Search Results (231)

RECK was first reported as a transformation suppressor gene in 1998 and gradually gained attention as evidence indicating its reduced expression in a wide variety of human cancers accumulated. RECK encodes a membrane-anchored glycoprotein exhibiting protease inhibitor activity against matrix metalloproteases. Restored expression of RECK in cancer xenograft models suggests it suppresses tumor growth and/or metastasis. RECK was also found to be essential for mammalian embryogenesis, especially in the maintenance of tissue integrity as well as the development of neural and vascular systems. Due to its functional versatility during animal development, we only recently began to obtain formal experimental evidence that RECK is a bona fide tumor suppressor. In the meantime, mechanisms by which RECK expression is reduced in cancer cells have been explored. Various stimuli that alter RECK expression have also been described. Furthermore, recent findings in the clinic as well as in animal studies indicate the involvement of RECK in disorders other than cancer. The aim of this article is to summarize our current knowledge of RECK and assist future efforts to understand its nature and functions and to develop useful applications. Full article

The premetastatic niche (PMN) represents a specialized microenvironment established in distant organs before the arrival of metastatic cells. This concept has fundamentally altered our understanding of cancer progression, shifting it from a random event-driven process to an orchestrated one. This review examines the critical role of extracellular proteases in PMN formation, focusing on matrix metalloproteinases (MMPs), serine proteases, and cysteine cathepsins that collectively orchestrate extracellular matrix remodeling, immune modulation, and vascular permeability changes essential for metastatic colonization. Key findings demonstrate that MMP9 and MMP2 facilitate basement membrane degradation and the recruitment of bone marrow-derived cells. At the same time, tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes organ-specific hepatic PMN recruitment through neutrophil recruitment mechanisms. The plasminogen–plasmin system emerges as a master regulator through its broad-spectrum proteolytic activity and ability to activate downstream proteases, with S100A10-mediated plasmin generation providing mechanistic pathways for remote PMN conditioning. Neutrophil elastase and cathepsin G contribute to the degradation of anti-angiogenic proteins, thereby creating pro-metastatic microenvironments. These protease-mediated mechanisms represent the earliest interventional window in metastatic progression, offering therapeutic potential to prevent niche formation rather than treat established metastases. However, significant methodological challenges remain, including the need for organ-specific biomarkers, improved in vivo methods for measuring protease activity, and a better understanding of temporal PMN dynamics across different target organs. Full article

Snakebite envenoming is a neglected tropical disease, responsible for approximately 140,000 deaths globally each year. Vipers and elapid snakes represent the most significant snake families in medical contexts, exhibiting a variety of venom components and clinical effects in bite victims. Metalloproteases, a primary component of venoms, are mainly accountable for haemotoxic and myotoxic effects. Although predominantly found in viper venoms, these enzymes are also present in varying levels in elapid snake venoms. Marimastat and prinomastat are matrix metalloprotease inhibitors initially developed as cancer therapies. Recently, extensive research has focused on these inhibitors to neutralise venom metalloproteases. However, their effects on different viper and elapid snake venoms remain unclear. Here, we report the sensitivity of seven elapid venoms (specifically, cobras) and 12 viper venoms to marimastat and prinomastat, utilising selective in vitro experiments and molecular docking analyses performed using representative metalloprotease (VAP2, a viper metalloprotease from the venom of Crotalus atrox and an elapid metalloprotease from the venom of Naja atra) structures. Both compounds inhibited the metalloprotease, fibrinogenolytic, and caseinolytic activities of most viper venoms. While prinomastat displayed prominent inhibitory effects on cobra venoms in these assays, marimastat demonstrated limited inhibitory effects on these venoms. These findings illustrate the role of matrix metalloprotease inhibitors in modulating metalloprotease activities across a range of viper and cobra venoms. Collectively, this study establishes the differential effects of marimastat and prinomastat on various levels of metalloproteases present in viper and elapid venoms. This will enhance understanding of the abundance of metalloproteases in snake venoms and their sensitivity to different matrix metalloprotease inhibitors. Full article

