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Search Results (953)

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Keywords = MMP-9 inhibitors

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14 pages, 2837 KiB  
Article
Design, Synthesis, and Bioactivity Assessment of Modified Vemurafenib Analog
by Fabiana Sélos Guerra, Rosana Helena Coimbra Nogueira de Freitas, Florina Moldovan, David Rodrigues da Rocha, Renato Sampaio Carvalho and Patricia Dias Fernandes
Pharmaceuticals 2025, 18(8), 1161; https://doi.org/10.3390/ph18081161 - 5 Aug 2025
Abstract
Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAFV600E mutation, for which vemurafenib, a selective BRAFV600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often [...] Read more.
Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAFV600E mutation, for which vemurafenib, a selective BRAFV600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAFV600E-mutated A375 cells, with RF-86A displaying the lowest IC50 value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article
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14 pages, 1886 KiB  
Review
Membrane-Type 5 Matrix Metalloproteinase (MT5-MMP): Background and Proposed Roles in Normal Physiology and Disease
by Deepak Jadhav, Anna M. Knapinska, Hongjie Wang and Gregg B. Fields
Biomolecules 2025, 15(8), 1114; https://doi.org/10.3390/biom15081114 - 3 Aug 2025
Viewed by 289
Abstract
The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several [...] Read more.
The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer’s disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer’s disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer’s disease and other pathologies. Full article
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26 pages, 1899 KiB  
Review
Extracellular Matrix (ECM) Aging in the Retina: The Role of Matrix Metalloproteinases (MMPs) in Bruch’s Membrane Pathology and Age-Related Macular Degeneration (AMD)
by Ali A. Hussain and Yunhee Lee
Biomolecules 2025, 15(8), 1059; https://doi.org/10.3390/biom15081059 - 22 Jul 2025
Viewed by 364
Abstract
The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted [...] Read more.
The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted as pro-forms and require activation to degrade ECM components. Their activity is modulated by tissue inhibitors of metalloproteinases (TIMPs). Aging disrupts this balance, leading to the accumulation of oxidized, cross-linked, and denatured matrix proteins, thereby impairing ECM function. Bruch’s membrane, a penta-laminated ECM structure in the eye, plays a critical role in supporting photoreceptor and retinal pigment epithelium (RPE) health. Its age-related thickening and decreased permeability are associated with impaired nutrient delivery and waste removal, contributing to the pathogenesis of age-related macular degeneration (AMD). In AMD, MMP dysfunction is characterized by the reduced activation and sequestration of MMPs, which further limits matrix turnover. This narrative review explores the structural and functional changes in Bruch’s membrane with aging, the role of MMPs in ECM degradation, and the relevance of these processes to AMD pathophysiology, highlighting emerging regulatory mechanisms and potential therapeutic targets. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)
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17 pages, 659 KiB  
Review
Insights into the Molecular Mechanisms and Novel Therapeutic Strategies of Stenosis Fibrosis in Crohn’s Disease
by Yuan Zhou, Huiping Chen, Qinbo Wang, Guozeng Ye, Yingjuan Ou, Lihong Huang, Xia Wu and Jiaxi Fei
Biomedicines 2025, 13(7), 1777; https://doi.org/10.3390/biomedicines13071777 - 21 Jul 2025
Viewed by 427
Abstract
Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical [...] Read more.
Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. Full article
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28 pages, 3171 KiB  
Article
Valproic Acid Reduces Invasiveness and Cellular Growth in 2D and 3D Glioblastoma Cell Lines
by Francesca Giordano, Martina Forestiero, Adele Elisabetta Leonetti, Giuseppina Daniela Naimo, Alessandro Marrone, Francesca De Amicis, Stefania Marsico, Loredana Mauro and Maria Luisa Panno
Int. J. Mol. Sci. 2025, 26(14), 6600; https://doi.org/10.3390/ijms26146600 - 9 Jul 2025
Viewed by 390
Abstract
Glioblastoma (GBM) is the most common malignant brain tumor, with a poor prognosis and low survival. Its treatment includes complete surgical resection followed by radiotherapy combined with temozolomide (TMZ). GBM contains glial stem cells (GSCs), which contribute to tumor progression, invasiveness, and drug [...] Read more.
