Elevated Levels Of Matrix Metalloproteinases Research Articles

Cannabiorcol as a novel inhibitor of the p38/MSK-1/NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis

BackgroundThe bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear. MethodsIn silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1β and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol's effects on OA and its fundamental mechanisms. ResultsCannabiorcol inhibits the expression of IL-1β-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa β (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats. ConclusionCannabiorcol inhibits IL-1β-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.

New Insights into the Pathophysiology of Coronary Artery Aneurysms.

Coronary aneurysms are typically defined as sections of a coronary artery where the diameter is more than 1.5 times that of an adjacent normal segment. In rare circumstances, these aneurysms can become exceedingly large, leading to the classification of giant coronary artery aneurysms. Despite their occurrence, there is no clear consensus on the precise definition of giant coronary artery aneurysms, and their etiology remains somewhat ambiguous. Numerous potential causes have been suggested, with atherosclerosis being the most prevalent in adults, accounting for up to 50% of cases. In pediatric populations, Kawasaki disease and Takayasu arteritis are the primary causes. Although often discovered incidentally, coronary artery aneurysms can lead to severe complications. These complications include local thrombosis, distal embolization, rupture, and vasospasm, which can result in ischemia, heart failure, and arrhythmias. The optimal approach to medical, interventional, or surgical management of these aneurysms is still under debate and requires further clarification. This literature review aims to consolidate current knowledge regarding coronary artery aneurysms' pathophysiology, emphasizing their definition, causes, complications, and treatment strategies. Recent research has begun to explore the molecular mechanisms involved in the formation and progression of coronary artery aneurysms. Various molecules, such as matrix metalloproteinases (MMPs), inflammatory cytokines, and growth factors, play crucial roles in the degradation of the extracellular matrix and the remodeling of vascular walls. Elevated levels of MMPs, particularly MMP-9, have been associated with the weakening of the arterial wall, contributing to aneurysm development. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6) have been implicated in promoting inflammatory responses that further degrade vascular integrity. Additionally, growth factors such as vascular endothelial growth factor (VEGF) may influence angiogenesis and vascular remodeling processes. Understanding these molecular pathways is essential for developing targeted therapies aimed at preventing the progression of coronary artery aneurysms and improving patient outcomes.

Matrix Metalloproteinases as Biomarkers for Ischemic Stroke: A Systematic Review

Background: Ischemic stroke, a leading cause of mortality and disability worldwide, occurs due to the disruption of blood flow to the brain, resulting in neuronal damage and death. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play a crucial role in the pathophysiology of ischemic stroke by degrading the extracellular matrix and contributing to blood-brain barrier disruption, inflammation, and neuronal cell death. This systematic review aims to comprehensively evaluate the current evidence regarding the potential of MMPs as biomarkers for ischemic stroke diagnosis, prognosis, and therapeutic monitoring. Methods: A systematic search of electronic databases (PubMed, Embase, and Cochrane Library) was conducted to identify relevant studies published between 2018 and 2024. Studies investigating the association between MMPs and ischemic stroke in human subjects were included. Data extraction and quality assessment were performed independently by two reviewers. Results: The search yielded 2,182 articles, of which 8 studies met the inclusion criteria. The included studies evaluated various MMPs, including MMP-2, MMP-3, MMP-9, and MMP-12, in different biological samples (serum, plasma, cerebrospinal fluid, and brain tissue) from ischemic stroke patients. The majority of studies reported elevated levels of MMPs in ischemic stroke patients compared to healthy controls, with MMP-9 being the most extensively studied. Furthermore, several studies demonstrated a correlation between MMP levels and stroke severity, functional outcome, and the risk of hemorrhagic transformation. Conclusion: The findings of this systematic review suggest that MMPs, particularly MMP-9, hold promise as potential biomarkers for ischemic stroke. However, further research is needed to validate their clinical utility and to explore their potential as therapeutic targets.