Background: Following myocardial infarction (MI), cardiac fibroblasts (CFs) adopt distinct phenotypes to ensure scar formation and healing. Although leukocytes are a critical driver of post-MI healing, the role of neutrophils in modulating CF phenotype remains insufficiently explored. We therefore investigated the impact of soluble mediators released by neutrophil subtypes found post-MI—pro-inflammatory (N1) and anti-inflammatory (N2)—on shaping CFs phenotype. Methods: In vitro, human 3D grown CFs were indirectly co-cultured with N1 or N2 neutrophil-like cells using a two-chamber Transwell system. After 24 h, expression of inflammatory, remodeling, and pro-fibrotic markers was evaluated in fibroblasts and conditioned media. In vivo, soluble mediators derived from polarized mouse neutrophils (SN1 or SN2) were injected into the infarcted myocardium of C57BL/6J after MI surgery. The effects on the healing process were investigated at 1 and 7 days post-MI. Results: In vitro, CFs were found to exhibit a pro-inflammatory and matrix-degrading phenotype following indirect co-culture with N1 cells, characterized by overexpression of IL-1β, IL-6, MCP-1, and metalloproteases MMP-3/MMP-9. In vivo, both SN1 and SN2 treatments significantly reduced pro-inflammatory markers IL-1β and IL-6 gene expression at day 1 post-MI (inflammatory phase). At day 7 post-MI (resolution phase), SN1/SN2 treatments continued to limit local inflammation, while mitigating fibrotic remodeling by reducing CCN2, α-SMA, and key extracellular matrix proteins. Conclusions: Together, these findings suggest that while N1-derived mediators promote a pro-inflammatory fibroblast phenotype in vitro, factors secreted by both N1 and N2 support a more balanced reparative response in vivo, by limiting local inflammation and potentially mitigating adverse remodeling post-MI. Full article

Matrix metalloproteases (MMPs) are zinc-dependent endopeptidases that are critical for extracellular matrix (ECM) remodeling, with key roles in tissue development and repair, and immune responses. Despite their evolutionary and functional importance, the diversification and regulatory dynamics of MMPs genes in teleosts remain poorly understood. This study investigates the evolutionary history of MMPs with collagenolytic activity in the vertebrates with an emphasis on teleosts. Using comparative genomics and phylogenetics we identified conserved single-copy mmp2 and mmp9 genes and duplicated mmp11 and mmp13 paralogs in all non-salmonid teleosts. Phylogenetic and synteny analyses suggest that mmp11 paralogs originated from the teleost-specific genome duplication (TSGD), whereas the origin of mmp13 paralogs originated from a more complex evolutionary scenario. Protein domain analysis confirmed conserved catalytic motifs across species, supporting functional retention. The expression patterns of paralog genes were studied in two model marine teleosts, the Sparus aurata (gilthead sea bream) and Dicentrarchus labrax (European sea bass). Developmental and adult tissue transcriptome analyses revealed three major expression patterns among the paralogs: similar expression, stage-specific or tissue-specific expression. The overall data point to varied evolutionary dynamics of MMP genes in the teleosts, tracing their origin to different whole-genome duplication events. Expression profiles on paralog genes in model teleosts suggest regulatory sub-functionalization as the most possible fate of retained MMPs paralogs in teleosts following whole-genome duplication. Full article

