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1
Ganea, E., M. Trifan, A. C. Laslo, G. Putina, and C. Cristescu. "Matrix metalloproteinases: useful and deleterious." Biochemical Society Transactions 35, no. 4 (July 20, 2007): 689–91. http://dx.doi.org/10.1042/bst0350689.
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MMPs (matrix metalloproteinases) are zinc-dependent endopeptidases that degrade both matrix and non-matrix proteins. They play an important role in morphogenesis, and in a wide range of processes including tissue repair and remodelling. Their abnormal expression contributes to pathological processes including arthritis, cancer, and cardiac and central nervous system diseases, which explains the large interest in finding specific MMP inhibitors for therapeutic use. In this review we describe the structural features of MMPs, with special emphasis on their interaction with specific inhibitors. The effect of new, hydroxamatebased inhibitors on MMP isolated from bovine brain is evaluated.
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Jakubowska, Katarzyna, Anna Pryczynicz, Piotr Iwanowicz, Andrzej Niewiński, Elżbieta Maciorkowska, Jerzy Hapanowicz, Dorota Jagodzińska, Andrzej Kemona, and Katarzyna Guzińska-Ustymowicz. "Expressions of Matrix Metalloproteinases (MMP-2, MMP-7, and MMP-9) and Their Inhibitors (TIMP-1, TIMP-2) in Inflammatory Bowel Diseases." Gastroenterology Research and Practice 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/2456179.
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Crohn’s disease (CD) and ulcerative colitis (UC) belong to a group of inflammatory bowel diseases (IBD). The aim of our study was to evaluate the expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 in ulcerative colitis and Crohn’s disease. The study group comprised 34 patients with UC and 10 patients with CD. Evaluation of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 expression in tissue samples was performed using immunohistochemistry. The overexpression of MMP-9 and TIMP-1 was dominant in both the glandular epithelium and inflammatory infiltration in UC patients. In contrast, in CD subjects the positive expression of MMP-2 and TIMP-1 was in glandular tubes while mainly MMP-7 and TIMP-2 expression was in inflammatory infiltration. Metalloproteinases’ expression was associated with the presence of erosions, architectural tissue changes, and inflammatory infiltration in the lamina propria of UC patients. The expression of metalloproteinase inhibitors correlated with the presence of eosinophils and neutrophils in UC and granulomas in CD patients. Our studies indicate that the overexpression of metalloproteinases and weaker expression of their inhibitors may determine the development of IBD. It appears that MMP-2, MMP-7, and MMP-9 may be a potential therapeutic target and the use of their inhibitors may significantly reduce UC progression.
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De, S., J. E. Fenton, and A. S. Jones. "Matrix metalloproteinases and their inhibitors in non-neoplastic otorhinolaryngological disease." Journal of Laryngology & Otology 119, no. 6 (June 2005): 436–42. http://dx.doi.org/10.1258/0022215054273269.
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Matrix metalloproteinases (MMPs) are a family of zinc and calcium-dependent endopeptidases that play a key role in extracellular matrix (ECM) degradation. MMPs are known to be important in normal remodelling processes. Overexpression and activation of MMPs or an imbalance of active MMPs and tissue inhibitors of metalloproteinases (TIMPs) has been linked with a number of specific disease states associated with the breakdown and remodelling of the extracellular matrix. MMPs and TIMPs play a role in the development and progression of conditions such as acute and chronic otitis media, nasal polyposis and Sjogren’s disease of salivary glands. Their role in allergic rhinitis has not been proven although they do appear to have a role in asthma, a condition closely linked to rhinitis. The use of a broad spectrum MMP inhibitor has been shown to alter the outcome of acute otitis media and otitis media with effusion. Therapeutic strategies with anti-MMP molecules are currently being developed and may play a role in modulating the course of non-neoplastic otorhinolaryngological disease in the future.
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Titovska, S. O. "EFFECTIVENESS OF MATRIX METALLOPROTEINASES INHIBITORS FOR PREVENTIVE TREATMENT OF GENERALIZED PERIODONTITIS." Ukrainian Dental Almanac, no. 2 (June 27, 2022): 10–15. http://dx.doi.org/10.31718/2409-0255.2.2022.02.
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Generalized periodontitis is one of the most widespread human stomatological diseases; it is diagnosed in 11.0 % of the world's population. Despite the recognition of the microbial factor as leading in its etiopathogenesis, antimicrobial treatment of gingivitis, added with removal of dental plaque, does not prevent the further development of periodontitis. Dysbacteriosis causes inflammation which leads to an increase of proteolysis products. They are a nutrient medium for periodontal pathogenic microflora, they contribute to its growth. So, the use of anti-inflammatory drugs, such as matrix metalloproteinase inhibitors, is promising for preventive treatment of generalized periodontitis.
The aim of the work is to conduct a clinical trial of complex treatment which includes matrix
metalloproteinase inhibitors in patients with diffuse gingivitis and generalized periodontitis of chronic course.
Materials and methods of the research. 60 patients with chronic course of diffuse gingivitis and generalized periodontitis of initial, I and II stages, were treated. The effectiveness of the treatment was evaluated in the early and distant term (after 1 year) according to data of the clinical and radiological examination, computer tomography, biochemical examination of oral fluid for matrix metalloproteinases-8 and -9 (MMP-8, -9) and immunohistochemical study of gingival biopsies for cytoplasmic expression of matrix metalloproteinase-1 (MMP-1).
Results of the research. According to the data of the clinical examination, complete elimination of inflammatory symptoms in periodontal tissues was achieved in 93.3% of patients in the comparison group in 12-14 days and in 96.7% in the base group in 10-12 days. In patients in whom the developed therapeutic scheme was used, the best dynamics of the index assessment of the state of hygiene, gingiva and periodontal complex was established. The main difference between the research groups was the preservation of obtained results in 1 year after treatment in patients of the base group (p ˂ 0.05). In particular, a year later, the results of bone mineral density measurement for patients of the base group did not change from baseline, while in the comparison group there was their significant decrease (p ˂ 0.05), indicating the progression of inflammatory-destructive process in periodontal tissues.
After treatment, a significant reduction in the level of MMP-8 and MMP-9 in the oral fluid of patients of both groups was achieved (p ˂ 0.05). In patients of the base group, in contrast to the comparison, these results were the same in the distant term (p ˂ 0.05). When assessing the cytoplasmic expression of MMP-1 in epithelial and stromal cells after treatment, zero result was in 96.7% of patients in the base group and in 80.0% – in the comparison group, and after 1 year – in 90.0% vs 63.3% respectively.
It should be noted that the differences between the base and comparison groups were most observed for patients with gingivitis and generalized periodontitis of initial stage without destructive processes in periodontal tissues. It suggests the greatest effectiveness of the proposed treatment in the early stages of pathological process.
Thus, based on the fact that the activity of matrix metalloproteinases characterizes the course of the inflammatory process in periodontal tissues, a decrease in their level according to biochemical and immunohistochemical studies in the base group against the comparison indicates a better anti-inflammatory effect of the developed treatment to prevent the progression of generalized periodontitis.
Conclusion. The obtained results allow recommending the use of matrix metalloproteinase inhibitors as a preventive pathogenetic treatment for the patients with chronical course of gingivitis and generalized periodontitis of the initial stage, to inhibit the inflammatory component of the pathological process.
Prospects for further research. It should be studied the indication for repeated courses of matrix metalloproteinase inhibitors in patients with periodontal disease.
5
Beletskaya, Inessa Stanislavovna, and Sergey Yurievich Astakhov. "The role of matrix metalloproteinases in glaucoma pathogenesis." Ophthalmology journal 8, no. 3 (December 15, 2015): 28–43. http://dx.doi.org/10.17816/ov2015328-43.
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Matrix metalloproteinases belong to an enzyme family, which assure a proteolysis of practically all components of the extracellular matrix of connective tissues in normal and pathological conditions. At physiological conditions, there are evidences on the impact of this enzyme group in the embryogenesis, morphogenesis, angiogenesis, and tissue involution. The activity impairment of matrix metalloproteinases and of their specific inhibitors leads to the biosynthesis misbalance and to the degradation of extracellular matrix components; it plays a role in the development of such diseases as diabetes mellitus, rheumatoid arthritis, and arteriosclerosis. Laboratory tests and clinical investigation results confirm the role of these enzymes in tissue remodeling of different eyeball structures in glaucoma (in particular, of the trabecular meshwork and the optic disc); it leads to intraocular fluid outflow impairment and to the glaucomatous optic neuropathy development. In the review, the analysis of clinical and experimental studies is performed that are dedicated to the investigation of matrix metalloproteinases role in the pathogenesis of different glaucoma types, of the possibility to use them as biomarkers, as well as therapeutic action targets in this disease.