Glioblastoma (GBM) is the most common malignant brain tumor, with a poor prognosis and low survival. Its treatment includes complete surgical resection followed by radiotherapy combined with temozolomide (TMZ). GBM contains glial stem cells (GSCs), which contribute to tumor progression, invasiveness, and drug resistance. The histone deacetylase (HDAC) inhibitor valproic acid (VA) has been shown to be a potent antitumor and cytostatic agent. In this study, we tested the effects of VA on glioma cell proliferation, migration, and apoptosis using T98G monolayer and spheroid cells. T98G and U-87MG glioblastoma cell viability was determined by MTT. Cell cycle and ROS levels were analyzed by flow cytometry, and gene and protein levels were detected, respectively, by RT-PCR and immunoblotting. VA reduces cell viability in 2D and 3D T98G and U-87MG cells and blocks the cell cycle at the G0/G1 with decreased levels of cyclin D1. VA addresses apoptosis and ROS production. In addition, VA significantly decreases the mRNA levels of the mesenchymal markers, and it counteracts cell migration, also decreasing MMP2. The results confirm the inhibitory effect of VA on the growth of the T98G and U-87MG cell lines and its ability to counteract migration in both 2D and 3D cellular models. Full article
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14 pages, 2893 KiB  
Article
Morphological and Molecular Evaluation of a Gel Based on Hyaluronic Acid and Spermidine for Oral Regenerative Purposes
by Dolaji Henin, Elena Canciani, Daniela Carmagnola, Stefano Ferrero, Gaia Pellegrini, Mariachiara Perrotta, Riccardo Sirello, Claudia Dellavia and Nicoletta Gagliano
Cells 2025, 14(14), 1047; https://doi.org/10.3390/cells14141047 - 9 Jul 2025
Viewed by 400
Abstract
Background: Oral wound healing is a complex process influenced by extracellular matrix (ECM) remodeling and cellular migration. Hyaluronic acid (HA) and spermidine (SP) have shown regenerative potential, but their combined effects on oral tissues remain unexplored. This study aimed to characterize the effect [...] Read more.
Background: Oral wound healing is a complex process influenced by extracellular matrix (ECM) remodeling and cellular migration. Hyaluronic acid (HA) and spermidine (SP) have shown regenerative potential, but their combined effects on oral tissues remain unexplored. This study aimed to characterize the effect of a gel composed of a mixture of HA and SP on the epithelial and connective compartments of oral tissue separately, evaluating (i) collagen turnover and cell migration on primary human gingival fibroblasts (HGFs) and (ii) epithelial integrity and cell proliferation on gingival organotypic cultures (OCs). Methods: HGFs were cultured, treated with HA-SP gel (1:0.5 HA-SP ratio) and evaluated for collagen types I and III (COL-I, COL-III), matrix metalloproteinase (MMP-1) protein and tissue inhibitor of MMP-1 (TIMP-1) levels secreted by the cells upon gel treatment, compared to CT. HGFs were also analyzed through a wound healing assay. Gingival samples were obtained to set OCs and were treated with different HA-SP formulations (HA 0.2%; 1:0.5 HA-SP ratio; 1:5 HA-SP ratio) to evaluate the beneficial addition of SP to HA for epithelial tissue. OC samples were formalin-fixed and paraffin-embedded and were stained with hematoxylin and eosin and immunostained for Ki-67 analysis. Results: In HGFs, the gel induced increased COL-III gene expression relative to that of COL-I after 48 h and stimulated cell migration, in turn favoring connective tissue remodeling and repair. In OCs, the gel preserved epithelial integrity up to 48 h, with the best effects observed with the 1:0.5 HA-SP ratio. After 72 h, epithelial detachment was more evident in HA formulations, suggesting that SP contributes to epithelial integrity. Conclusions: The HA-SP gel may support oral tissue healing by modulating ECM remodeling and maintaining epithelial integrity. The gel containing HA and SP at the 1:0.5 ratio may provide a promising solution for enhancing wound healing. Full article
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18 pages, 2012 KiB  
Article
ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential
by Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine and Fumio Matsuda
Metabolites 2025, 15(7), 461; https://doi.org/10.3390/metabo15070461 - 7 Jul 2025
Viewed by 641
Abstract
Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In [...] Read more.
Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H+/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability. Full article
(This article belongs to the Section Cell Metabolism)
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16 pages, 2252 KiB  
Article
Elucidating the Role of Toxoplasma gondii’s Mitochondrial Superoxide Dismutase
by James Alexander Tirtorahardjo, Christopher I-H. Ma, Areej Shaikh and Rosa M. Andrade
Biomolecules 2025, 15(7), 972; https://doi.org/10.3390/biom15070972 - 7 Jul 2025
Viewed by 389
Abstract
Toxoplasma gondii is an Apicomplexan parasite that possesses a well-developed system of scavengers of reactive oxygen species (ROS). Among its components, T. gondii mitochondrial superoxide dismutase (TgSOD2) is essential, as predicted by the CRISPR phenotype index and evidenced by the non-viability of its [...] Read more.
Toxoplasma gondii is an Apicomplexan parasite that possesses a well-developed system of scavengers of reactive oxygen species (ROS). Among its components, T. gondii mitochondrial superoxide dismutase (TgSOD2) is essential, as predicted by the CRISPR phenotype index and evidenced by the non-viability of its constitutive knockouts. As an obligate intracellular parasite, TgSOD2 is upregulated during extracellular stages. Herein, we generated a viable TgSOD2 knockdown mutant using an inducible auxin–degron system to explore the biological role of TgSOD2 in T. gondii. Depletion of TgSOD2 led to impaired parasite growth and replication, reduced mitochondrial membrane potential (MMP), abnormalities in the distribution of ATP synthase within its mitochondrial electron transport chain (mETC), and increased susceptibility to mETC inhibitors. Through a proximal biotinylation approach, we identified the interactions of TgSOD2 with complexes IV and V of its mETC, suggesting that these sites are sensitive to ROS. Our study provides the first insights into the role of TgSOD2 in maintaining its mitochondrial redox homeostasis and subsequent parasite replication fitness. Significance: Toxoplasma gondii infects nearly a third of the world population and can cause fetal miscarriages or life-threatening complications in vulnerable patients. Current therapies do not eradicate the parasite from the human hosts, rendering them at risk of recurrence during their lifetimes. T. gondii has a single mitochondrion, which is well-known for its susceptibility to oxidative damage that leads to T. gondii’s death. Therefore, targeting T. gondii mitochondrion remains an attractive therapeutic strategy for drug development. T. gondii’s mitochondrial superoxide dismutase is an antioxidant protein in the parasite mitochondrion and is essential for its survival. Understanding its biological role could reveal mitochondrial vulnerabilities in T. gondii and provide new leads for the development of effective treatments for T. gondii infections. Full article
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15 pages, 3414 KiB  
Article
Dual Inhibition of SRC Family Kinases and Sorafenib Enhances Anti-Tumor Activity in Hepatocellular Carcinoma Cells
by Loraine Kay Cabral, Cyrollah Disoma, Paola Tarchi, Korri Elvanita El-Khobar, Agustiningsih Agustiningsih, Francesco Dituri, Claudio Tiribelli and Caecilia Sukowati
Int. J. Mol. Sci. 2025, 26(13), 6506; https://doi.org/10.3390/ijms26136506 - 6 Jul 2025
Viewed by 1100
Abstract
Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate and limited response to monotherapies, such as sorafenib—the standard first-line therapy for advanced HCC. This is partly attributed to its cellular heterogeneity. Increasing evidence implies SRC family kinase (SFK) [...] Read more.
Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate and limited response to monotherapies, such as sorafenib—the standard first-line therapy for advanced HCC. This is partly attributed to its cellular heterogeneity. Increasing evidence implies SRC family kinase (SFK) activation in HCC progression, highlighting the potential of SRC-targeted therapies. In this study, we observed that SRC and YES1 were significantly upregulated in clinical HCC specimens compared to its adjacent non-tumoral tissues (p < 0.001), suggesting relevance as therapeutic targets. High SRC expression was noticed in patients with poor prognosis, as confirmed in TCGA cohort. To evaluate the efficacy of dual targeting, we assessed the combination between SRC inhibitors, saracatinib and dasatinib, with sorafenib in six hepatic cell models, representing both S1 and S2 subtypes. Cytotoxicity assays demonstrated reduced cell viability with the combination therapies compared to either monotherapy, irrespective of the HCC subtype. Wound healing and Transwell migration assays revealed inhibition of cell migration and invasion following combination treatment, underscoring its potential to suppress metastatic behavior. RT-qPCR analysis further confirmed downregulation of the expression of MMP2 and MMP9, genes associated with HCC cell invasion. Additionally, combined therapies decreased VEGFA and HIF1A expression compared to sorafenib alone, suggesting a potential to counteract the adaptive resistance mechanisms of cells to sorafenib. In summary, the combination of SFK inhibitors with sorafenib significantly enhances anti-tumor activity, offering a promising strategy to address HCC cellular heterogeneity and improve treatment efficacy. Full article
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19 pages, 937 KiB  
Review
Tissue Repair Mechanisms of Dental Pulp Stem Cells: A Comprehensive Review from Cutaneous Regeneration to Mucosal Healing
by Jihui He, Jiao Fu, Ruoxuan Wang, Xiaojing Liu, Juming Yao, Wenbo Xing, Xinxin Wang and Yan He
Curr. Issues Mol. Biol. 2025, 47(7), 509; https://doi.org/10.3390/cimb47070509 - 2 Jul 2025
Viewed by 648
Abstract
Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp [...] Read more.
Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp stem cells (DPSCs) and their derivatives, including extracellular vesicles, conditioned medium, and intracellular factors, in accelerating skin wound healing. The key mechanisms include: (1) DPSCs regulating inflammatory microenvironments by promoting anti-inflammatory M2 macrophage polarization; (2) DPSCs activating vascular endothelial growth factor (VEGF) to drive angiogenesis; (3) DPSCs optimizing extracellular matrix (ECM) spatial structure through matrix metalloproteinase/tissue inhibitor of metalloproteinase (MMP/TIMP) balance; and (4) DPSCs enhancing transforming growth factor-β (TGF-β) secretion to accelerate granulation tissue formation. Collectively, these processes promote wound healing. In addition, we explored potential factors that accelerate wound healing in DPSCs, such as oxidative stress, mechanical stimulation, hypertension, electrical stimulation, and organoid modeling. In addition to demonstrating the great potential of DPSCs for skin repair, this review explores their translational prospects in mucosal regenerative medicine. It covers the oral cavity, esophagus, colon, and fallopian tube. Some studies have found that combining DPSCs and their derivatives with drugs can significantly enhance their biological effects. By integrating insights from skin and mucosal models, this review offers novel ideas and strategies for treating chronic wounds, inflammatory bowel disease, and mucosal injuries. It also lays the foundation for connecting basic research results with clinical practice. This represents a significant step forward in tackling these complex medical challenges and lays a solid scientific foundation for developing more targeted and efficient regenerative therapies. Full article
(This article belongs to the Section Molecular Medicine)
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30 pages, 1700 KiB  
Review
The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia
by Aurelio Pio Russo, Ylenia Pastorello, Lóránd Dénes, Klara Brînzaniuc, Jerzy Krupinski and Mark Slevin
Int. J. Mol. Sci. 2025, 26(13), 6237; https://doi.org/10.3390/ijms26136237 - 27 Jun 2025
Viewed by 636
Abstract
Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, [...] Read more.
Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article
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17 pages, 7173 KiB  
Article
Inhibition of Matrix Metalloproteinase-7 Attenuates Subpleural Fibrosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease
by Li Xiong, Li-Mei Liang, Shu-Yi Ye, Xiao-Lin Cui, Shi-He Hu, Chen-Yue Lian, Wen-Jia Sun, Yang-Ping Lv, He-De Zhang, Meng Wang, Fei Xiang, Liang Xiong, Hong Ye, Wan-Li Ma and Lin-Jie Song
Biomedicines 2025, 13(7), 1581; https://doi.org/10.3390/biomedicines13071581 - 27 Jun 2025
Viewed by 640
Abstract
Background: Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a significant complication of RA which lacks effective treatments with high mortality. This study aimed to investigate the role of matrix metalloproteinase-7 (MMP-7) in mediating RA-ILD. Methods: Based on the database of RA-ILD [...] Read more.
