampicin (100 mg/kg, p.o.) were administered to Group II to VI rats for 21 days; this caused hepatocellular damage. CHY was administered in the dose of 50, 75, and 100 mg/kg, p.o. body weight to Group III to V rats before administration of INH + RFM. In this study, Group VI Silymarin (100 mg/kg, p.o.) functioned as the standard drug. The blood was drawn as the study was done, and tests for oxidative stress indicators, haematological parameters, biochemical parameters, and pro-inflammatory cytokines were performed. The liver samples were subjected to histopathology. The administration of CHY (50, 75, and 100 mg/kg) restored serum biochemical, haematological, proteins, and lipid parameters. Due to the administration of CHY, the levels of superoxide dismutase (SOD), glutathione oxidase (GSH), myeloperoxidase (MPO) and catalase (CAT) were also restored. The inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), transforming growth factor-β (TGF-β), malondialdehyde (MDA), myeloperoxidase (MPO) and nitric oxide (NO) levels were found to be decreased. The alterations in the biochemical parameters were reinforced by histological analysis of liver tissue.ConclusionsIt is concluded that the CHY protects against INH + RFM-induced oxidative liver injury in rats.Graphical abstract

Suppression of METTL3 expression attenuated matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the extracellular matrix in pelvic organ prolapse.

Fibrosis of the connective tissue in the vaginal wall predominates in pelvic organ prolapse (POP), which is characterized by excessive fibroblast-to-myofibroblast differentiation and abnormal deposition of the extracellular matrix (ECM). Our study aimed to investigate the effect of ECM stiffness on vaginal fibroblasts and to explore the role of methyltransferase 3 (METTL3) in the development of POP. Polyacrylamide hydrogels were applied to create an ECM microenvironment with variable stiffness to evaluate the effects of ECM stiffness on the proliferation, differentiation, and expression of ECM components in vaginal fibroblasts. METTL3small interfering RNA and an overexpression vector were transfected into vaginal fibroblasts to evaluate the effects of METTL3silencing and overexpression on matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the ECM. Both procedures were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining, Western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), and immunofluorescence (IF). Vaginal fibroblasts from POP patients exhibited increased proliferation ability, increased expression of α-smooth muscle actin (α-SMA), decreased expression of collagen I/III, and significantly decreased expression of tissue inhibitors of matrix metalloproteinases (TIMPs) in the stiff matrix (P<0.05). Compared with those from non-POP patients, vaginal wall tissues from POP patients demonstrated a significant increase in METTL3 content (P<0.05). However, silencing METTL3 expression in vaginal fibroblasts with high ECM stiffness resulted in decreased proliferation ability, decreased α-SMA expression, an increased ratio of collagen I/III, and increased TIMP1 and TIMP2 expression. Conversely, METTL3 overexpression significantly promoted the process of increased proliferation ability, increased α-SMA expression, decreased ratio of collagen I/III and decreased TIMP1 and TIMP2 expression in the soft matrix (P<0.05). Elevated ECM stiffness can promote excessive proliferation, differentiation, and abnormal ECM modulation, and the expression of METTL3 plays an important role in alleviating or aggravating matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal ECM modulation.

Expression of MMP1, MMP3, and TIMP1 in intervertebral discs under simulated overload and microgravity conditions

ObjectiveThis study aims to investigate changes in matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) levels in the intervertebral discs of New Zealand white rabbits under simulated overload and microgravity conditions, focusing on the expression of MMP1, MMP3, and TIMP1. The findings aim to provide a theoretical foundation for preventing and delaying lumbar disc degeneration in these environments.MethodsOverload was simulated using an animal centrifuge, and microgravity was mimicked through tail suspension. A randomized single-blind method was applied to divide 120 age- and weight-matched New Zealand white rabbits into six groups: control groups (30 d, 60 d, 90 d) and overload/microgravity groups (30 d, 60 d, 90 d), with 20 rabbits per group. The expression of MMP1, MMP3, and TIMP1 in the lumbar intervertebral discs was measured and analyzed using statistical methods, including chi-square tests and t-tests, across different exposure times.ResultsIn the experimental groups, MMP1 and MMP3 expression levels were significantly higher than those in the corresponding control groups at all time points (P < 0.01). MMP1 and MMP3 levels progressively increased with longer exposure durations, showing statistically significant differences (P < 0.01). TIMP1 expression was significantly higher in the 30-day and 60-day experimental groups than in the control group (P < 0.01), but decreased in the 90-day group, indicating a late-stage imbalance in the MMP/TIMP1 ratio.ConclusionSimulated overload and microgravity conditions lead to elevated MMP1, MMP3, and TIMP1 expression in lumbar intervertebral discs, promoting accelerated disc degeneration.