Varying Properties of Extracellular Matrix Grafts Impact Their Durability and Cell Attachment and Proliferation in an In Vitro Chronic Wound Model

While acute wounds typically progress through the phases of wound healing, chronic wounds often stall in the inflammatory phase due to elevated levels of matrix metalloproteinases (MMPs) and proinflammatory cytokines. Dysregulated expression of MMPs can result in the breakdown of extracellular matrix (ECM) formed during the wound healing process, resulting in stalled wounds. Native collagen-based wound dressings offer a potential wound management option to sequester excess MMPs and support cellular interactions that allow wound progression through the natural healing process. Herein, we utilized commercially available ECM matrices, two derived from porcine small intestinal submucosa (PCMP, 2 layers; PCMP-XT, 5 layers) and one derived from propria submucosa (ovine forestomach matrix, OFM, 1 layer), to demonstrate the impact of processing methodologies (e.g., layering and crosslinking) on functional characteristics needed for the management of chronic wounds. Grafts were evaluated for structural composition using scanning electron microscopy and histology, ability to reduce MMPs using fluorometric assays, and durability in an in vitro degradation chronic wound model. Both intact (nondegraded) and partially degraded grafts were assessed for their ability to serve as a functional cell scaffold using primary human fibroblasts. Grafts differed in matrix substructure and composition. While all grafts demonstrated attenuation of MMP activity, PCMP and PCMP-XT showed larger reductions of MMP levels. OFM rapidly degraded in the in vitro degradation model (<3 hours), while PCMP and PCMP-XT were significantly more durable (>7 days). The ability of PCMP and PCMP-XT to serve as scaffolds for cellular attachment was not impacted by degradation in vitro. Three ECM grafts with varying structural and functional characteristics exhibited differential durability when degraded in a simulated chronic wound model. Those that withstood rapid degradation maintained their ability to function as a scaffold to support attachment and proliferation of fibroblasts, a cell type important for wound healing.

Relationship between the Expression of Matrix Metalloproteinases and Their Tissue Inhibitors in Patients with Brain Tumors.

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play critical roles in regulating processes associated with malignant behavior. These endopeptidases selectively degrade components of the extracellular matrix (ECM), growth factors, and their receptors, contributing to cancer cell invasiveness and migratory characteristics by disrupting the basal membrane. However, the expression profile and role of various matrix metalloproteinases remain unclear, and only a few studies have focused on differences between diagnoses of brain tumors. Using quantitative real-time PCR analysis, we identified the expression pattern of ECM modulators (n = 10) in biopsies from glioblastoma (GBM; n = 20), astrocytoma (AST; n = 9), and meningioma (MNG; n = 19) patients. We found eight deregulated genes in the glioblastoma group compared to the benign meningioma group, with only MMP9 (FC = 2.55; p = 0.09) and TIMP4 (7.28; p < 0.0001) upregulated in an aggressive form. The most substantial positive change in fold regulation for all tumors was detected in matrix metalloproteinase 2 (MNG = 30.9, AST = 4.28, and GBM = 4.12). Notably, we observed an influence of TIMP1, demonstrating a positive correlation with MMP8, MMP9, and MMP10 in tumor samples. Subsequently, we examined the protein levels of the investigated MMPs (n = 7) and TIMPs (n = 3) via immunodetection. We confirmed elevated levels of MMPs and TIMPs in GBM patients compared to meningiomas and astrocytomas. Even when correlating glioblastomas versus astrocytomas, we showed a significantly increased level of MMP1, MMP3, MMP13, and TIMP1. The identified metalloproteases may play a key role in the process of gliomagenesis and may represent potential targets for personalized therapy. However, as we have not confirmed the relationship between mRNA expression and protein levels in individual samples, it is therefore natural that the regulation of metalloproteases will be subject to several factors.

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children.

Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

Prognostic value of matrix metalloproteinases in patients with anthracycline-induced heart failure

Highlights. Elevated levels of matrix metalloproteinases 2 and 9 are associated with the initiation and severity of CHF developed after breast cancer therapy with anthracyclines, which may contribute to cardiac remodeling and the progression of systolic dysfunction. Concentrations of matrix metalloproteinases-2 and -9 in blood serum serve as predictors of the unfavorable course of anthracycline-induced heart failure.Aim. To assess the role of matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) in the development and course of anthracycline-induced chronic heart failure (CHF) during 24 months of observation.Methods. The study included 114 women 12 months after completion of chemotherapy (CT) for breast cancer and developed CHF. The control group (n = 70) consisted of women (mean age 45.0 [42.0; 50.0] years old) who received doxorubicin as part of chemotherapy, but they did not develop CHF 12 months after completion of chemotherapy. The levels of biomarkers (MMP-2, MMP-9, NT-proBNP) in blood serum were determined using a sandwich immunoassay.Results. Patients with CHF had signs of cardiac remodeling and higher values of NT-proBNP, MMP-2 and MMP-9 (p&lt;0.001) than women from the control group. After 24 months of observation, all patients with CHF were divided into 2 groups: group 1 – women with an unfavorable course of CHF (n = 54), group 2 – women with favorable course of pathology (n = 60). Criteria for the unfavorable course of CHF: the emergence of new or worsening of existing symptoms/signs of heart failure; and/or hospitalization due to HF decompensation; decrease in left ventricular ejection fraction by more than 10%; or an increase in the functional class of CHF by 1 or more. Baseline echocardiographic parameters and NT-proBNP values did not differ in groups 1 and 2. Levels of MMP-2 were higher by 8% (p = 0.017) and MMP-9 by 18.4% (p&lt;0.001) in group 1. In 1 group the level of MMP-2 decreased after 24 months of observation. In group 2 the level of MMP-2 increased by the end of the observation period. MMP-2 levels ≥388.2 pg/ml (sensitivity 46%, specificity 80%; AUC = 0.64; p = 0.013) and MMP-9 ≥21.3 pg/ml (sensitivity 86%, specificity 84.4%; AUC = 0.9; p&lt;0.001) were determined as predictors of an unfavorable course of CHF.Conclusion. Remodeling of the extracellular matrix may play an important role in the pathogenesis of CHF initiated by drugs of the anthracycline class. Elevated levels of MMP-2 and MMP-9 in the blood serum are associated with an unfavorable course of anthracycline-induced CHF and can be recommended when assessing the risk of an unfavorable course of pathology.

A mini review on the associations of matrix metalloproteinases (MMPs) -1, -8, -13 with periodontal disease

Matrix metalloproteinases (MMPs) are one of the most important endopeptidases in periodontal disease that generally degrade extracellular matrix (ECM) components of periodontal supporting tissues, leading to tooth loss. Among the MMP family, MMP-1, -8 and -13, which are also known as the collagenase group, play a vital role in the degradation of ECM collagen and non-collagen substances. Elevated levels of MMP -1, -8 and -13 are markedly significant within tissue, gingival crevicular fluid (GCF), and saliva of patients with periodontitis, which help to explain the progression pattern of the disease. This review provides an overview of MMP -1, -8, and -13 on their structures, functions and their critical role in periodontitis.

International consensus document. Implementing TIMERS: the race against hard-to-heal wounds. Part 1