Background: Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a significant complication of RA which lacks effective treatments with high mortality. This study aimed to investigate the role of matrix metalloproteinase-7 (MMP-7) in mediating RA-ILD. Methods: Based on the database of RA-ILD patients, a bioinformatics analysis was performed. A protein–protein interaction (PPI) network focusing on MMP-7 was simulated. Pleural mesothelial cells (PMCs) were treated with RA-ILD patients’ serum or RA-ILD-related inflammatory factors, and the protein expressions of collagen-I and MMP-7 were examined. An arthritis model was established using complete Freund’s adjuvant (CFA). Changes in the weight and joints of mice were recorded, and lung tissues were evaluated by Masson staining and Sirius red stain techniques. MMP-7 inhibitor, MMP-7 siRNA and MMP shRNA lentivirus were used to inhibit MMP-7 and investigate changes in collagen-I and fibrosis in vivo and in vitro. Results: MMP-7 was found to be significantly expressed in RA-ILD lung tissue by bioinformatics analysis, and MMP-7 to maybe interact with collagen-I. In vitro experiments indicated cytokines IL-1β, IL-6 and TNF-α promoted MMP-7 and collagen-I expression in PMCs. Serum obtained from patients with RA-ILD also upregulated MMP-7 and collagen-I expression in PMCs. Inhibition of MMP-7 with MMP-7 siRNA or MMP inhibitor prevented collagen-I synthesis in PMCs. In vivo, CFA induced arthritis and subpleural lung inflammation in rats, but the MMP-7 inhibitor and MMP-7 siRNA attenuated CFA-induced lung inflammation and subpleural lung fibrosis. Conclusions: MMP-7 mediated subpleural lung inflammation as well as fibrosis in RA-ILD. It provided theoretical and experimental support for MMP-7 being a therapeutic target in RA-ILD. Full article
(This article belongs to the Special Issue Pathogenesis, Diagnostics, and Therapeutics for Rheumatic Diseases)
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15 pages, 1059 KiB  
Article
Kidney Transplant Recipients with Acute Antibody-Mediated Rejection Show Altered Levels of Matrix Metalloproteinases and Their Inhibitors: Evaluation of Circulating MMP and TIMP Profiles
by Miguel A. Vázquez-Toledo, Fausto Sánchez-Muñoz, Iván Zepeda-Quiroz, Carlos A. Guzmán-Martín, Horacio Osorio-Alonso, Juárez-Villa Daniel, Ma. Virgilia Soto-Abraham, Bernardo Moguel-González, Rommel Chacón-Salinas, César Flores-Gama and Rashidi Springall
Int. J. Mol. Sci. 2025, 26(13), 6011; https://doi.org/10.3390/ijms26136011 - 23 Jun 2025
Viewed by 714
Abstract
Antibody-mediated rejection (ABMR) remains a major cause of renal graft dysfunction and loss. The histological hallmark of antibody-mediated rejection is progressive tissue damage, in which extracellular matrix turnover plays an important role. This turnover is mainly regulated by matrix metalloproteinases (MMPs) and tissue [...] Read more.