Host-Directed Therapy with Inhalable Lovastatin Microspheres for Matrix Metalloproteinase Inhibition in Tuberculosis.

Tuberculosis (TB) triggers a robust immune response, which leads to significant destruction of the lung tissue at the site of infection, aiding in the transmission of Mycobacterium tuberculosis (Mtb) to the hosts. The excessive inflammatory response contributes heavily to extracellular matrix (ECM) damage, which is linked to high mortality rates among TB patients. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are pivotal in the breakdown of the ECM, worsening tissue destruction. In the context of host-directed therapy (HDT), a strategy aimed at modulating the immune response rather than directly targeting the pathogen, we evaluated the potential of lovastatin (LOV). LOV has shown promise in reducing MMP activity and inflammation, which could alleviate the immune-mediated pathology in TB. However, its clinical use has been limited due to poor solubility and biocompatibility, reducing its therapeutic efficacy. To overcome these limitations, we designed inhalable gelatin microspheres (GA-MS) loaded with LOV using the spray-drying technology. This approach improved the solubility and allowed for the controlled release of the drug. The resulting LOV-loaded gelatin microspheres (LOV/GA-MS) had an optimal particle size of 2.395 ± 0.67 μm, facilitating macrophage uptake due to their aerodynamic properties. In in vitro studies using Mtb-infected macrophages, LOV/GA-MS effectively suppressed MMP expression and reduced levels of pro-inflammatory cytokines at a concentration of 20 μg/mL, demonstrating substantial anti-inflammatory potential. Moreover, these microspheres showed a synergistic effect when combined with standard anti-TB drugs, enhancing the overall therapeutic efficacy in in vitro experiments. The findings suggest that inhalable LOV/GA-MS microspheres represent a promising adjunctive host-directed therapy for TB. By modulating the host's immune response and targeting key inflammatory mediators such as MMPs, this approach could mitigate lung tissue damage, improve clinical outcomes, and provide a more holistic treatment option for TB.

Inhibitory Effects of Different Doses of Matrine on Breast Cancer and Its Relationship with miR-188

Background Malignant tumors represented by breast cancer still have limitations in clinical treatment methods. Matrine is a compound with anticancer activity, but its inhibitory effect on breast cancer and its mechanism for regulating miR-188 are still unclear. Purpose Therefore, it is necessary to explore more effective breast cancer treatment methods and understand the intervention mechanism of matrine and its effect on miR-188. Methods A nude mouse model of breast cancer was in this study constructed and divided into a model group, 4 mg/kg group, 8 mg/kg group, drug group, and miR-188 mimic group. Different concentrations of matrine were administered intragastrically, and cell proliferation and apoptosis were observed. At the same time, a specific mechanism for miR-188 in the anti-breast cancer effect of matrine was explored by overexpressing miR-188. Results It was found that matrine inhibited the proliferation of breast cancer cells and caused cancer cell apoptosis. In addition, it inhibited cell migration in a dose-dependent manner. At the same time, miR-188 was lowly expressed in breast cancer and significantly increased after matrine treatment. Overexpression of miR-188 enhanced the antitumor effect of matrine. Phosphatase and tensin homolog (PTEN) was also activated in the surface by matrine, and expressions of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) were inhibited. This study shows that matrine has a significant inhibitory effect on breast cancer, and its mechanism is related to upregulation of miR-188, activation of PTEN, and inhibition of MMP-9 and MMP-2 expressions. Conclusion miR-188 is involved in the anti-breast cancer process, which can be used as the theoretical basis of matrine potential drugs for breast cancer treatment. Meanwhile, miR-188 and matrine will also have great potential in developing new breast cancer treatment methods, which can provide ideas and a basis for further development of related studies.