British Journal of Healthcare AssistantsVol. 13, No. 12 ClinicalInternational consensus document. Implementing TIMERS: the race against hard-to-heal wounds. Part 1Menna Lloyd JonesMenna Lloyd JonesConsultant Editor, BJHCASearch for more papers by this authorMenna Lloyd JonesPublished Online:11 Dec 2019https://doi.org/10.12968/bjha.2019.13.12.578AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View articleReferencesAtkin, Bućko Z, Conde Montero E et al.. Implementing TIMERS: the race against hard-to-heal wounds. J Wound Care. 2019 Mar 1;23(Sup3a):S1–50. doi: https://doi.org/10.12968/jowc.2019.28.Sup3a.S1 Link, Google ScholarEuropean Wound Management Association. Position document: wound bed preparation in practice. 2004. https://tinyurl.com/s69m876 (accessed 22 November 2019) Google ScholarNHS England. CQUIN Indicator Specification Information on CQUIN 2017/18–2018/19. Indicator 10. 2016. https://tinyurl.com/qv8hsv9 (accessed 22 November 2019) Google ScholarGuest JF, Ayoub N, McIlwraith T et al.. Health economic burden that wounds impose on the National Health Service in the UK. BMJ Open. 2015. https://tinyurl.com/ujcbkm4 (accessed 22 November 2019) Google ScholarJones ML. Fundamentals of tissue viability, Series 2.1. Wounds: introduction. British Journal of Healthcare Assistants. 2017; 11(7):336–338 Link, Google ScholarLazaro JL, Izzo V, Meaume S et al.. Elevated levels of matrix metalloproteinases and chronic wound healing: updated review of clinical evidence. J Wound Care. 2016; 25(5):277–287 Link, Google ScholarVowden K. TIME to identify and manage tissue types present in the wound bed. Wound Care Today. 2017; 4(1):12–17 Google ScholarWebb R, Fronzo C. Foreword. In: Atkinet al.. Implementing TIMERS: the race against hard-to-heal wounds. J Wound Care. 2019; 28(3 Suppl 3):S1–49 Google ScholarWounds UK. Best practice statement, Holistic management of venous leg ulceration. 2016. https://tinyurl.com/yaaopmhf (accessed 20 September 2019) Google Scholar FiguresReferencesRelatedDetailsCited byTIMERS: the race against hard to heal wounds. Part 4, Sections 5 and 6: advanced and adjunctive product use; management of patient-related factorsMenna Lloyd Jones12 March 2020 | British Journal of Healthcare Assistants, Vol. 14, No. 3International consensus document. Implementing TIMERS: the race against hard-to-heal wounds. Part 2Menna Lloyd Jones8 January 2020 | British Journal of Healthcare Assistants, Vol. 14, No. 1 2 December 2019Volume 13Issue 12ISSN (print): 1753-1586ISSN (online): 2052-4420 Metrics History Published online 11 December 2019 Published in print 2 December 2019 Information© MA Healthcare LimitedPDF download

Synthesis and secretome release by human bone marrow mesenchymal stem cell spheroids within three-dimensional collagen hydrogels: Integrating experiments and modelling.

Myocardial infarction results in loss of cardiac cell types, inflammation, extracellular matrix (ECM) degradation, and fibrotic scar. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) is being explored as they could differentiate into cardiomyocyte-like cells, integrate into host tissue, and enhance resident cell activity. The ability of these cells to restore lost ECM, remodel the inflammatory scar tissue, and repair the injured myocardium remains unexplored. We here elucidated the synthesis and deposition of ECM (e.g., elastin, sulfated glycosaminoglycans, hyaluronan, collagen type III, laminin, fibrillin, lysyl oxidase, and nitric oxide synthases), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), and other secretome (cytokines, chemokines, and growth factors) in adult human BM-MSC spheroid cultures within three-dimensional collagen gels. The roles of species-specific type I collagen and 5-azacytadine were assessed over a 28-day period. Results revealed that human collagen (but not rat-derived) suppressed MSC proliferation and survival, and MSCs synthesized and released a variety of ECM proteins and secretome over the 28 days. Matrix deposition is at least an order of magnitude lower than their release levels at every time point, most possibly due to elevated MMP levels and interleukins with a concomitant decrease in TIMPs. Matrix synthesis over the 28-day period was fitted to a competitive inhibition form of Michaelis-Menten kinetics, and the production and decay rates of ECM, MMPs, and TIMPs, along with the kinetic model parameters quantified. Such an integrated experimental and modelling approach would help elucidate the critical roles of various parameters (e.g., cell encapsulation and delivery vehicles) in stem cell-based transplantation therapies.

Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment

BackgroundMatrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis – diabetes comorbidity (TB-DM) is not well understood.MethodsTo study the association of MMP levels with severity and extent of disease as well as bacterial burden in TB-DM, we examined the systemic levels of MMP-1, − 2, − 3, − 7, − 8, − 9, − 10, − 12 and − 13 in individuals with TB-DM and compared them to those with TB alone (TB) or healthy controls (HC).ResultsCirculating levels of MMP-1, − 2, − 3, − 7, − 10 and − 12 were significantly higher in TB-DM compared to both TB and HC and MMP -13 levels were higher in comparison to HC alone. To understand the effect of standard anti-tuberculosis therapy (ATT) on these MMP levels in TB-DM, we measured the levels of MMPs at the end of treatment (post-treatment). Our findings indicate that ATT is associated with a significant reduction in the levels of MMP-1, − 2, − 3, − 8 and − 13 post-treatment. Moreover, the levels of MMP-1, − 2, − 3, − 9 and − 12 were significantly higher in TB-DM individuals with cavitary disease and/or bilateral disease at baseline but not post-treatment. Similarly, the levels of MMP -1, − 2, − 3 and − 8 exhibited a significant positive relationship with bacterial burden and HbA1c levels at baseline but not post-treatment. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited significantly higher levels of MMP-1, − 2, − 10 and − 12 at baseline and of MMP-1 and -3 post-treatment compared to those newly diagnosed with DM (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of MMP-1, − 2, − 3, − 7, − 9 and − 12 at baseline and of MMP-7 post-treatment.ConclusionsOur data demonstrate that systemic MMP levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.

Lax eyelid syndrome (LES), obstructive sleep apnea (OSA), and ocular surface inflammation

PurposeLax eyelid syndrome (LES) is defined as the association of distensible “floppy” eyelids and chronic papillary conjunctivitis. LES is also found in patients with obstructive sleep apnea (OSA) who have systemic elevation of inflammatory markers, including matrix metalloproteinases (MMP). Locally elevated MMP levels have also been demonstrated co-localized with elastin loss in eyelids of patients with LES, accounting for their “floppiness.” The purpose of this study was to investigate tear film MMP levels and determine their association with eyelid laxity and OSA. We also evaluated 3 previous grading systems to determine the severity of lid laxity and introduced a new “laxometer” device. MethodsThirty-seven subjects underwent bilateral eyelid laxity assessments prior to polysomnography testing. OSA severity was graded using the apnea hypopnea index (AHI). The degree of eyelid laxity was determined using three published methods and a newly proposed “laxometer” method. Commercially available InflammaDry® kits were used to determine the presence of MMP-9 in the tear film. ResultsThere was a significant elevation in tear MMP-9 levels in patients with LES compared to controls (p < .05). Of the 37 total patients enrolled in this study, 2 patients (5.4%) did not have sleep study results. Thirty-two of the remaining 35 patients (91.4%) were determined to have OSA (AHI > 5). In this sample, there was no meaningful association between OSA and MMP-9 (p = .12). Although there were positive associations between OSA severity, laxometer measurements, and previously established grading methods, none achieved statistical significance (all p > .05). ConclusionsThere was an elevation of MMP-9 in tears of patients with LES. Elevated tear MMP-9 was also not associated with OSA. Although there is some evidence to support the association of eyelid laxity and OSA, the most accurate and reliable method for grading eyelid laxity remains unclear.

Long-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review.

Sepsis is systemic inflammatory response syndrome with a life-threatening organ dysfunction that is caused by an unbalanced host immune response in an attempt to eliminate invasive microorganisms. We posed questions, "Does sepsis survivor patients have increased risk of neuropsychiatric manifestations?" and "What is the mechanism by which sepsis induces long-term neurological sequelae, particularly substantial cognitive function decline in survivor patients and in pre-clinical sepsis models?" The studies were identified by searching PubMed/MEDLINE (National Library of Medicine), PsycINFO, EMBASE (Ovid), LILACS (Latin American and Caribbean Health Sciences Literature), IBECS (Bibliographical Index in Spanish in Health Sciences), and Web of Science databases for peer-reviewed journals that were published until January 2018. A total of 3555 papers were included in the primary screening. After that, 130 articles were selected for the study. A number of pre-clinical studies have shown an auto amplification of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in the first few hours after sepsis induction, also increased blood-brain barrier permeability, elevated levels of matrix metalloproteinases, increased levels of damage-associated molecular patterns were demonstrated. In addition, the rodents presented long-term cognitive impairment in different behavioral tasks that were prevented by blocking the mechanism of action of these inflammatory mediators. Clinical studies have showed that sepsis survivors presented increased bodily symptoms such as fatigue, pain, visual disturbances, gastrointestinal problems, and neuropsychiatric problems compared to before sepsis. Sepsis leaves the survivors with an aftermath of physiological, neuropsychiatric, and functional impairment. Systematic review registration: CRD42017071755.