6
Docherty, Andy J., Tom Crabbe, James P. O'Connell, and Colin R. Groom. "Proteases as drug targets." Biochemical Society Symposia 70 (September 1, 2003): 147–61. http://dx.doi.org/10.1042/bss0700147.
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The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways--regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.
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Elgezawi, Moataz, Rasha Haridy, Khalid Almas, Moamen A. Abdalla, Omar Omar, Hatem Abuohashish, Abeer Elembaby, Uta Christine Wölfle, Yasir Siddiqui, and Dalia Kaisarly. "Matrix Metalloproteinases in Dental and Periodontal Tissues and Their Current Inhibitors: Developmental, Degradational and Pathological Aspects." International Journal of Molecular Sciences 23, no. 16 (August 11, 2022): 8929. http://dx.doi.org/10.3390/ijms23168929.
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Objectives: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value. Design: The sections of this review discuss MMPs’ involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years. Results: 119 published papers, two textbooks and two doctoral theses were selected for preparing the current review. Conclusions: MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens.
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Doll, Carla U., Sabine Niebert, and Janina Burk. "Mesenchymal Stromal Cells Adapt to Chronic Tendon Disease Environment with an Initial Reduction in Matrix Remodeling." International Journal of Molecular Sciences 22, no. 23 (November 26, 2021): 12798. http://dx.doi.org/10.3390/ijms222312798.
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Tendon lesions are common sporting injuries in humans and horses alike. The healing process of acute tendon lesions frequently results in fibrosis and chronic disease. In horses, local mesenchymal stromal cell (MSC) injection is an accepted therapeutic strategy with positive influence on acute lesions. Concerning the use of MSCs in chronic tendon disease, data are scarce but suggest less therapeutic benefit. However, it has been shown that MSCs can have a positive effect on fibrotic tissue. Therefore, we aimed to elucidate the interplay of MSCs and healthy or chronically diseased tendon matrix. Equine MSCs were cultured either as cell aggregates or on scaffolds from healthy or diseased equine tendons. Higher expression of tendon-related matrix genes and tissue inhibitors of metalloproteinases (TIMPs) was found in aggregate cultures. However, the tenogenic transcription factor scleraxis was upregulated on healthy and diseased tendon scaffolds. Matrix metalloproteinase (MMPs) expression and activity were highest in healthy scaffold cultures but showed a strong transient decrease in diseased scaffold cultures. The release of glycosaminoglycan and collagen was also higher in scaffold cultures, even more so in those with tendon disease. This study points to an early suppression of MSC matrix remodeling activity by diseased tendon matrix, while tenogenic differentiation remained unaffected.
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Cho, Chul-Hyun, Kwang-Soon Song, Beom-Soo Kim, Du Hwan Kim, and Yun-Mee Lho. "Biological Aspect of Pathophysiology for Frozen Shoulder." BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/7274517.
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It is fairly well understood that frozen shoulder involves several stages, which reflect the series of process from capsular inflammation and fibrosis to spontaneous resolution of this fibrosis. However, the underlying pathophysiologic process remains poorly determined. For this reason, management of frozen shoulder remains controversial. Determining the pathophysiological processes of frozen shoulder is a pivotal milestone in the development of novel treatment for patients with frozen shoulder. This article reviews what is known to date about the biological pathophysiology of frozen shoulder. Although articles for the pathophysiology of frozen shoulder provide inconsistent and inconclusive results, they have suggested both inflammation and fibrosis mediated by cytokines, growth factors, matrix metalloproteinases, and immune cells. Proinflammatory cytokines and growth factors released from immune cells control the action of fibroblast and matrix remodeling is regulated by the matrix metalloproteinases and their inhibitors. To improve our understanding of the disease continuum, better characterizing the biology of these processes at clearly defined stages will be needed. Further basic studies that use standardized protocols are required to more narrowly identify the role of cytokines, growth factors, matrix metalloproteinases, and immune cells. The results of these studies will provide needed clarity into the control mechanism of the pathogenesis of frozen shoulder and help identify new therapeutic targets for its treatment.
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Laghezza, Antonio, Luca Piemontese, Leonardo Brunetti, Alessia Caradonna, Mariangela Agamennone, Fulvio Loiodice, and Paolo Tortorella. "(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone." Pharmaceuticals 14, no. 2 (January 24, 2021): 85. http://dx.doi.org/10.3390/ph14020085.
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Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group.
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Rangasamy, Geronimo, Ortín, Coderch, Zapico, Ramos, and de Pascual-Teresa. "Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs)." Molecules 24, no. 16 (August 16, 2019): 2982. http://dx.doi.org/10.3390/molecules24162982.
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Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.
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Janowska-Wieczorek, A., Leah A. Marquez-Curtis, Kenton Gan, Loree Larratt, and Anthony Woods. "TNF-α Stimulates Matrix Metalloproteinase Expression in Myelodysplastic Syndromes (MDS): Therapeutic Potential for Inhibitors of TNF-α and MMPs." Blood 106, no. 11 (November 16, 2005): 3447. http://dx.doi.org/10.1182/blood.v106.11.3447.3447.
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Abstract MDS is characterized by ineffective hematopoiesis with increased intramedullary apoptosis which has been correlated in turn with high levels of tumor necrosis factor (TNF)- α. Previously, we showed that TNF-α strongly upregulates the secretion of the matrix metalloproteinases (MMP)-2 and -9 in normal CD34+ cells. Elevated expression of MMPs has been suggested to contribute to cancer progression and leukemic dissemination and MMPs also facilitate the secretion of TNF-α. In this work, we hypothesized that TNF-α-induced MMP production plays a role in the progression of MDS. We therefore examined the effects of recombinant human (rh) TNF-α on the expression and secretion of MMP-2, MMP-9 and membrane type (MT) 1-MMP (known activator of MMP-2), by MNC from MDS patients (using RT-PCR, zymography and Western blotting), as well as the effects of TNF-α on migration of MDS MNC across the reconstituted basement membrane Matrigel. We observed higher mean levels of TNF-α in media conditioned by mononuclear cells (MNC) obtained from 20 patients diagnosed with MDS (RAEB-T (4); RAEB (5), RA (10) and RARS (1)) in comparison to normal controls. We found that (i) MMP-9 is secreted by MDS MNC and this secretion is increased by TNF-α, (ii) MT1-MMP is expressed by the majority of MDS MNC and this expression is upregulated by TNF-α, and (iii) MMP-2 is detectable only in RAEB-T MNC samples and is activated by TNF-α. TNF-α also stimulated the migration of MDS MNC across Matrigel, which was inhibited by the inhibitor of MT1-MMP, epigallocatechin-3-gallate. Moreover, Enbrel (soluble TNF receptor fusion protein), which blocks TNF-α, also inhibited the expression of MT1-MMP and secretion of MMP-9 by MDS MNC as well as their migration across Matrigel. In addition, we observed increased activation of the latent form of MMP-2 in co-cultures of MDS MNC with bone marrow fibroblastic cells. We suggest that in MDS patients, TNF-α stimulates the expression of MMP-9 and MT1-MMP, inducing a highly proteolytic environment in bone marrow which could further increase processing and secretion of endogenous TNF-α. Therefore, we suggest that use of TNF-α inhibitors combined with MMP inhibitors could have therapeutic value in abrogating the progression of MDS.
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Davis, Max E., Jonathan P. Gumucio, Kristoffer B. Sugg, Asheesh Bedi, and Christopher L. Mendias. "MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix." Journal of Applied Physiology 115, no. 6 (September 15, 2013): 884–91. http://dx.doi.org/10.1152/japplphysiol.00137.2013.
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The extracellular matrix (ECM) of skeletal muscle and tendon is composed of different types of collagen molecules that play important roles in the transmission of forces throughout the body, and in the repair and regeneration of injured tissues. Fibroblasts are the primary cells in muscle and tendon that maintain, repair, and modify the ECM in response to mechanical loading, injury, and inactivity. Matrix metalloproteinases (MMPs) are enzymes that digest collagen and other structural molecules, which are synthesized and excreted by fibroblasts. MMPs are required for baseline ECM homeostasis, but disruption of MMP regulation due to injury or disease can alter the normal ECM architecture and prevent proper force transmission. Chronic injuries and diseases of muscles and tendons can be severely debilitating, and current therapeutic modalities to enhance healing are quite limited. This review will discuss the mechanobiology of MMPs, and the potential use of MMP inhibitors to improve the treatment of injured and diseased skeletal muscle and tendon tissue.