Antibody-mediated rejection (ABMR) remains a major cause of renal graft dysfunction and loss. The histological hallmark of antibody-mediated rejection is progressive tissue damage, in which extracellular matrix turnover plays an important role. This turnover is mainly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Recent studies suggest that MMP/TIMP imbalance may favor the progression of renal damage, inflammation, and fibrosis, but the utility of these molecules as a biomarker of antibody-mediated turnover has not been fully explored. We measured plasma MMP and TIMP levels by ELISA in 15 patients with antibody-mediated renal transplant rejection and 12 patients without rejection. There was a significant increase in MMP-1, MMP-2, and MMP-3 concentrations in the plasma of patients with rejection, directly correlating with the severity of different renal lesions. In contrast, TIMP-3 levels were elevated in patients without rejection, showing a negative correlation with the severity of histopathological lesions. The concentrations of these molecules demonstrated good diagnostic capacity for patients with rejection. Our results show that MMP-1, MMP-2, MMP-3, and TIMP-3 could be potential biomarkers of rejection. Full article
(This article belongs to the Special Issue Advances in Kidney Transplantation)
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18 pages, 5903 KiB  
Article
Oxidative Stress Mediates the Dual Regulatory Effects of Bovine Uterine ECM Remodeling Through the TGF-β1/Smad3 Pathway: Molecular Mechanisms of MMPs and COL-IV Imbalances
by Jiamei Tan, Zongjie Wang, Mingmao Yang, Ruihang Zhang, Zhongqiang Xue, Dong Zhou, Aihua Wang, Pengfei Lin and Yaping Jin
Animals 2025, 15(13), 1847; https://doi.org/10.3390/ani15131847 - 23 Jun 2025
Viewed by 543
Abstract
Bovine endometritis is a common endocrine and reproductive disorder in postpartum dairy cows, closely associated with elevated systemic oxidative stress. This disease can lead to delayed uterine involution, repeated breeding failure, and significant economic losses in the dairy industry. Studies suggest that oxidative [...] Read more.
Bovine endometritis is a common endocrine and reproductive disorder in postpartum dairy cows, closely associated with elevated systemic oxidative stress. This disease can lead to delayed uterine involution, repeated breeding failure, and significant economic losses in the dairy industry. Studies suggest that oxidative stress may contribute to the pathological progression of endometritis by regulating ECM remodeling, but the specific molecular mechanisms remain unclear. ECM homeostasis relies on the coordinated action of matrix metalloproteinases (e.g., MMP2, MMP9) and collagen (e.g., type IV collagen, COL-IV), while the TGFβ1/Smad3 signaling pathway is implicated in ECM metabolic regulation. Therefore, elucidating the regulatory mechanisms of oxidative-stress-mediated TGFβ1/Smad3 signaling on ECM remodeling is crucial for understanding the pathogenesis of endometritis. This study investigates postpartum bovine uterine tissues, comparing inflammatory cytokines (IL-1β, IL-6, TNF-α) and oxidative-stress-related factors (GPx, SOD, CAT) between healthy and endometritis groups. Additionally, the differences in ECM-remodeling-associated proteins (MMP2, MMP9, COL-IV) and TGFβ1/Smad3 pathway activity are analyzed. To further validate the mechanisms, an oxidative stress model is established in vitro by treating bovine endometrial epithelial cells (bEECs) with 200 μM H2O2 for 4 h, followed by the valuation of the same indicators. Furthermore, gene silencing to downregulate Smad3 expression or inhibitor-mediated suppression of TGFβ1/Smad3 pathway activity is performed to observe their regulatory effects on MMP2, MMP9, and COL-IV. The results demonstrate that oxidative-stress-mediated endometritis significantly upregulates MMP2, MMP9, and the TGFβ1/Smad3 pathway activity, while suppressing COL-IV expression. Functional genetic experiments further reveal the dual regulatory role of the TGFβ1/Smad3 pathway in ECM remodeling: (1) pathway activation promotes MMP2/MMP9 expression, accelerating COL-IV degradation; (2) Smad3 positively regulates COL-IV synthesis. These findings provide a theoretical basis for targeting the TGFβ1/Smad3 pathway to mitigate the pathological progression of endometritis. Full article
(This article belongs to the Special Issue Physiology and Pathology of Bovine Reproduction)
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12 pages, 2251 KiB  
Article
The Rab18/Ras/ERK/FosB/MMP3 Signaling Pathway Mediates Cell Migration Regulation by 2′3′-cGAMP
by Yu Deng, Runjie Yuan and Pengda Liu
Int. J. Mol. Sci. 2025, 26(12), 5758; https://doi.org/10.3390/ijms26125758 - 16 Jun 2025
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Abstract
The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of [...] Read more.
The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2′3′-cGAMP. Binding of 2′3′-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2′3′-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2′3′-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2′3′-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2′3′-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2′3′-cGAMP-induced migratory responses. Full article
(This article belongs to the Section Molecular Biology)
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