Regulation of TGF-β1, PI3K/PIP3/Akt, Nrf-2/Keap-1 and NF-κB signaling pathways to avert bifenthrin induced hepatic injury: A palliative role of daidzein.

Bifenthrin (BFN) is a noxious insecticide which is reported to damage various body organs. Daidzein (DZN) is a natural flavone with excellent pharmacological properties. This research was conducted to evaluate the alleviative strength of DZN to counteract BFN prompted liver toxicity in male albino rats. Thirty-two rats were divided into 4 groups i.e., the control, BFN (7 mg /kg), BFN (7 mg/kg) + DZN (20 mg/kg) and DZN (20 mg/kg) alone group. The biochemical assessment was performed by using qRT PCR as well as standard ELISA protocols. The findings are validated by applying pharmacodynamic techniques including molecular simulation. It was observed that BFN reduced the gene expressions of phosphoinositide 3-kinase (PI3K), phosphatidylinositol-3, 4, 5-triphosphate (PIP3), Protein kinase B (Akt), nuclear factor erythroid 2-related factor 2 (Nrf-2) while promoting the gene expressions of Kelch-like ECH-associated protein 1 (Keap-1). Moreover, BFN notably reduced the activities of glutathione reductase (GSR), heme-oxygenase-1 (HO-1), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) while elevating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). BFN promoted the levels of matrix metallopeptidase 2 (MMP-2), Procollagen III N-terminal Pro-peptide (PIIINP), alkaline phosphatase (ALP), transforming growth factor-beta-1 (TGF-β1), aspartate aminotransferase (AST), tissue inhibitor of matrix metalloproteinases 1 (TIMP1), and alanine aminotransferase (ALT). The levels of nuclear factor- kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) were increased following the BFN intoxication. BFN enhanced the expressions of cysteine-aspartic acid protease-3 (Caspase-3) and Bcl-2-associated X protein (Bax) while suppressing the gene expression of B-cell lymphoma-2 (Bcl-2). Moreover, BFN disrupted the normal histology of liver tissues. Nonetheless, DZN treatment remarkably alleviated hepatic damages owing to its antioxidative, anti-apoptotic as well as anti-inflammatory abilities. However, DZN supplementation remarkably safeguarded which is further confirmed by in-silico assessment.

Tetracyclines in Rheumatoid Arthritis: Dual Anti-Inflammatory and Immunomodulatory Roles, Effectiveness, and Safety Insights.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation, joint pain, and progressive cartilage and bone erosion. Despite advancements in RA management with disease-modifying antirheumatic drugs (DMARDs) and biologics, some patients remain refractory to conventional treatments. Tetracyclines, such as minocycline and doxycycline, exhibit anti-inflammatory and immunomodulatory properties, making them potential supplementary treatments. This narrative review explores their effectiveness, mechanisms of action, safety profiles, and current challenges in RA care. Tetracyclines have demonstrated significant immunomodulatory effects, including the inhibition of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), which are critical in RA pathology. Clinical trials, including double-blind, placebo-controlled studies, have shown efficacy in reducing RA symptoms, particularly in early and refractory cases. However, their use remains limited by inconsistent evidence, small sample sizes, and concerns about antimicrobial resistance. Current guidelines for RA management do not explicitly recommend tetracyclines due to these limitations, although off-label use may be considered in specific cases. The use of tetracycline for RA is restricted by drug interactions causing bacterial resistance alongside unpredictable patient responses, hence the necessity for prudence in its prescription within a clinical setting. To overcome these limitations, the development of safer compounds, in-depth in silico analyses, and integration with personalized medicine approaches are needed. Overall, tetracyclines show promise as adjunct therapies in RA management due to their dual anti-inflammatory and immunomodulatory actions. This review highlights the need for further research to address gaps in evidence, including the development of modified tetracyclines with reduced antimicrobial effects and improved safety profiles, as well as the integration of personalized medicine approaches to optimize patient outcomes.