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Qiu, Zheng, Jianghai Chen, Hanmei Xu, Philippe E. Van den Steen, Ghislain Opdenakker, Min Wang, and Jialiang Hu. "Inhibition of Neutrophil Collagenase/MMP-8 and Gelatinase B/MMP-9 and Protection against Endotoxin Shock." Journal of Immunology Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/747426.
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Endotoxin shock is a life-threatening disorder, associated with the rapid release of neutrophil enzymes, including neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9). After activation, these enzymes cleave extracellular matrix components and cytokines and thus may contribute to shock syndrome development. MMP inhibitors have been suggested as immunotherapy of endotoxin shock. However, little is known about the therapeutic time window of MMP inhibition. Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections. With the use of a specific ELISA the plasma P2 concentrations were monitored. Whereas we corroborated the treatment strategy of MMP targeting in endotoxin shock with a new inhibitor, we also demonstrated that the time window, within which effective MMP inhibition increased the survival rates, is rather limited.
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Bai, Qian, Mengzhou Xue, and V. Wee Yong. "Microglia and macrophage phenotypes in intracerebral haemorrhage injury: therapeutic opportunities." Brain 143, no. 5 (January 9, 2020): 1297–314. http://dx.doi.org/10.1093/brain/awz393.
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Abstract The prognosis of intracerebral haemorrhage continues to be devastating despite much research into this condition. A prominent feature of intracerebral haemorrhage is neuroinflammation, particularly the excessive representation of pro-inflammatory CNS-intrinsic microglia and monocyte-derived macrophages that infiltrate from the circulation. The pro-inflammatory microglia/macrophages produce injury-enhancing factors, including inflammatory cytokines, matrix metalloproteinases and reactive oxygen species. Conversely, the regulatory microglia/macrophages with potential reparative and anti-inflammatory roles are outcompeted in the early stages after intracerebral haemorrhage, and their beneficial roles appear to be overwhelmed by pro-inflammatory microglia/macrophages. In this review, we describe the activation of microglia/macrophages following intracerebral haemorrhage in animal models and clinical subjects, and consider their multiple mechanisms of cellular injury after haemorrhage. We review strategies and medications aimed at suppressing the pro-inflammatory activities of microglia/macrophages, and those directed at elevating the regulatory properties of these myeloid cells after intracerebral haemorrhage. We consider the translational potential of these medications from preclinical models to clinical use after intracerebral haemorrhage injury, and suggest that several approaches still lack the experimental support necessary for use in humans. Nonetheless, the preclinical data support the use of deactivator or inhibitor of pro-inflammatory microglia/macrophages, whilst enhancing the regulatory phenotype, as part of the therapeutic approach to improve the prognosis of intracerebral haemorrhage.
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Purcell, Brendan P., Shayne C. Barlow, Paige E. Perreault, Lisa Freeburg, Heather Doviak, Julia Jacobs, Abigail Hoenes, et al. "Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling." American Journal of Physiology-Heart and Circulatory Physiology 315, no. 4 (October 1, 2018): H814—H825. http://dx.doi.org/10.1152/ajpheart.00076.2018.
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Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-μl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-μl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-μg/100-μl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.
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Xie, Chunfang, Laura-Oana Albulescu, Mátyás A. Bittenbinder, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, and Jeroen Kool. "Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins." Biomedicines 8, no. 9 (August 20, 2020): 297. http://dx.doi.org/10.3390/biomedicines8090297.
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Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.
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Fisher, Courtney L., and Stacie L. Demel. "Nonsteroidal Anti-Inflammatory Drugs: A Potential Pharmacological Treatment for Intracranial Aneurysm." Cerebrovascular Diseases Extra 9, no. 1 (April 30, 2019): 31–45. http://dx.doi.org/10.1159/000499077.
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Background: Saccular intracranial aneurysms (IAs) are outpouchings of the vessel wall of intracranial arteries. Rupture of IAs results in subarachnoid hemorrhage which is associated with high morbidity and mortality. Surgical interventions, such as clipping and coiling, have associated risks. Currently, there are no proven pharmacological treatments to prevent the growth or rupture of IAs. Infiltration of proinflammatory cytokines in response to increased wall sheer stress is a hallmark of IA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are being investigated as potential therapeutic agents for reduction in growth and/or prevention of IA through inhibition of inflammatory pathways. Summary: This review will discuss the role of NSAIDs in attenuating the inflammation that drives IA progression and rupture. There are two main subtypes of NSAIDs, nonselective COX and selective COX-2 inhibitors, both of which have merit in treating IA. Evidence will be presented which shows that NSAIDs inhibit several key inflammatory mediators involved in IA progression including nuclear factor-κB, tumor necrosis factor-α, and matrix metalloproteinases. In addition, the role of NSAIDs in limiting inflammatory cell adhesion to endothelial cells and attenuating endothelial cell senescence will be discussed. Key Messages: There is an abundance of basic science and preclinical data that support NSAIDs as a promising treatment for IA. Additionally, a combination treatment strategy of low-dose aspirin given concomitantly with a selective COX-2 inhibitor may result in a reduced side effect profile compared to aspirin or selective COX-2 inhibitor use alone. Several large clinical trials are currently planned to further investigate the efficacy of NSAIDs as an effective nonsurgical treatment for IAs.
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Sato, Aki, Yoshihiko Tashiro, Chiemi Nishida, Ismael Gritli, Kaori Kusubata, Satoshi Takahashi, Beate Heissig, Koichi Hattori, and Hiromitsu Nakauchi. "A Plasmin Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice." Blood 118, no. 21 (November 18, 2011): 1897. http://dx.doi.org/10.1182/blood.v118.21.1897.1897.
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Abstract Abstract 1897 Proinflammatory cytokines released upon cell damage can cause excessive tissue destruction in acute graft-versus-host disease (GVHD). Certain key cytokines for GVHD like TNF-α and Fas-ligand, are secreted by ectodomain shedding from matrix metalloproteinases (MMPs). Many MMP inhibitors have been developed and used over the last three or four decades, but its widespread use is hampered by severe side effects. We reported that the fibrinolytic system, above all plasmin formation promotes the activation of several MMPs. Therefore we hypothesized that plasmin inhibition might be a novel means to control acute GVHD in part by suppressing MMP and inflammatory cytokine secretion. We found that the fibrinolytic system is activated during the development of acute GVHD in mice and in humans. Here, we examined a novel plasmin inhibitor (YO-2) that inhibits MMP activation and inflammatory cytokines release for lethal acute GVHD model in mice. Administration of YO-2 into (BALB/c × C57BL/6) F1 that received C57BL/6 spleen cells showed markedly reduced mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. Furthermore, our results suggest that administaration of YO-2 blocked the processing of inflammatory cytokines through MMP inhibition in vitro and in vivo. These data have major implications for transplantation medicine, as pharmacological inhibition of plasmin does not require the need for intensive immunosuppression. Our results suggest that YO-2 could be a novel molecular therapeutic agent for GVHD. Disclosures: No relevant conflicts of interest to declare.
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Wang, Dan-Dan, Wen-Xiu Xu, Wen-Quan Chen, Lei Li, Su-Jin Yang, Jian Zhang, and Jin-Hai Tang. "Identification of TIMP2 as a Prognostic Biomarker and Its Correlation with Tumor Immune Microenvironment: A Comprehensive Pan-Cancer Analysis." Journal of Oncology 2022 (October 18, 2022): 1–12. http://dx.doi.org/10.1155/2022/9133636.
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Background. Tissue inhibitor of metalloproteinase-2 (TIMP2), an endogenous inhibitor of matrix metalloproteinases, has been disclosed to participate in the development and carcinogenesis of multiple malignancies. However, the prognosis of TIMP2 in different cancers and its correlation with tumor microenvironment and immunity have not been clarified. Methods. In this study, we conducted a comprehensive bioinformatics analysis to evaluate the prognostic and therapeutic value of TIMP2 in cancer patients by utilizing a series of databases, including Oncomine, GEPIA, cBioPortal, GeneMANIA, Metascape, and Sangerbox online tool. The expression of TIMP2 in different cancers was analyzed by Oncomine, TCGA, and GTEx databases, and mutation status of TIMP2 in cancers was then verified using the cBioPortal database. The protein-protein interaction (PPI) network of the TIMP family was exhibited by GeneMANIA. The prognosis of TIMP2 in cancers was performed though the GEPIA database and Cox regression. Additionally, the correlations between TIMP2 expression and immunity (immune cells, gene markers of immune cells, TMB, MSI, and neoantigen) were explored using Sangerbox online tool. Results. The transcriptional level of TIMP2 in most cancerous tissues was significantly elevated. Survival analysis revealed that an elevated expression of TIMP2 is associated with unfavorable survival outcome in multiple cancers. Enrichment analysis demonstrated the possible mechanisms of TIMPs and their associated genes mainly involved in pathways including extracellular matrix (ECM) regulators, degradation of ECM and ECM disassembly, and several other signaling pathways. Conclusions. Our findings systematically dissected that TIMP2 is a potential prognostic maker in various cancers and use the inhibitor of TIMP2, which may be an effective strategy for cancer therapy to improve the poor cancer survival and prognostic accuracy, but concrete mechanisms need to be validated by subsequent experiments.