Investigation of markers for myocardial remodeling during experimental hypobaric hypoxia in the correction with cytoflavin

To reveal the peculiarities of changes in the markers of myocardial remodeling in experimental hypobaric hypoxia. The investigation was conducted on 26 mature male Wistar rats weighing 220-310 g, which were divided into 3 groups: 1) 6 intact animals; 2) 10 rats that were exposed to 30-day simulated hypobaric hypoxia without correction; 3) 10 rats that were given once-daily intraperitoneal injections of cytoflavin solution at a rate of 0.5 ml/100 g of body weight for 30 days before immersion in a hypobaric chamber. The early stages of myocardial remodeling in hypobaric hypoxia were found to be characterized by structural re-systematization of the components of the normal ventricular wall, which was manifested by cardiomyocyte hypertrophy and ischemia; circulatory disorders; fibroblast proliferation that dramatically enhances the extracellular expression of protein matrix, which can lead to the formation of fibrous tissue and irreversible myocardial dysfunction. Elevated matrix metalloproteinase levels are evidence for collagen degradation and cardiac remodeling. In the authors' opinion, the cyto- and angioprotective effects of cytoflavin in rats treated with the latter used in combination therapy are associated with the composition of the drug, the active components of which have mutually potentiating effects, are inducers of the major metabolic pathways in the cells and are also activators of key energy-generating processes. Identification of the molecular mechanisms of myocardial remodeling is of great practical importance. This enables remodeling markers to be considered as a potential therapeutic target in the treatment of hypoxia-induced myocardial injury.

Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis.

Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R. Similarly, establishing a multicellular three-dimensional model of human oral mucosa with induced inflammation promoted MMP12 production and reduced CD200R surface expression by monocyte-derived cells. MMP12 production by monocyte-derived cells was induced by CSF2 rather than the cyclooxygenase-2 pathway, and treatment of monocyte-derived cells with a CD200R ligand reduced CSF2-induced MMP12 production. Further, MMP12-mediated degradation of the extracellular matrix proteins tropoelastin and fibronectin in the tissue model coincided with a loss of Ki-67, a protein strictly associated with cell proliferation. Reduced amounts of tropoelastin were confirmed in gingival tissue from PD patients. Thus, this novel association of the CD200/CD200R pathway with MMP12 production by monocyte-derived cells may play a key role in PD progression and will be important to take into consideration in the development of future strategies to diagnose, treat, and prevent PD.

Macrophage-Restricted Shp2 Tyrosine Phosphatase Acts as a Rheostat for MMP12 through TGF-β Activation in the Prevention of Age-Related Emphysema in Mice.

Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-β1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheless, the mechanism for this MMP-dependent pathogenesis has yet to be clearly investigated. Recently, we identified an important role for tyrosine phosphatase Src homology domain-containing protein tyrosine phosphatase 2 (Shp2) in regulating the activation of alveolar macrophages. Over a long-term observation period, mice with Shp2 deletion in macrophages (LysMCre:Shp2fl/fl ) develop spontaneous, progressive emphysema-like injury in the lungs, characterized by massive destruction of alveolar morphology, interstitial extracellular matrix degradation, and elevated levels of MMPs, particularly, significant increases of macrophage elastase (MMP12) in aged mice. Further analysis demonstrated that MMP12 suppression by TGF-β1 activation was apparently abrogated in LysMCre:Shp2fl/fl mice, whereas the TGF-β1 concentration in the lungs was relatively the same. Mechanistically, we found that loss of Shp2 resulted in attenuated SMAD2/3 phosphorylation and nuclear translocation in response to TGF-β activation, thereby upregulating MMP12 expression in macrophages. Together, our findings define a novel physiological function of Shp2 in TGF-β1/MMP12-dependent emphysema, adding insights into potential etiologies for this chronic lung disorder.