Associations of serum and tissue TIMP1 with host response and survival in colorectal cancer

Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is a multifaceted, cytokine-like bioactive molecule whose levels are elevated in a wide range of inflammatory diseases and are associated with prognosis. Additionally, TIMP1 may play a role in driving systemic inflammation. TIMP1 immunohistochemistry and TIMP1 serum concentrations were analyzed in a cohort of 776 colorectal cancer patients. TIMP1 histoscore by cell type (tumor cell, other) was quantified using digital image analysis. Serum TIMP1 levels were evaluated for correlations with tumor TIMP1 expression, and their associations with tumor characteristics, inflammation, and prognosis were investigated. High serum TIMP1 concentrations associated with shorter overall survival (multivariable HR 1.85, 95% CI 1.30–2.65). Serum TIMP1 levels positively correlated with markers of systemic inflammation and tumor necrosis percentage but not with TIMP1 expression in tumor tissue. High TIMP1 intensity in tumor stroma associated with longer cancer-specific and overall survival in univariable analysis but not in multivariable models. T cell densities in tumor tissue positively correlated with tumor stromal TIMP1 expression and negatively with tumor epithelial TIMP1 expression. Serum TIMP1 levels show promise as a prognostic marker for colorectal cancer and correlate with systemic inflammatory markers, but do not correlate with TIMP1 expression in tumor tissue.

Nanostructured lipid carriers for enhanced batimastat delivery across the blood-brain barrier: an in vitro study for glioblastoma treatment.

Glioblastoma presents a significant treatment challenge due to the blood-brainbarrier (BBB) hindering drug delivery, and the overexpression of matrix metalloproteinases (MMPs), which promotes tumor invasiveness. This study introduces a novel nanostructured lipid carrier (NLC) system designed for the delivery of batimastat, an MMP inhibitor, across the BBB and into the glioblastoma microenvironment. The NLCs were functionalized with epidermal growth factor (EGF) and a transferrin receptor-targeting construct to enhance BBB penetration and entrapment within the tumor microenvironment. NLCs were prepared by ultrasonicator-assisted hot homogenization, followed by surface functionalization with EGF and the construct though carbodiimide chemistry. The construct was successfully conjugated with an efficiency of 81%. Two functionalized NLC formulations, fMbat and fNbat, differing in the surfactant amount, were characterized. fMbat had a size of 302nm, a polydispersity index (PDI) of 0.298, a ζ-potential (ZP) of -27.1mV and an 85% functionalization efficiency (%FE), whereas fNbat measured 285nm, with a PDI of 0.249, a ZP of -28.6mV and a %FE of 92%. Both formulations achieved a drug loading of 0.42μg/mg. In vitro assays showed that fNbat was cytotoxic and failed to cross the BBB, while fMbat showed cytocompatibility at concentrations 10 times higher than the drug's IC50. Additionally, fMbat inhibited MMP-2 activity between 11 and 62% across different cell lines and achieved a three-fold increase in BBB penetration upon functionalization. Our results suggest that the fMbat formulation has potential for enhancing GB treatment by overcoming current drug delivery limitations and may be combined with other therapeutic strategies for improved outcomes.

Use of Photoreactive Riboflavin and Blue Light Irradiation in Improving Dentin Bonding-Multifaceted Evaluation.

Recently, photoactivated riboflavin (RF) treatments have been approved to improve resin-dentin bonding by enhancing dentinal collagen crosslinking. This study aimed to evaluate whether RF activated by blue light (BL, 450 nm) strengthens the collagen matrix, increases resistance to enzymatic degradation, and improves adhesion as effectively as ultraviolet A (UVA, 375 nm) activation. Six groups were examined: control (no treatment); RF0.1UV2 (0.1% RF with 2 min of UVA irradiation); RF0.1BL1, RF0.1BL2, RF1BL1, and RF1BL2 (0.1% and 1% RF with 1 or 2 min of BL irradiation). The effects of RF/BL on collagen crosslinking were validated by gel electrophoresis. A nanoindentation test showed that both RF/UVA and RF/BL treatments enhanced the elastic modulus and nanohardness of demineralized dentin. A zymography assay using collagen extracted from demineralized dentin also revealed significant matrix metalloproteinase-2 inhibition across all RF treatments. Microtensile bond strength (µTBS) tests conducted both post-treatment and after 7-day enzymatic degradation showed that three RF0.1 groups (RF0.1UV2, RF0.1BL1, and RF0.1BL2) maintained high µTBS values after degradation, while RF0.1BL1 generated a significantly thicker hybrid layer compared to other groups. These findings suggest that RF/BL is as effective as RF/UVA in crosslinking dentinal collagen and resisting enzymatic degradation, with 0.1% RF proving superior to 1% RF in enhancing dentin bonding.

MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α

Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death.

Vitamin D supplementation modifies clinical and biological markers of keratoconus progression

Aims/Purpose: evaluation of vitamin D (Vit D) supplementation on clinical progression and systemic biomarkers in adolescent patients affected by keratoconus (KC) and Vit D insufficiency.Methods: forty adolescent patients (age range: 12–19) meeting the criteria of KC diagnosis and Vit D insufficiency ( &lt; 30 ng/mL) were enrolled and followed for 12 months. Vit D supplementation was prescribed for the first 6 months and patients were then followed up for additional 6 months. Clinical parameters, including best spectacle‐corrected visual acuity, maximal keratometry, and corneal thickness were measured at month 0, 2, 4, 6, 9, 12 after enrollment to monitor the KC progression. Moreover, at month 0 and 6 after enrollment we evaluated serum biomarkers, including Vit D levels and metabolism, collagen degradation, and inflammation by ELISA and RT‐PCR.Results: after 6 months of Vit D supplementation, serum Vit D levels were significantly increased and remained clinically stable up to month 12. Two‐thirds of patients responded to treatment and showed KC stabilization 12 months after enrollment. Interestingly, Vit D receptor was upregulated only in stable patients (p &lt; 0.01) at month 6. Serum markers indicated that type I collagen degradation product, procollagen type I carboxyl‐terminal propeptide, and the ratio between matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinase 1 were statistically decreased (p &lt; 0.05) only in stable patients. Vit D supplementation was associated with increased expression of CD 14 (p &lt; 0.0001) and decreased levels of lactoferrin (p &lt; 0.0001).Conclusions: these data demonstrated that Vit D treatment stabilized KC progression in the majority of patients. These stable patients showed reduced systemic inflammation and collagen catabolism, thus suggesting that KC could be considered a systemic disease.

Exploring the remarkable effect of ursodeoxycholic acid and Allium sativum combination on MMP-9 and TIMP-1 levels in cholestatic rat’s model

Background: Cholestasis is a disturbance in the production or flow of bile that causes excessive accumulation of bile fluid and damage in the liver. Chronic liver damage will lead to liver fibrosis. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloprotease-1 (TIMP-1) play a critical role in liver fibrosis formation. Although ursodeoxycholic acid (UDCA) and Allium sativum extracts have long been renowned for improving liver function, their combination in alleviating liver fibrosis through the MMP-9 and TIMP-1 inhibitory pathways has yet to be studied.Objective: This study was conducted to assess the efficacy of UDCA and Allium sativum extract combination in altering MMP-9 and TIMP-1 levels, which are the main factors in the progression of liver fibrosis.Methods: We performed an experimental study with a post-test-only control group on 36 Sprague-Dawley rats, which were randomly grouped into healthy, negative, positive, and three treatment groups with UDCA (13.5 mg) and graded doses of Allium sativum extract (3.6 mg; 7.2 mg; and 14.4 mg). Cholestasis induction was done by a choledochal duct ligation, and treatment was given for 14 days. Levels of MMP-9 and TIMP-1 were analyzed after treatment.Results: Combining UDCA and Allium sativum improved the MMP-9 levels significantly in cholestatic rats, compared to administrating UDCA only (p &lt;0.05). Combining UDCA and Allium sativum increased the TIMP-1 level (p &lt; 0.05). Although the MMP-9 level results were under our existing hypothesis, TIMP-1 results showed surprising results. Matrix metalloproteinase-9 levels were strongly negatively correlated with TIMP-1 levels, with a r-value= 0.981.Conclusion: Combining Allium sativum and UDCA alleviates liver fibrosis progression through lowering levels of MMP-9 and increasing levels of TIMP-1.

Characterizing Curing Efficiency of EGCG-Encapsulated Halloysite Nanotube Modified Adhesives for Durable Dentin-Resin Interfaces.