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Castellazzi, Massimiliano, Tiziana Bellini, Alessandro Trentini, Serena Delbue, Francesca Elia, Matteo Gastaldi, Diego Franciotta, et al. "Serum Gelatinases Levels in Multiple Sclerosis Patients during 21 Months of Natalizumab Therapy." Disease Markers 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/8434209.
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Background. Natalizumab is a highly effective treatment approved for multiple sclerosis (MS). The opening of the blood-brain barrier mediated by matrix metalloproteinases (MMPs) is considered a crucial step in MS pathogenesis. Our goal was to verify the utility of serum levels of active MMP-2 and MMP-9 as biomarkers in twenty MS patients treated with Natalizumab.Methods. Serum levels of active MMP-2 and MMP-9 and of specific tissue inhibitors TIMP-1 and TIMP-2 were determined before treatment and for 21 months of therapy.Results. Serum levels of active MMP-2 and MMP-9 and of TIMP-1 and TIMP-2 did not differ during the treatment. The ratio between MMP-9 and MMP-2 was increased at the 15th month compared with the 3rd, 6th, and 9th months, greater at the 18th month than at the 3rd and 6th months, and higher at the 21st than at the 3rd and 6th months.Discussion. Our data indicate that an imbalance between active MMP-9 and active MMP-2 can occur in MS patients after 15 months of Natalizumab therapy; however, they do not support the use of serum active MMP-2 and active MMP-9 and TIMP-1 and TIMP-2 levels as biomarkers for monitoring therapeutic response to Natalizumab.
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Saleh, Samar R., Rana Attia, and Doaa A. Ghareeb. "The Ameliorating Effect of Berberine-Rich Fraction against Gossypol-Induced Testicular Inflammation and Oxidative Stress." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/1056173.
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This study was aimed at evaluating the efficacy of berberine-rich fraction (BF) as a protective and/or a therapeutic agent against inflammation and oxidative stress during male infertility. Sexually mature Sprague-Dawley male rats were divided into five groups treated with either corn oil, BF (100 mg/kg BW, orally, daily for 30 days), gossypol acetate (5 mg/kg BW, i.p.) eight times for 16 days, BF alone for 14 days then coadministered with gossypol acetate for the next 16 days (protected group), or gossypol acetate for 16 days then treated with BF for 30 days (treated group). All animals completed the experimental period (46 days) without obtaining any treatments in the gap period. Sperm parameters, oxidative index, and inflammatory markers were measured. Gossypol injection significantly decreased the semen quality and testosterone level that resulted from the elevation of testicular reactive oxygen and nitrogen species (TBARS and NO), TNF-α, TNF-α-converting enzyme, and interleukins (IL-1β, IL-6, and IL-18) by 230, 180, 12.5, 97.9, and 300%, respectively, while interleukin-12 and tissue inhibitors of metalloproteinases-3 were significantly decreased by 59 and 66%, respectively. BF (protected and treated groups) significantly improved the semen quality, oxidative stress, and inflammation associated with male infertility. It is suitable to use more advanced studies to validate these findings.
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Galm, Oliver, Edgar Jost, Claudia Schubert, James G. Herman, Tim H. Brümmendorf, and Stefan Wilop. "Epigenetic Dysregulation of the Tissue Inhibitor of Metalloproteinases-2 Gene in Multiple Myeloma." Blood 118, no. 21 (November 18, 2011): 5089. http://dx.doi.org/10.1182/blood.v118.21.5089.5089.
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Abstract Abstract 5089 Background: Multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of malignant plasma cells in the bone marrow (BM) as well as abundant BM angiogenesis. Aberrant methylation of CpG islands near gene promoter regions is the most widely studied epigenetic abnormality in human malignancies and is associated with loss of gene expression. There is increasing evidence for a role of the tissue inhibitor of metalloproteinases 2 (TIMP2) gene as a tumor suppressor. Overexpression of TIMP2 may result in decreased invasive potential, suppression of tumor growth and vascularization as well as inhibition of angiogenesis. We could previously show that TIMP2 may become hypermethylated in association with transcriptional silencing in indolent and aggressive non-Hodgkin's lymphomas. Recently, downregulation of TIMP2 was also reported in MM, and this is thought to contribute to increased BM angiogenesis. In this study, we determined the methylation status of the promoter-associated CpG island of TIMP2 in primary MM samples and investigated correlations between TIMP2 methylation and clinical parameters. Methods: Methylation of the promoter-associated CpG island of TIMP2 was analyzed by methylation-specific polymerase chain reaction (MSP) in samples from 76 MM patients (median age 65 years [range 40–94]; 44 males, 32 females; 71 BM samples, 5 peripheral blood samples). Overall survival curves were plotted according to the method of Kaplan and Meier and compared using the log-rank test. Correlations between variables were analyzed using the Fisher's exact two-sided test and independent t-test, respectively. Results: MSP analysis revealed that there was aberrant methylation of the TIMP2 promoter region in 4/76 MM patient samples. We found an association of TIMP2 hypermethylation with plasma cell leukemia (p<0.0001) and decreased platelet counts (257.1 G/l vs. 111.5 G/l; p=0.04). There was a trend towards an inferior overall survival in MM cases with a hypermethylated TIMP2 gene, but this difference was not statistically significant (p=0.11). Conclusions: Our study shows that promoter hypermethylation of TIMP2 is a novel epigenetic event in MM that may contribute to disease progression and could serve as a prognostic biomarker. Further studies are warranted to elucidate the functional consequences of epigenetic dysregulation of TIMP2 in the pathogenesis of MM. Additionally, the increasing evidence for the role of DNA methylation changes in MM may serve as a basis for the use of epigenetically targeted therapeutic approaches in malignant plasma cell disorders. Disclosures: Herman: MDxHealth: Consultancy.
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Barrows, Brad D., and Jun Teruya. "Use of the ADAMTS13 Activity Assay Improved the Accuracy and Efficiency of the Diagnosis and Treatment of Suspected Acquired Thrombotic Thrombocytopenic Purpura." Archives of Pathology & Laboratory Medicine 138, no. 4 (April 1, 2014): 546–49. http://dx.doi.org/10.5858/arpa.2013-0170-oa.
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Context.—Acquired thrombotic thrombocytopenic purpura (A-TTP) is a rare but significant disease requiring rapid diagnosis and treatment. The diagnosis is often difficult because of variability in the presence of specific clinical criteria. The primary etiology of A-TTP involves inhibitors directed against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Literature has shown that the ADAMTS13 activity assay is sensitive and specific for identifying cases of A-TTP, and application of this test as an on-site screening method has not been fully explored. Objective.—Our objective is to determine if the ADAMTS13 activity assay can be used as a successful, on-site diagnostic modality to rapidly identify cases of A-TTP and prevent unnecessary use of prophylactic therapeutic plasma exchange. Design.—A retrospective analysis was performed including 152 patients with clinically suspected A-TTP, screened using the ADAMTS13 activity assay. Results were correlated with potential therapeutic plasma exchange treatment for all cases highly suspicious for A-TTP and evaluated for unnecessary patient morbidity and financial cost. Results.—The ADAMTS13 activity assay had an overall sensitivity and specificity of 100% and 99%, respectively. The positive predictive value was 91% and the negative predictive value was 100%. In 95% of the studies ordered, A-TTP was ruled out, leading to decreased patient morbidity and $1.7 million of potential treatment costs avoided. Conclusion.—Implementation of the fluorescence energy transfer–based ADAMTS13 activity assay as a point-of-care laboratory study decreased patient morbidity while also directing more efficient employment of therapeutic plasma exchange in cases of suspected A-TTP.
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Majumder, Romit, Madhuri Datta, Aindrila Chattopadhyay, and Debasish Bandyopadhyay. "Melatonin promotes gastric healing by modulating the components of matrix metalloproteinase signaling pathway: a novel scenario for gastric ulcer management." Melatonin Research 4, no. 2 (March 30, 2021): 213–31. http://dx.doi.org/10.32794/mr11250092.