Therapeutic strategies targeting “tumor-educated platelets” (TEPs) and platelet–tumor interactions by key signaling pathways (ITAM, P2Y12) may reduce metastasis and cancer. Using a TEP gene expression dataset originally created to study swarm intelligence-enhanced detection of lung cancer cells (GSE89843), we did perform extensive transcriptome analysis to integrate these data with directed protein–protein interactions and build a TEP-specific signaling network. We analyze network topology and controllability and identify critical and indispensable nodes, as well as high-weight, usually high-score nodes. We reconstruct (pharmacological) controllable subnetworks of TEP signaling, which we then explore for drugs targets. We found 111 upregulated and 108 downregulated genes compared to control platelets, enriched in pathways related to extracellular matrix interactions, cytoskeleton organization, immune signaling, and platelet activation. Ribosomal function, apoptosis, and immune signaling were among the downregulated processes, highlighting unique TEP profiles in non-small-cell lung cancer (NSCLC). Our integrative analysis of TEPs in NSCLC reveals key transcriptional and network-based alterations harmful for the cancer patient. Using four complementary strategies, we identified five high-confidence genes (Gene symbols always given throughout the paper), ITGA2B, FLNA, GRB2, FCGR2A, and APP, as central to TEP signaling. These can be targeted by FDA-approved drugs. Fostamatinib, an SYK inhibitor, emerged as the top candidate drug to disrupt ITAM-mediated platelet activation selectively; metastasis-promoting metalloprotease and cytoskeletal targets influencing adhesion were also identified. A low-dose combination therapy of fostamatinib, Aducanumab, and acetylsalicylic acid (aspirin) may control TEP effects. In conclusion, our preclinical in silico approach revealed FDA-approved drugs that allow therapeutic targeting of metastasis-promoting TEPs and target NSCLC at the same time. Full article

ADAM10 is a transmembrane metalloprotease that regulates diverse signalling functions via the shedding of membrane protein ectodomains, and is implicated in tumour development, including glioblastoma multiforme (GBM) and gastrointestinal (GI) cancers, where high ADAM10 expression is associated with poor prognosis. We assessed the role of ADAM10 by gene knockout (KO) in U251 GBM cells, and its effects on protein shedding and protein expression on cell proliferation and on the growth of tumour xenografts in mice. The growth of tumours was severely delayed, relative to modest effects on proliferation in vitro, suggesting roles particularly in the context of the tumour microenvironment (TME). Proteomics analysis of KO cell-conditioned medium showed decreased levels of known ADAM10 targets such as Notch and Eph receptors and ligands, as well as other proteins involved in cell–cell adhesion, migration, signalling, metabolism, differentiation, and development, including angiogenesis. KO cell and tumour lysate analysis also showed modulation of proteins associated with metabolic and catalytic activity, cell–matrix organisation and differentiation. Similar effects were also observed in the SW620 colon cancer model, indicating broader significance. Furthermore, expression of the associated protein sets also correlated with ADAM10 expression in human GBM and colon cancer specimens (TCGA datasets), indicating clinical relevance. Collagens and proteins associated with matrix deposition and fibril organisation were notably reduced in ADAM10 KO GBM tumours, and histology confirmed decreased collagen fibrils and blood vessels. Unexpectedly, increased chondrocyte differentiation was evident in ADAM10 KO U251 tumours, suggesting a role for ADAM10 in maintaining an undifferentiated phenotype in vivo. Together, our data indicate the importance of ADAM10 in diverse signalling mechanisms in tumours and the TME that promote tumour development. Full article

Wound healing dysregulation often results in visible scarring with significant psychological impact, particularly affecting individuals with darker skin phototypes. This study investigates the efficacy of an aqueous extract of Australian Jellybush honey (Leptospermum polygalifolium) in improving scar appearance across diverse skin tones. Our research demonstrated the extract reduced IL-8 production by 42%, decreased reactive oxygen species by 14.6%, and increased pro-collagen I synthesis by 28%. Ex vivo experiments revealed a 44% increase in neo-epidermal tongue length after 10 days while gene expression analysis showed coordinated wound healing through timed modulation of key markers such as filaggrin, matrix metalloproteases, keratins. In a double-blind clinical study involving 21 volunteers (phototypes II–VI) with acne scars, 8-week application of 2% Jellybush honey extract improved skin homogeneity by 15%, reduced scar surface area by 3% and decreased atrophic and hypertrophic scars dimensions by 9% and 16%, respectively, versus placebo. These improvements were consistent across all phototypes, including V-VI. Jellybush honey extract offers a promising approach for scar management through balanced modulation of wound healing pathways across all skin phototypes. Full article