Matrix metalloproteinase (MMP)-induced collagen degradation at the resin-dentin interface remains a significant challenge for maintaining the longevity of dental restorations. This study investigated the effects of epigallocatechin-3-gallate (EGCG), a potent MMP inhibitor, on dental adhesive curing efficiency when encapsulated in halloysite nanotubes (HNTs). EGCG-loaded HNTs were incorporated into a commercial dental adhesive (Adper Scotchbond Multi-Purpose) at 7.5% and 15% w/v concentrations. To isolate the effects of each component, the study included three control groups: unmodified adhesive (negative control), adhesive containing only HNTs, and adhesive containing only EGCG (0.16% and 0.32%, equivalent to the EGCG content in EGCG-HNT groups). Degree of conversion (DC), polymerization conversion (PC), and Vickers micro-hardness (VHN) were assessed to evaluate curing efficiency. The addition of 7.5% EGCG-encapsulated HNTs maintained curing properties similar to the control, showing no significant differences in DC (80.97% vs. 81.15%), PC (86.59% vs. 85.81%), and VHN (23.55 vs. 24.12) (p > 0.05). In contrast, direct incorporation of EGCG at 0.32% significantly decreased DC (73.59%), PC (80.63%), and VHN (20.56) values compared to both control and EGCG-HNT groups (p < 0.05). Notably, HNT encapsulation mitigated these negative effects on polymerization, even at higher EGCG concentrations. These findings demonstrate that EGCG encapsulation in HNTs can maintain the curing efficiency of dental adhesives while potentially preserving the MMP-inhibitory benefits of EGCG.

Comparative evaluation of effect of three different MMP inhibitors on flexural bond strength of resin composite used to restore NCCL - In vitro study

Interface between resin composite and dentin is critical and important for the success of restoration. Application of MMP inhibitor may alter surface characteristic of dentin that improves bond strength of resin composite. This study evaluated and compared the effect of three different Matrix Metalloproteinase (MMP) inhibitors on flexural bond strength of resin composite restorations; done to restore non carious cervical lesions (NCCL).: Standardized NCCL was simulated on 41 freshly extracted and selected human premolars. The teeth were randomly assigned into four groups i.e. Group I: Control group (no MMP inhibitor). Group II: Chlorhexidine. Group III: Chitosan and group IV: Proanthocyanidin. NCCL were pretreated with MMP inhibitor of respective group prior to its restoration with nanofilled resin composite. Restorations in each group were finished and polished with an appropriate finishing and polishing kit. The flexural bond strength was evaluated using the universal testing machine. Data were analysed using one-way analysis of variance and Tukey's test. Among the tested MMP inhibitors; Group II (90.73 Mpa) and Group III (90.17 Mpa) showed highest mean flexural bond strength with insignificant difference ( P = 1.0) between them. Group IV showed higher but insignificantly different (P= 0.768) flexural bond strength to that of group I. Group II and Group III worked best to increase the flexural bond strength of resin composite indirectly representing its higher MMP inhibition and collagen stabilizing activity than Group IV and Group I.

Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis.

Tyrosine kinase inhibitors (TKIs) have markedly improved the overall survival rate of patients with chronic myeloid leukemia (CML), enabling them to achieve a normal life expectancy. However, toxicity, relapse, and drug resistance continue to pose major challenges in the clinical treatment of CML. The progression of leukemia is directly connected to higher expression levels and enzymatic actions of matrix metalloproteinase-2 (MMP-2). It is also associated with increased expression and enzymatic actions of matrix metalloproteinase-9 (MMP-9). From this perspective, MMP-2 and MMP-9 offers a promising strategy for developing novel therapeutic molecules that could be effective in treating CML. This study is the Part-III of D(-)-glutamine-based MMP-2 inhibitors series for the management of chronic myeloid leukemia. Fourteen newly synthesized p-tosyl-D(-)-glutamine derivatives were examined in cell culture-based antileukemic assays and also evaluated for their ability to inhibit MMPs. The lead compounds 5g and 5j demonstrated the most promising antileukemic potential. Compounds 5g and 5j are safe for normal cells and effectively block gelatinases (MMP-2 and MMP-9). The best active molecule 5g induced significant apoptosis. Compound 5g reduced MMP-2 levels in the K562 cell line. It also had strong antiangiogenic effects in the ACHN cell line. The strongest MMP-2 inhibitor, 5g, had stable binding at the MMP-2 active site, which is linked to its effective inhibition of MMP-2. In conclusion, these p-tosyl-D(-)-glutamine derivatives are promising MMP-2 inhibitors. They have strong anti-CML effects and should be studied more for future CML treatment.