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Over the past few decades, since the induction of antibiotics and proton pump inhibitors (PPI) as a therapeutic tool in controlling gastropathy, a substantial decline in the incidence of gastric ulcer and its related manifestations has been achieved globally. However, there are a lot of skeptics on the steady rise in the list of complications following long-term use of these drugs, especially in chronic and elderly patients. Hence, the search for a sustainable cure for these gastropathies has never actually ended; this let us consider that melatonin, an endogenous antioxidant, might have a utility in this respect. Although researchers have linked melatonin with accelerated post ulcerative wound healing, many of these studies have failed to identify the confounding factors and plausible healing mechanisms. In this review, we attempt to identify the underline mechanisms as to the protective effects of melatonin on a variety of gastropathies. Based on the evidence, we select the matrix metalloproteinases (MMPs) to be the main targets of melatonin. MMPs play a key role in maintaining the balance between extracellular matrix degradation and tissue remodeling, therefore, they act as the integral connection between the ulcer manifestation and healing. Thus, gastric ulceration occurs where this balance is disrupted. Melatonin can preserve this balance during the onset of gastric ulcers. In this review, we have also discussed the effects of melatonin on the different isoforms of MMPs and their roles in gastric ulceration, respectively. We hope that this will bestow us with a better understanding of the development of the gastric ulcer, as well as its cure.
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El-Baz, Farouk K., Abeer Salama, and Rania A. A. Salama. "Therapeutic Effect of Dunaliella salina Microalgae on Thioacetamide- (TAA-) Induced Hepatic Liver Fibrosis in Rats: Role of TGF-β and MMP9." BioMed Research International 2019 (September 24, 2019): 1–9. http://dx.doi.org/10.1155/2019/7028314.
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Liver fibrosis represents a serious global health-care problem and is the outcome of many chronic liver diseases, cirrhosis, hepatitis, and toxin accumulation. The present study aimed to evaluate the antifibrotic curative effect of Dunaliella salina (D. salina) on thioacetamide- (TAA-) induced liver fibrosis in rats. Liver fibrosis was induced by TAA (200mg/kg; i.p.) twice per week for 6 weeks. D. salina was given orally (100 and 200 mg/kg) and silymarin was given orally (100 mg/kg) daily, for 4 weeks after TAA. Serum transaminase activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA significantly (p<0.05) elevated serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum levels of total bilirubin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β) with a reduction in albumin. In addition, TAA increased hepatic contents of collagen I, a-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase (TIMP-1), reduced matrix metalloproteinase 9 (MMP9), and finally produced marked degeneration and fibrosis of hepatocytes. Treatment with D. salina or silymarin improved the histological feature of hepatocytes and ameliorated the deleterious effects of TAA in a dose-dependent manner. Based on these results, it could be concluded that the use of D. salina could be assigned for liver fibrosis treatment via its anti-inflammatory and antifibrotic properties.
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Taherkhani, Amir, Athena Orangi, Shirin Moradkhani, Alireza Jalalvand, and Zahra Khamverdi. "Identification of Potential Anti-tooth-decay Compounds From Organic Cinnamic Acid Derivatives by Inhibiting Matrix Metalloproteinase-8: An In Silico Study." Avicenna Journal of Dental Research 14, no. 1 (March 29, 2022): 25–32. http://dx.doi.org/10.34172/ajdr.2022.05.
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Background: Matrix metalloproteinase-8 (MMP-8) is the most abundant member of the MMP family in human dentin. It takes a part in the normal physiology of tissue remodeling and wound healing, while the overexpression/hyperactivity of this protein leads to several oral disorders, including dental caries and peri-implant inflammation/diseases, and therefore, MMP-8 inhibition may have therapeutic effects. Accordingly, the current study aimed to identify potential MMP-8 inhibitors from cinnamic acid derivatives. Methods: The binding affinity of cinnamic acid and its several derivatives to the MMP-8 active site were estimated using the AutoDock 4.0 software. The pharmacokinetics, toxicity, and bioavailability of top-ranked MMP-8 inhibitors were also predicted by utilizing bioinformatics web tools. Results: Five of the studied components, including chlorogenic acid (CGA), caffeic acid 3-glucoside, rosmarinic acid, N-p-Coumaroyltyramine, and caffeic acid phenethyl ester (CAPE) demonstrated a salient affinity of binding to the MMP-8 catalytic site (∆Gbinding<-10 kcal/mol). It was estimated that these compounds can inhibit the MMP-8 at the nanomolar concentration, and therefore, were considered as top-ranked MMP-8 inhibitors. Finally, none of the top-ranked components revealed a considerable side effect and thus were found to be suitable for oral use. Conclusions: The results of the present study suggested that CGA, caffeic acid 3-glucoside, rosmarinic acid, N-p-coumaroyltyramine, and CAPE might have protective effects on tooth decay and peri-implant inflammation/diseases.
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Brune, Kay, Hugo A. Katus, Joachim Moecks, Eberhard Spanuth, Allan S. Jaffe, and Evangelos Giannitsis. "N-Terminal Pro–B-Type Natriuretic Peptide Concentrations Predict the Risk of Cardiovascular Adverse Events from Antiinflammatory Drugs: A Pilot Trial." Clinical Chemistry 54, no. 7 (July 1, 2008): 1149–57. http://dx.doi.org/10.1373/clinchem.2007.097428.
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Abstract Background: We investigated whether higher concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP) predicts cardiovascular adverse events (CV-AEs) in patients with osteoarthritis treated with antiinflammatory drugs. Methods: NT-proBNP was measured in baseline samples from 433 patients enrolled in a prospective randomized study designed to test the therapeutic effect of a novel metalloproteinase inhibitor. We monitored CV-AEs and retrospectively investigated their relationship to the concomitant use of selective cyclooxygenase-2 inhibitors (coxibs), traditional nonsteroidal antiinflammatory drugs (tNSAIDs), and glucocorticoids. CV-AEs included myocardial infarction, stroke, new or worsening of preexisting arterial hypertension, congestive heart failure, and several less severe CV-AEs. Results: We observed 82 mild to serious CV-AEs during an observational period of 200 days. The risk of such events was 1.95-fold higher in patients who were taking tNSAIDs, glucocorticoids, or coxibs (i.e., any inhibitor) and who had NT-proBNP concentrations ≥100 ng/L than in patients taking any inhibitor who had NT-proBNP values <100 ng/L (P < 0.05). Patients taking coxibs (alone or in addition to tNSAIDs or glucocorticoids) with baseline NT-proBNP values ≥100 ng/L had a 7.41-fold higher risk for CV-AEs than those with baseline values <100 ng/L (P < 0.01). Patients who were taking 2 or more antiinflammatory drugs and had NT-proBNP values ≥100 ng/L had a 3.74-fold higher risk for CV-AEs than those with NT-proBNP values <100 ng/L (P < 0.05). An NT-proBNP value <100 ng/L was associated with negative predictive values of >85% across all treatment groups. Conclusions: NT-proBNP may be a useful marker for anticipating cardiovascular risk associated with the use of antiinflammatory drugs for osteoarthritis.
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Soto-Gamez, Abel, Deng Chen, Anke G. E. Nabuurs, Wim J. Quax, Marco Demaria, and Ykelien L. Boersma. "A Bispecific Inhibitor of the EGFR/ADAM17 Axis Decreases Cell Proliferation and Migration of EGFR-Dependent Cancer Cells." Cancers 12, no. 2 (February 10, 2020): 411. http://dx.doi.org/10.3390/cancers12020411.
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Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers.
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Gao, Ming, Trung T. Nguyen, Mark A. Suckow, William R. Wolter, Major Gooyit, Shahriar Mobashery, and Mayland Chang. "Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy." Proceedings of the National Academy of Sciences 112, no. 49 (November 23, 2015): 15226–31. http://dx.doi.org/10.1073/pnas.1517847112.
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Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body’s response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9–knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds.
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Skuratov, A. G., A. N. Lyzikov, and V. M. Mitsura. "ASSESSMENT OF PORTAL HYPERTENSION SEVERITY IN LIVER CIRROSIS." Novosti Khirurgii 30, no. 1 (February 21, 2022): 20–27. http://dx.doi.org/10.18484/2305-0047.2022.1.20.