The dried root extract of Astragalus membranaceus, also known as Astragali radix, is widely used in traditional Chinese medicine for its multiple health benefits and well-established safety profile. Astragalus root extract exhibits several bioactive properties, including anti-inflammatory, antioxidant, antiviral and hepatoprotective effects. Due to its unique features, it is being investigated in a novel application as a complementary remedy in the management of joint disorders. In this study, we evaluated the effect of Astragalus membranaceus hydroalcoholic root extract (0.01 and 0.1 mg/mL) in vitro on the HTB-94 cell line, a well-known model for studying inflammatory pathways in human chondrocytes. The mRNA modulation levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR), while the protein secretion levels were assessed using an Enzyme-Linked Immunosorbent Assay (ELISA). Results obtained demonstrated that this extract is able to decrease the tumor necrosis factor-α (TNF-α)-induced inflammatory response by downregulating both the mRNA expression and release of the pro-inflammatory mediators Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Interelukin-8 (IL-8), as well as matrix metalloproteases, including Matrix Metalloprotease-3 (MMP-3), Matrix Metalloprotease-13 (MMP-13) and A disintegrin, and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5). Moreover, the interleukin and matrix metalloprotease production was also assessed in non-TNF-α-stimulated cells, revealing that the extract did not alter the basal levels of these mediators. Finally, our findings highlight the potential benefits of Astragalus membranaceus extract, both in terms of its favorable safety profile and its efficacy mitigating joint inflammatory responses. These results support the potential of this extract as a nutraceutical agent for joint health support. Full article

The focus in this study was to investigate the proteolytic functions of matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease (ADAM) proteins in the progression of diabetic retinopathy (DR) and to evaluate their potential as therapeutic targets for eye diseases. This study involved three groups: non-proliferative diabetic retinopathy patients (NPDR) (n = 27), proliferative diabetic retinopathy patients (PDR) (n = 32), and a control group of 30 healthy individuals. Serum levels of ADAM9 and MMP9 were measured across these groups for comparative analysis. Serum ADAM9 levels were significantly lower in the NPDR and PDR groups than in the control group (p = 0.031, p < 0.001). Although ADAM9 levels were lower in the PDR group than in the NPDR group, this difference was not significant (p = 0.142). Serum MMP9 levels in the PDR group were significantly lower than those in both the control and NPDR groups (p = 0.039, p = 0.013). The findings of this study indicate that ADAM9, MMP9, and left-eye ocular parameters may have potential value in the assessment of DR. The notable variation in the MMP9 marker in the proliferative stage, as opposed to its stability in the non-proliferative stage, suggests a distinct role in retinopathy staging. This underscores the specific importance of MMP9 in the proliferative stage. Full article

Recent advances have highlighted the multifaceted roles of the lymphatic vasculature in immune cell trafficking, immunomodulation, nutrient transport, and fluid homeostasis. Beyond these physiological functions, lymphatic vessels are critically involved in pathologies such as cancer metastasis and lymphedema, rendering their structural and functional regulation of major interest. Emerging evidence suggests that limited proteolysis is a key regulatory mechanism for lymphatic vascular function. In dyslipidemic conditions, dysregulated calpain activity impairs lymphatic trafficking and destabilizes regulatory T cells, partly via the limited proteolysis of mitogen-activated kinase kinase kinase 1 and inhibitor of κBα. In addition, a disintegrin and metalloprotease with thrombospondin motifs-3-mediated proteolytic activation of vascular endothelial growth factor-C has been implicated in both developmental and tumor-associated lymphangiogenesis. Proteolytic shedding of lymphatic vessel endothelial hyaluronan receptor-1 by a disintegrin and metalloprotease 17 promotes lymphangiogenesis, whereas cleavage by membrane-type 1 matrix metalloproteinase inhibits it. This review is structured around two core aspects—lymphatic inflammation and lymphangiogenesis—and highlights recent findings on how limited proteolysis regulates each of these processes. It also discusses the therapeutic potential of targeting these proteolytic machineries and currently unexplored research questions, such as how intercellular junctions of lymphatic endothelial cells are controlled. Full article