Cerebrospinal fluid matrix metalloproteinase 9 levels, blood-brain barrier permeability, and treatment outcome in tuberculous meningitis

ObjectivesTuberculous meningitis is characterized by elevated levels of matrix metalloproteinase 9 (MMP9) in the cerebrospinal fluid (CSF). However, it is unclear whether elevated MMP9 levels are associated with poor treatment outcome. We tested the hypothesis that pretreatment MMP9 levels in the CSF would be higher in tuberculous meningitis patients experiencing a poor treatment outcome.MethodsWe prospectively assessed the treatment outcome in a consecutive sample of human immunodeficiency virus-negative patients with tuberculous meningitis. We defined good outcome as survival without severe neurological disability (modified Rankin scale scores 0–2). We estimated levels of MMP9 and its tissue inhibitor (TIMP1) on pretreatment CSF samples. We used albumin index to assess blood-brain barrier permeability.ResultsWe studied 40 patients (23 males [58%]) with tuberculous meningitis. Sixteen patients (40%) had stage 3 disease. On follow-up, 18 (45%) patients had a poor treatment outcome—15 patients died and 3 had severe neurological disability. Pretreatment MMP9 levels were not associated with treatment outcome (median [interquartile range], 254 [115–389] vs. 192 [60–383] ng/mL in good vs. poor outcome groups; P = 0.693). MMP9 levels did not correlate with the albumin index (Spearman’s rho = 0.142; P = 0.381). However, MMP9 levels significantly correlated with CSF glucose levels (rho = −0.419; P = 0.007) and admission Glasgow coma scale score (rho = 0.324; P = 0.032). Likewise, TIMP1 levels also did not differ by treatment outcome (1239 [889–1511] vs. 1522 [934–1949] ng/mL; P = 0.201). MMP9/TIMP1 ratio that reflects net proteolytic activity was also not different between the two groups (0.191 [0.107–0.250] vs. 0.163 [0.067–0.34]; P = 0.625).ConclusionOur findings do not support the hypothesis that pretreatment levels of MMP9 would be higher in tuberculous meningitis patients experiencing a poor treatment outcome. Further, MMP9 levels in the CSF did not correlate with blood-brain barrier permeability in patients with tuberculous meningitis.

Fundamentals of tissue viability, Series 2.1. Wounds: introduction

British Journal of Healthcare AssistantsVol. 11, No. 7 ClinicalFundamentals of tissue viability, Series 2.1. Wounds: introductionMenna Lloyd JonesMenna Lloyd JonesSearch for more papers by this authorMenna Lloyd JonesPublished Online:12 Jul 2017https://doi.org/10.12968/bjha.2017.11.7.336AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Dealey C (1999) The Care Of Wounds. A Guide For Nurses. 2nd edn. Blackwell Science, Birmingham Google ScholarDougherty LLister S, eds (2012) Royal Marsden Hospital Manual Of Clinical Procedures. Student edn. 8th edn. Wiley-Blackwell, London Google ScholarDowsett C, Biebly A, Searle R (2014) Reconciling increasing wound care demands with available resources. J Wound Care 23(11): 552–62 Link, Google ScholarDrew P, Posnett J, Rusling L (2007) The cost of wound care for a local population of England. Int Wound J 4(2): 149–55 Crossref, Google ScholarFlanagan M (1996) Wound Healing. Churchill Livingston, Edinburgh Google ScholarHarding K (2017) Innovation and wound healing. J Wound Care 24(4 Suppl): 7–13. doi: https://doi.org/10.12968/jowc.2015.24.Sup4b.7 Link, Google ScholarLazaro JL, Izzo V, Meaume S et al. (2016) Elevated levels of matrix metalloproteinases and chronic wound healing: updated review of clinical evidence. J Wound Care 25(5): 277–87 Link, Google ScholarPosnett J, Franks PF (2007) The cost of skin breakdown and ulceration in the UK. In: Skin breakdown the silent epidemic. Smith and Nephew Foundation, Hull Google ScholarVuolo J (2009) Wound Care Made Incredibly Easy. 1st UK edn. Lippincott Williams & Wilkins, London Google ScholarWounds UK (2017) Best Practice Statement: Making Day-To-Day Management Of Biofilm Simple. http://tinyurl.com/y9he3nxt (accessed 5 July 2017) Google Scholar FiguresReferencesRelatedDetailsCited byInternational consensus document. Implementing TIMERS: the race against hard-to-heal wounds. Part 1Menna Lloyd Jones11 December 2019 | British Journal of Healthcare Assistants, Vol. 13, No. 12 2 July 2017Volume 11Issue 7ISSN (print): 1753-1586ISSN (online): 2052-4420 Metrics History Published online 12 July 2017 Published in print 2 July 2017 Information© MA Healthcare LimitedPDF download

Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye.

BackgroundThe presence of clinically significant inflammation has been confirmed in the tears of 40%–65% of patients with symptoms of dry eye. Ocular surface inflammation may lead to tear film instability, epithelial cell irregularities, and permeability, resulting in chronic symptomatic pain and fluctuating vision as well as negative surgical outcomes.Patients and methodsA retrospective single center medical chart review of 100 patients was conducted. All patients were tested with the InflammaDry test to determine if patients exhibited elevated levels of matrix metalloproteinase 9 (MMP-9). InflammaDry-positive patients were started on a combination of cyclosporine 0.05% twice daily, 2,000–4,000 mg oral omega-3 fatty acids, and frequent artificial tear replacement. InflammaDry-negative patients were started on 2,000–4,000 mg of oral omega-3 fatty acids and frequent artificial tear replacement. Each patient was retested at ~90 days. A symptom questionnaire was performed at the initial visit and at 90 days.Results60% of the patients with dry eye symptoms tested positive for elevated MMP-9 at the initial visit. 78% of all patients returned for follow-up at ~90 days including 80% (48/60) of the previously InflammaDry-positive patients and 75% (30/40) of the previously InflammaDry-negative patients. A follow-up symptom questionnaire reported at least 75% symptomatic improvement in 65% (31/48) of the originally InflammaDry-positive patients and in 70% (21/30) of the initially InflammaDry-negative patients. Symptomatic improvement of at least 50% was reported in 85% (41/48) of previously InflammaDry-positive patients and 86% (26/30) of previously InflammaDry-negative patients. Following treatment, 54% (26/48) of previously InflammaDry-positive patients converted to a negative InflammaDry result.ConclusionIdentifying which symptomatic dry eye patients have underlying inflammation may predict patient responses to treatment and influence clinical management strategies.

Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence.

In the past 20 years, research and clinical trials on the healing process of chronic wounds have highlighted the key role of the family of enzymes called matrix metalloproteinases (MMPs). If a strong correlation between the course of healing of chronic wounds and the levels of a biological marker can be demonstrated, then it may be possible to: i) identify the best marker threshold to predict the clinical evolution of the pathology; and ii) if causality has been found between the marker and pathology, to improve the healing outcome, to change the marker level. The databases Medline and Embase were searched to identify clinical trials pertaining to the assessment of MMPs in chronic wounds with the following keywords 'metalloproteinase' or 'metalloprotease' and 'wound healing'. Clinical trials were considered for inclusion if they enrolled patients with cutaneous chronic wounds and were published in English. More than 50 clinical trials, consensus documents and guidelines were assessed for this review. MMPs play key roles in the wound healing process, and excessive expression and activation of some of these enzymes is seen in chronic cutaneous wounds where healing is delayed. Levels of MMPs are affected by a number of factors, including patient and wound characteristics. Levels of MMPs can be used to indicate the prognosis of chronic wounds and protease modulating treatments used to improve healing rates. The authors report no conflicts of interest in this work.