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Objective. Development of a non-invasive assessing diagnostic and severity grading accuracy of portal hypertension in cirrhosis of the liver. Methods. To identify diagnostically significant indicators, a statistical analysis of the data of laboratory and instrumental diagnostics was carried out in 60 patients with liver cirrhosis. The followingbiochemical indicators weredetermined: general and biochemical blood tests, coagulogram, general urine analysis; the level of interleukin-6 (IL-6), matrix metalloproteinases 1 and 9 (MMP-1, MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), hepatocyte growth factor (HGF); abdominal ultrasound examination, esophagogastroscopy. The index of the ratio of the number of blood platelets (N×10<sup>9</sup> / L) to the transverse size (D) of the spleen in millimeters (PSR - Platelet count to Spleen diameter Ratio) was calculated: PSR = NTr / D spleen. Results. The following indicators turned out to be diagnostically significant (predictive values based on ROC analysis are presented): blood levels of IL-6 (>19.9 pg/ml), MMP-1 (>8.06 ng/ml), cholesterol (≤4,5mmol/L), portal vein diameter (>13 mm), PSR (≤1.89). Diagnosticmethods for cirrhosis and portal hypertension was developed, based on a point assessment of a set of laboratory and instrumental criteria (AUC = 0.931; p <0.001). The method can be used in a complex of medical services aimed at diagnosis of portal hypertension severity in patients with cirrhosis of the liver, as well as medical prevention of life-threatening complications of the disease. Conclusion. The developed method makes it possible to identify patients with a «severe» form of portal hypertension, to recommend an unscheduled FEGDS with an endoscopic assessment of the risk of bleeding, and to carry out preventive and therapeutic procedures. If a low probability of a “severe” form of PH is identified, FEGDS should be refrained from if the patient has absolute or relative contraindications to the use of this diagnostic method. The method can be used in a complex of medical services aimed at diagnosing the severity of portal hypertension against the background of liver cirrhosis. What this paper adds For the first time, a method for diagnosis of portal hypertension in liver cirrhosis has been developed. It is based on a score assessment of a set of laboratory and instrumental criteria, including blood levels of interleukin-6, matrix metalloproteinase-1, cholesterol, platelet count, portal vein diameter and transverse size of the spleen. The method can be used in a complex of medical services aimed to estimate the severity of portal hypertension in cirrhosis of the liver, as well as medical prevention of life-threatening complications of the disease.
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Mukhopadhyay, Partha, Mohanraj Rajesh, Sándor Bátkai, Yoshihiro Kashiwaya, György Haskó, Lucas Liaudet, Csaba Szabó, and Pál Pacher. "Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 5 (May 2009): H1466—H1483. http://dx.doi.org/10.1152/ajpheart.00795.2008.
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Doxorubicin (DOX) is a potent available antitumor agent; however, its clinical use is limited because of its cardiotoxicity. Cell death is a key component in DOX-induced cardiotoxicity, but its mechanisms are elusive. Here, we explore the role of superoxide, nitric oxide (NO), and peroxynitrite in DOX-induced cell death using both in vivo and in vitro models of cardiotoxicity. Western blot analysis, real-time PCR, immunohistochemistry, flow cytometry, fluorescent microscopy, and biochemical assays were used to determine the markers of apoptosis/necrosis and sources of NO and superoxide and their production. Left ventricular function was measured by a pressure-volume system. We demonstrated increases in myocardial apoptosis (caspase-3 cleavage/activity, cytochrome c release, and TUNEL), inducible NO synthase (iNOS) expression, mitochondrial superoxide generation, 3-nitrotyrosine (NT) formation, matrix metalloproteinase (MMP)-2/MMP-9 gene expression, poly(ADP-ribose) polymerase activation [without major changes in NAD(P)H oxidase isoform 1, NAD(P)H oxidase isoform 2, p22 phox, p40 phox, p47 phox, p67 phox, xanthine oxidase, endothelial NOS, and neuronal NOS expression] and decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment to mice. All these effects of DOX were markedly attenuated by peroxynitrite scavengers. Doxorubicin dose dependently increased mitochondrial superoxide and NT generation and apoptosis/necrosis in cardiac-derived H9c2 cells. DOX- or peroxynitrite-induced apoptosis/necrosis positively correlated with intracellular NT formation and could be abolished by peroxynitrite scavengers. DOX-induced cell death and NT formation were also attenuated by selective iNOS inhibitors or in iNOS knockout mice. Various NO donors when coadministered with DOX but not alone dramatically enhanced DOX-induced cell death with concomitant increased NT formation. DOX-induced cell death was also attenuated by cell-permeable SOD but not by cell-permeable catalase, the xanthine oxidase inhibitor allopurinol, or the NADPH oxidase inhibitors apocynine or diphenylene iodonium. Thus, peroxynitrite is a major trigger of DOX-induced cell death both in vivo and in vivo, and the modulation of the pathways leading to its generation or its effective neutralization can be of significant therapeutic benefit.
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Iakovlev, A. A., A. Volkov, I. Shcherbakova, G. Tarasova, S. Malakhanov, and O. Bashtovaya. "P390 New features of molecular diagnostics of the regulation of molecular apoptotic pathway in ulcerative colitis." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S363—S365. http://dx.doi.org/10.1093/ecco-jcc/jjz203.519.
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Abstract Background The incidence rate of ulcerative colitis (UC) in Russia is 5–30 cases per 100,000 per year. Molecular pathways of the UC development are not clear. The purpose of the work was to study the molecular interactions of the apoptotic pathway in patients with UC. Methods The clinical trial included 92 patients with UC. The clinical presentation of UC depends on the extent of involvement: distal colitis, extensive colitis; the severity of the disease. Criteria of the diagnosis of UC corresponded to ECCO Consensus. Mucosal specimens were graded according to grades 0, 1, 2, 3. The separation of proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, Bruker, USA). The getting of mass-spectrogram was determined by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, Bruker, USA). Statistical analysis was performed using the software Statistica 10.0 (Statsoft). Results HSP2 controls the apoptosis of colonocytes and immune response in damaged colon mucosa by Bcl-2 and IL-17, and is also responsible for the resistance to therapeutic strategies. Anti-apoptotic functions of HSP27 is possible through the interaction with DAXX7, the activation of Akt and the inhibition of the apoptosis. HSP47 interacts with collagen I, II, III, IV and V types, that contributes to the launch of autoimmune process in UC. Caspase 8 protects colonocytes from TNFα-induced cell death through necroptosis mechanism via the blockade of the expression of RIP3. Significant decrease of the expression of PPARγ promotes the activation of STAT and AP-1 signalling pathways, that promotes the increase of the synthesis of IL-2, -6, -8, -12, TNFα, matrix metalloproteinases, the activity of immune and inflammation processes in the colon mucosa. Results of qualitative proteomic analysis in patients with UC (Tab.) Conclusion Proteomic analysis has demonstrated the cascade with caspases 8, 9, 10, the release of cytochrome C from mitochondria, which interacts with Apaf-1, causing activation of caspase-9 in UC colon mucosa. TNF-α activates of initiator caspase-2, -8, and -10 in the apoptotic pathway. The NF-kB pathway induces cellular inhibitors of apoptosis, which function as specific caspase inhibitors in UC colonic mucosa.
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BLAVIER, LAURENCE, PATRICK HENRIET, SUZAN IMREN, and YVES A. DECLERCK. "INHIBITION OF MATRIX METALLOPROTEINASES THERAPEUTIC APPLICATIONS. Tissue Inhibitors of Matrix Metalloproteinases in Cancer." Annals of the New York Academy of Sciences 878, no. 1 INHIBITION OF (June 1999): 108–19. http://dx.doi.org/10.1111/j.1749-6632.1999.tb07677.x.
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Mitkin, Nikita, Alisa Gorbacheva, Alina Ustiugova, Aksinya Uvarova, Kirill Korneev, Vsevolod Pavshintsev, and Nikita Mitkin. "713 Antibody-based approach of MT1-MMP metalloprotease inhibition results in decreased invasive properties of pancreatic cancer cells." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A755. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0713.