Particulate matter (PM), mainly PM_0.5, represents a significant concern for human health, particularly relating to lung homeostasis, and more research is required to ascertain its tissue tropism and the molecular pathways involved. In this study, we first focus on classical in vitro toxicological endpoints (cytotoxicity and cell growth) in human bronchial and alveolar epithelial cell lines mimicking the two pulmonary target tissues. Air samples were collected in five Italian cities (Brescia, Lecce, Perugia, Pisa, Turin) during winter and spring. To better decipher the PM_0.5 effects on pulmonary cells, a further winter sampling was performed in Brescia, and studies were extended to assess tumour promotion, oxidative stress, and the activity of Matrix metalloproteases (MMP). The results confirmed that the effect of air pollution is linked to the seasons (winter is usually more cytotoxic than spring) and is correlated with the peculiar characteristics of the cities studied (meteoclimatic conditions, economic/anthropogenic activities). Alveolar cells were often less sensitive than bronchial cells. All PM samples from Brescia inhibited intercellular communication mediated by gap junctions (GJIC), increased the total content in glutathione, and decreased the reduced form of glutathione, whereas the Reactive Oxygen Species (ROS) content was almost constant. Long-term treatments at higher doses of PM decreased MMP2 and MMP9 activity. Taken together, the results confirmed that PM is cytotoxic and can potentially act as tumour promoters, but the mechanisms involved in oxidative stress and lung homeostasis are dose- and time-dependent and quite complex. Full article

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

(1) Objective: Cardiovascular diseases (CVD) are one of the main entities responsible for the progressive increase in morbidity and mortality worldwide. Some of the biomarkers involved in these processes are matrix metalloproteases (MMPs) and disintegrants and metalloproteases (ADAMS), produced by multiple tissues and whose main function is the excessive degradation of the extracellular matrix (ECM). The aim of this study is to describe the existing literature on the role of MMP in the pathophysiology of CVD and its usefulness in clinical practice for the diagnostic and therapeutic approach. (2) Methods: A systematic exploratory review of the literature was carried out according to the guidelines of the Joanna Briggs Institute. The information was collected from the PubMed/Medline and Embase databases, using the search strategy “cardiovascular disease” AND “Metalloprotease”. (3) Results: Thirty eight papers that mainly mention 17 types of MMPs were included. Pathologies such as atherosclerosis, coagulation diseases, atrial fibrillation, ischemic heart disease, heart failure, hypertension, dyslipidemias, congenital cyanotic heart disease and Takotsubo cardiomyopathy were identified. (4) Conclusions: The stimulation or inhibition of these biomolecules could generate positive and/or negative effects, which impact the development and prognosis of the disease. Furthermore, they can be potential biomarkers for new diagnostic and even therapeutic approaches in the future. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) accumulation and neuroinflammation. A previous multicenter, phase 2, double-blind, placebo-controlled trial randomized 179 participants into placebo or resveratrol over 52 weeks. Sub-analysis of CSF biomarkers of neuronal damage, inflammation, and microglial activity was performed in a subset of patients treated with a placebo (n = 21) versus resveratrol (n = 30). Markers of neuronal damage, including neuron-specific enolase and hyperphosphorylated neurofilaments, were reduced. Microglial activation was measured via a triggering receptor expressed on myeloid cells (TREM)-2 at baseline and after resveratrol treatment. Resveratrol significantly reduced CSF TREM2 levels and decreased inflammation and tissue damage, including matrix metalloprotease (MMP)-9. Cathepsin D, a lysosomal marker of autophagy, was reduced in the resveratrol group compared with placebo, while angiogenin, a marker of vascular angiogenesis, was increased. These data suggest that resveratrol may exert anti-inflammatory and neuroprotective effects in AD by reducing CSF TREM2 and other markers of neuronal damage. Further research is needed to assess the significance of these biomarker changes on clinical outcomes in patients with neurodegenerative diseases. Full article