An eGFP-Col4a2 mouse model reveals basement membrane dynamics underlying hair follicle morphogenesis.

Precisely controlled remodeling of the basement membrane (BM) is crucial for morphogenesis, but its molecular and tissue-level dynamics, underlying mechanisms, and functional significance in mammals remain largely unknown due to limited visualization tools. We developed mouse lines in which the endogenous collagen IV gene (Col4a2) was fused with a fluorescent tag. Through live imaging of developing hair follicles, we reveal a spatial gradient in the turnover rate of COL4A2 that is closely coupled with both the BM expansion rate and the proliferation rate of epithelial progenitors. Epithelial progenitors are displaced with directionally expanding BMs but do not actively migrate on stationary BM. The addition of a matrix metalloproteinase inhibitor delays COL4A2 turnover, restrains BM expansion, and increases perpendicular divisions of epithelial progenitors, altering hair follicle morphology. Our findings highlight the spatially distinct dynamics of BM and their key roles in orchestrating progenitor cell behavior and organ shape during development.

RHO-Associated Coiled-Coil-Containing Protein Kinase Inhibitors Significantly Modulate the Epithelial-Mesenchymal Transition Induced by TGF-β2 in the 2-D and 3-D Cultures of Human Corneal Stroma Fibroblasts.

The objective of the present study was to examine the unidentified effects that RHO-associated coiled-coil-containing protein kinase 1 and 2 antagonists exert on the transforming growth factor beta2-induced epithelial-mesenchymal transition of the human corneal stroma. In the presence or absence of pan-RHO-associated coiled-coil-containing protein kinase inhibitors, ripasudil or Y27632 and RHO-associated coiled-coil-containing protein kinase 2 inhibitor, KD025, we analyzed the following: (1) planar proliferation caused by trans-endothelial electrical resistance and the cellular metabolic characteristics of the two-dimensional cultures of human corneal stroma fibroblasts; (2) the physical properties of a three-dimensional human corneal stroma fibroblasts spheroid; and (3) the gene expressions and their regulators in the extracellular matrix, along with the tissue inhibitors of metalloproteinases and matrix metalloproteinases and the endoplasmic reticulum stress-related factors of the two-dimensional and three-dimensional cultures in human corneal stroma fibroblasts. Exposure to 5 nM of the transforming growth factor beta2 markedly increased the trans-endothelial electrical resistance values as well as the metabolic function in two-dimensional cultures of human corneal stroma fibroblasts. With an increase in stiffening, this exposure also reduced the size of three-dimensional human corneal stroma fibroblast spheroids, which are typical cellular phenotypes of the epithelial-mesenchymal transition. Both pan-RHO-associated coiled-coil-containing protein kinase inhibitors and RHO-associated coiled-coil-containing protein kinase 2 inhibitors substantially modulated these transforming growth factor beta2-induced effects, albeit in a different manner. Gene expression analysis supported such biological alterations via either with transforming growth factor beta2 alone or with the RHO-associated coiled-coil-containing protein kinase inhibitors variants with the noted exception being the transforming growth factor beta2-induced effects toward the three-dimensional human corneal stroma fibroblast spheroid. The findings presented herein suggest the following: (1) the epithelial-mesenchymal transition could be spontaneously evoked in the three-dimensional human corneal stroma fibroblast spheroid, and, therefore, the epithelial-mesenchymal transition induced by transforming growth factor beta2 could differ between two-dimensional and three-dimensional cultured HCSF cells; and (2) the inhibition of ROCK1 and 2 significantly modulates the transforming growth factor beta2-induced an epithelial-mesenchymal transition in both two-dimensionally and three-dimensionally cultured human corneal stroma fibroblasts, albeit in a different manner.