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BackgroundPancreatic cancer (PC) is one of the most aggressive types of malignant tumors due to the fact, that early stages of the disease are asymptomatic and difficult to diagnose. Matrix metalloproteinases (MMP) play a key role in progression of early PC stages through proteolysis of collagen and a range of regulators that promotes tumor invasion and angiogenesis. MMPs are considered as promising therapeutic targets, but MMP inhibitors exhibit significant efficacy exclusively in a narrow time window, that makes it difficult to use them for prevention of local relapses. That is why MMP inhibitors and blocking antibodies demonstrated moderate results in clinical trials – progressive tumor stages could not be effectively treated with these agents, while their use in the early stages still looks very promising. The aim of the present work was to study the effects of longterm and preventive suppression of the activity of MT1MMP (a key initiator of tumor proliferation and invasion) in pancreatic cancer using the approach of active immunization.MethodsWe performed active immunization of SPF C57BL/6 mice using different variants of the vaccine: peptide fragments of MT1-MMP protein or DNA expression vectors coding these peptide fragments. 2-fold vaccine administration and serums collection were performed according to the previously published protocol.1 The serums were collected on the 21 day of the experiment. We applied ELISA to estimate the levels of anti-MT1-MMP antibodies. The functional activity of the serums was tested using enzymatic assay and in vitro metastatic assay according to previously described protocols.2ResultsWe selected the serum containing high titers of anti-MT1-MMP antibodies which effectively suppressed MT1-MMP activity in the absence of the effect on MMP9. This feature of the serum is fundamental due to the fact, that MMP9 is currently regarded as an undesirable target of anticancer therapy. The functional activity of selected serum and its ability to inhibit pancreatic cancer cell invasion was shown in an in vitro metastatic assay using the PC mouse cell line. In addition, we demonstrated the ability of this serum to inhibit the activity of MMP2 and TGFβ in conditioned mediums and lysates of PC cells, that suggests its additional anticancer properties associated with the suppression of the ability of MT1-MMP to proteolytic activation of a number of tumor modulators.ConclusionsThe selected mode could be used for effective immunization against MT1-MMP.AcknowledgementsThis project is supported by grant 19-74-00096 from Russian Science Foundation.ReferencesPavshintsev VV, Mitkin NA, Frolova OY, Kushnir EA, Averina OA, Lovat ML. Individual roles of brain and serum alcohol dehydrogenase isoforms in regulation of alcohol consumption in SPF Wistar rats. Physiology & behavior 2017;179:458–466.Korneev KV, Sviriaeva EN, Mitkin NA, Gorbacheva AM, Uvarova AN, Ustiugova AS, Polanovsky OL, Kulakovskiy IV, Afanasyeva MA, Schwartz AM, Kuprash DV. Minor C allele of the SNP rs7873784 associated with rheumatoid arthritis and type-2 diabetes mellitus binds PU. 1 and enhances TLR4 expression. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2020;1866(3):165626.
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Gangadaran, Prakash, Ramya Lakshmi Rajendran, Ji Min Oh, Eun Jung Oh, Chae Moon Hong, Ho Yun Chung, Jaetae Lee, and Byeong-Cheol Ahn. "Identification of Angiogenic Cargo in Extracellular Vesicles Secreted from Human Adipose Tissue-Derived Stem Cells and Induction of Angiogenesis In Vitro and In Vivo." Pharmaceutics 13, no. 4 (April 5, 2021): 495. http://dx.doi.org/10.3390/pharmaceutics13040495.
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Angiogenesis is defined as the generation of new blood vessels or the sprouting of endothelial cells from a pre-existing vascular network. Angiogenesis occurs during the growth and development of an organism, the response of organs or tissues to injury, and during cancer development and progression. The majority of studies on stem-cell-derived extracellular vesicles (EVs) have used cell lines, and have primarily focused on well-known solitary proteins. Here, we isolated stem cells from human adipose tissue (ADSCs), and we isolated EVs from them (ADSC-EVs). The ADSC-EVs were characterised and 20 angiogenic proteins were analysed using an angiogenic antibody array. Furthermore, we analysed the ability of ADSC-EVs to induce angiogenesis in vitro and in vivo. ADSC-EVs were positive for CD81 and negative for GM130, calnexin, and cytochrome-C. ADSC-EVs showed typical EV spherical morphology and were ~200 nm in size. ADSC-EVs were found to contain angiogenic proteins as cargo, among which interleukin 8 (IL-8) was the most abundant, followed by chemokine (C-C motif) ligand 2 (CCL2), a tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, and vascular endothelial growth factor-D (VEGF-D). ADSC-EVs treatment increased the proliferation, migration, total vessel length, total number of junctions, and junction density of endothelial cells in vitro. The results of an in vivo Matrigel plug assay revealed that ADSC-EVs induced more blood vessels in the Matrigel compared with the control. These results demonstrate that ADSC-EVs contain angiogenic proteins as cargo and promote angiogenesis in vitro and in vivo. Therefore, ADSC-EVs have potential for therapeutic use in ischaemia.
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Skiles, Jerry W., Nina C. Gonnella, and Arco Y. Jeng. "Inhibitors of Matrix Metalloproteinases: Design, Structure and Therapeutic Applications." Frontiers in Medicinal Chemistry - Online 1, no. 1 (January 1, 2004): 29–75. http://dx.doi.org/10.2174/1567204043396262.
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Mollace, Vincenzo, Giuseppe M. C. Rosano, Stefan D. Anker, Andrew J. S. Coats, Petar Seferovic, Rocco Mollace, Annamaria Tavernese, et al. "Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review." Nutrients 13, no. 1 (January 17, 2021): 257. http://dx.doi.org/10.3390/nu13010257.
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There is evidence demonstrating that heart failure (HF) occurs in 1–2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium–glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds.
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Michel, Piotr, Sebastian Granica, Anna Magiera, Karolina Rosińska, Małgorzata Jurek, Łukasz Poraj, and Monika Anna Olszewska. "Salicylate and Procyanidin-Rich Stem Extracts of Gaultheria procumbens L. Inhibit Pro-Inflammatory Enzymes and Suppress Pro-Inflammatory and Pro-Oxidant Functions of Human Neutrophils Ex Vivo." International Journal of Molecular Sciences 20, no. 7 (April 9, 2019): 1753. http://dx.doi.org/10.3390/ijms20071753.
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Salicylate-rich plants are an attractive alternative to synthetic anti-inflammatory drugs due to a better safety profile and the advantage of complementary anti-inflammatory and antioxidant effects of the co-occurring non-salicylate phytochemicals. Here, the phytochemical value and biological effects in vitro and ex vivo of the stems of one of such plants, Gaultheria procumbens L., were evaluated. The best extrahent for effective recovery of the active stem molecules was established in comparative studies of five extracts. The UHPLC-PDA-ESI-MS3, HPLC-PDA, and UV-photometric assays revealed that the selected acetone extract (AE) accumulates a rich polyphenolic fraction (35 identified constituents; total content 427.2 mg/g dw), mainly flavanols (catechins and proanthocyanidins; 201.3 mg/g dw) and methyl salicylate glycosides (199.9 mg/g dw). The extract and its model components were effective cyclooxygenase-2, lipoxygenase, and hyaluronidase inhibitors; exhibited strong antioxidant capacity in six non-cellular in vitro models (AE and procyanidins); and also significantly and dose-dependently reduced the levels of reactive oxygen species (ROS), and the release of cytokines (IL-1β, IL-8, TNF-α) and proteinases (elastase-2, metalloproteinase-9) in human neutrophils stimulated ex vivo by lipopolysaccharide (LPS) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The cellular safety of AE was demonstrated by flow cytometry. The results support the application of the plant in traditional medicine and encourage the use of AE for development of new therapeutic agents.
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Uhl, Franziska E., Sarah Vierkotten, Darcy E. Wagner, Gerald Burgstaller, Rita Costa, Ina Koch, Michael Lindner, Silke Meiners, Oliver Eickelberg, and Melanie Königshoff. "Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures." European Respiratory Journal 46, no. 4 (April 30, 2015): 1150–66. http://dx.doi.org/10.1183/09031936.00183214.
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Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage (per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs.
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Pasternak, Björn, and Per Aspenberg. "Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics." Acta Orthopaedica 80, no. 6 (December 2009): 693–703. http://dx.doi.org/10.3109/17453670903448257.
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Napoli, Salvatore, Chiara Scuderi, Giuseppe Gattuso, Virginia Di Bella, Saverio Candido, Maria Sofia Basile, Massimo Libra, and Luca Falzone. "Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma." Cells 9, no. 5 (May 7, 2020): 1151. http://dx.doi.org/10.3390/cells9051151.
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The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.
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Zask, Arie, Jeremy I. Levin, Loran M. Killar, and Jerauld S. Skotnicki. "Inhibition of Matrix Metalloproteinases: Structure Based Design." Current Pharmaceutical Design 2, no. 6 (December 1996): 624–61. http://dx.doi.org/10.2174/1381612802666221004190555.
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Matrix metalloproteinases (MMP) have been implicated in a variety of diseases in which the destruction of connective tissue is an important pathological event. These include osteo and rheumatoid arthritis, tumor metastasis and angiogenesis, and corneal ulceration. As a result, there has been a great deal of activity directed towards the design of MMP inhibitors as therapeutic agents for the treatment of these conditions. Progress in the field has now evolved to a degree where potent, low molecular weight, orally active inhibitors have been discovered and advanced to clinical trials. While a majority of inhibitors are dipeptide derivatives, a non-peptide, orally active inhibitor has recently been reported. Some success has also been achieved in the design of subtype selective MMP inhibitors. The elucidation of X-ray and 0NMR structures of several MMPs, and the ability to create homology models of others has provided an understanding of some of the structural requirements leading to potency and specificity. Herein is a review of recent advances in the biology and chemistry of MMPs and MMP inhibitors, including the association of MMPs with specific disease processes, structure activity relationships of MMP inhibitors and factors affecting enzyme specificity and their correlation with MMP structure.
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Liva, Francesca, Doretta Cuffaro, Elisa Nuti, Susanna Nencetti, Elisabetta Orlandini, Giovanni Vozzi, and Armando Rossello. "Age-related Macular Degeneration: Current Knowledge of Zinc Metalloproteinases Involvement." Current Drug Targets 20, no. 9 (June 11, 2019): 903–18. http://dx.doi.org/10.2174/1389450120666190122114857.
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Background: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. The disease is characterized by photoreceptor loss in the macula and reduced Retinal Pigment Epithelium (RPE) function, associated with matrix degradation, cell proliferation, neovascularization and inflammation. Matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play a critical role in the physiology of extracellular matrix (ECM) turnover and, in turn, in ECM pathologies, such as AMD. A balance between the activities of MMPs and Tissue Inhibitors of Metalloproteinase (TIMPs) is crucial for the integrity of the ECM components; indeed, a dysregulation in the ratio of these factors produces profound changes in the ECM, including thickening and deposit formation, which eventually might lead to AMD development. Objective: This article reviews the relevance and impact of zinc metalloproteinases on the development of AMD and their roles as biomarkers and/or therapeutic targets. We illustrate some studies on several inhibitors of MMPs currently used to dissect physiological properties of MMPs. Moreover, all molecules or technologies used to control MMP and ADAM activity in AMD are analyzed. Conclusion: This study underlines the changes in the activity of MMPs expressed by RPE cells, highlights the functions of already used MMP inhibitors and consequently suggests their application as therapeutic agents for the treatment of AMD.
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Młynarczyk, G., J. Kudelski, B. Darewicz, Z. Galewska, and L. Romanowicz. "Matrix metalloproteinases in urinary system tumours. Part I - Matrix metalloproteinases in renal cell carcinoma." Progress in Health Sciences 7, no. 1 (March 3, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.1878.
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Extracellular matrix metalloproteinases - MMPs, also referred to as matrixines, provide a group of proteolytic enzymes. They belong to the family of endopeptidases that break down elements of extracellular matrix, resulting in its continuous remodelling. Their activity is regulated at multiple levels, while tissue inhibitors of metalloproteinases play a major role in this process. Metalloproteinases play a significant part in neoplastic processes due to their contribution to local tumour invasion and formation of distant metastases, as well as to angiogenesis Urinary tract tumours pose a significant diagnostic and therapeutic challenge and their incidence tends to grow every year. The aim of this part of review is to describe extracellular matrix and matrix metalloproteinases and to highlight the contribution of matrix metalloproteinases in the development of renal clear cell carcinoma.
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Goetzl, E. J., M. J. Banda, and D. Leppert. "Matrix metalloproteinases in immunity." Journal of Immunology 156, no. 1 (January 1, 1996): 1–4. http://dx.doi.org/10.4049/jimmunol.156.1.1.
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Abstract Matrix metalloproteinases (MMPs) are a family of zinc-containing endo-proteinases that share structural domains but differ in substrate specificity, cellular sources, and inducibility. Macrophage production and secretion of large quantities of many MMPs, after contact with matrix proteins, is enhanced by surface determinants on activated T cells and suppressed by cytokines from Th1 and Th2 cells. T cells secrete predominantly the gelatinases MMP-2 and -9, after beta 1, integrin- or vascular cell adhesion molecule (VCAM)-1-dependent stimulation by cytokines and inflammatory mediators. MMPs of both T cells and macrophages facilitate secretion of TNF-alpha, by cleavage of the membrane-bound form. T cell MMPs prepare connective tissue matrices for T cell chemotaxis across basement membranes and through tissues. The greater amounts of diverse MMPs from macrophages are capable of degrading connective tissues, which may release stored growth factors. In limited studies of animal models of autoimmunity, specific MMP inhibitors have significantly decreased edema and inflammatory tissue damage, suggesting possible therapeutic benefits.
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Chaussain-Miller, C., F. Fioretti, M. Goldberg, and S. Menashi. "The Role of Matrix Metalloproteinases (MMPs) in Human Caries." Journal of Dental Research 85, no. 1 (January 2006): 22–32. http://dx.doi.org/10.1177/154405910608500104.
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The objective of this review is to summarize our understanding of the role of host matrix metalloproteinases (MMPs) in the caries process and to discuss new therapeutic avenues. MMPs hydrolyze components of the extracellular matrix and play a central role in many biological and pathological processes. MMPs have been suggested to play an important role in the destruction of dentin organic matrix following demineralization by bacterial acids and, therefore, in the control or progression of carious decay. Host-derived MMPs can originate both from saliva and from dentin. They may be activated by an acidic pH brought about by lactate release from cariogenic bacteria. Once activated, they are able to digest demineralized dentin matrix after pH neutralization by salivary buffers. Furthermore, the degradation of SIBLINGs (Small Integrin-binding Ligand N-linked Glycoproteins) by the caries process may potentially enhance the release of MMPs and their activation. This review also explores the different available MMP inhibitors, natural or synthetic, and suggests that MMP inhibition by several inhibitors, particularly by natural substances, could provide a potential therapeutic pathway to limit caries progression in dentin.
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Młynarczyk, G., J. Kudelski, B. Darewicz, Z. Galewska, and L. Romanowicz. "Matrix metalloproteinases in urinary system tumors. Part II - Matrix metalloproteinases in urinary bladder carcinoma." Progress in Health Sciences 7, no. 1 (March 8, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.1879.
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Matrix metalloproteinases (MMPs), also referred to as matrixines, provide a group of proteolytic enzymes. They belong to the family of endopeptidases that break down elements of the extracellular matrix, resulting in its continuous remodeling. Their activity is regulated at multiple levels, while tissue inhibitors of metalloproteinases play a major role in this process. Metalloproteinases play a significant part in neoplastic processes due to their contribution to local tumor invasion, the formation of distant metastases, as well as to angiogenesis Urinary tract tumors pose a significant diagnostic and therapeutic challenge and their incidence tends to grow every year. The aim of this second part of the review is to describe the urinary system structure and function, and to highlight the contribution of matrix metalloproteinases to the development of urinary bladder tumors
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Smeglin, Anthony, and William H. Frishman. "Elastinolytic Matrix Metalloproteinases and Their Inhibitors as Therapeutic Targets in Atherosclerotic Plaque Instability." Cardiology in Review 12, no. 3 (May 2004): 141–50. http://dx.doi.org/10.1097/01.crd.0000105000.46909.81.
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Obermüller, Nicholas, Natividad Morente, Bettina Kränzlin, Norbert Gretz, and Ralph Witzgall. "A possible role for metalloproteinases in renal cyst development." American Journal of Physiology-Renal Physiology 280, no. 3 (March 1, 2001): F540—F550. http://dx.doi.org/10.1152/ajprenal.2001.280.3.f540.
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The expansion of cysts in polycystic kidneys bears several similarities to the invasion of the extracellular matrix by benign tumors. We therefore hypothesized that cyst-lining epithelial cells produce extracellular matrix-degrading metalloproteinases and that the inhibition of these enzymes may represent a potential target for therapeutic intervention. Using in situ hybridization, we first analyzed the expression of membrane-type metalloproteinase 1 (MMP-14), an essential matrix metalloproteinase, of its inhibitor TIMP-2, and of the cytokine transforming growth factor (TGF)-β2 in the ( cy/ +) rat model of autosomal-dominant polycystic kidney disease. Upregulated MMP-14 mRNA was predominantly located in cyst-lining epithelia and distal tubules, whereas TIMP-2 mRNA was confined almost exclusively to fibroblasts. TGF-β2, a cytokine known to regulate the expression of matrix metalloproteinases and their inhibitors, was also expressed by cyst wall epithelia. We then treated ( cy/ +) rats with the metalloproteinase inhibitor batimastat for a period of 8 wk. The treatment with the metalloproteinase inhibitor batimastat resulted in a significant reduction of cyst number and kidney weight. Our study suggests that metalloproteinase inhibitors represent a new therapeutic tool against polycystic kidney disease, which should be applicable independently of the background of the disease.