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• The serum levels of s-ICAM-1, P-selectin, MMP-9, TIMP-1, and S100B increase rapidly after tonic-clonic seizures in patients with epilepsy. • The pattern of increase in the studied markers may suggest endothelial activation and blood-brain barrier leakage during the first 24 h after seizures. • The levels of MMP-9, TIMP-1, and S100B are increased 72 h after seizures. • Seizures change the serum levels of various endothelial and blood-brain barrier proteins; therefore, the time since the last seizure should always be considered while analysing circulatory biomarkers in patients with epilepsy. Seizures have been shown to increase blood-brain barrier (BBB) permeability, yet the role of this phenomenon is not fully understood. Additionally, dysfunction of the BBB leads to initiation and propagation of seizures in animal models. To demonstrate the increased permeability of the BBB in time, we investigated changes of the serum levels of BBB markers in patients with epilepsy after bilateral tonic-clonic seizures. We chose markers that might reflect endothelial activation (ICAM-1, selectins), BBB leakage (MMP-9, S100B) and mechanisms of BBB restoration (TIMP-1, thrombomodulin -TM). We enrolled 50 consecutive patients hospitalised after bilateral tonic-clonic seizures who agreed to take part in the study and 50 participants with no history of epilepsy. Serum levels of selected markers were measured by ELISA at 1-3, 24, and 72 hours after seizures and one time in the control group. We found increased levels of S100B, ICAM-1, MMP-9 and P-selectin at 1-3 and 24 hours after seizures and TIMP-1 and TM at 24 and 72 hours after seizures as compared to the control group. The level of E-selectin was decreased at 72 hours after seizures. Our findings suggest early activation of endothelium and increased BBB permeability after seizures. While we are aware of the limitations due to the non-specificity of the tested proteins, our results might indicate the presence of prolonged BBB impairment due to seizure activity. [ABSTRACT FROM AUTHOR]

As the dentition forms and becomes functional, the alveolar bone is remodelled. Metalloproteinases are known to contribute to this process, but new regulators are emerging and their contextualization is challenging. This applies to Myb, a transcription factor recently reported to be involved in bone development and regeneration. The regulatory effect of Myb on Mmps expression has mostly been investigated in tumorigenesis, where Myb impacted the expression of Mmp1, Mmp2, Mmp7, and Mmp9. The aim of this investigation was to evaluate the regulatory influence of the Myb on Mmps gene expression, impacting osteogenesis and mandibular bone formation. For that purpose, knock-out mouse model was used. Gene expression of bone-related Mmps and the key osteoblastic transcription factors Runx2 and Sp7 was analysed in Myb knock-out mice mandibles at the survival limit. Out of the metalloproteinases under study, Mmp13 was significantly downregulated. The impact of Myb on the expression of Mmp13 was confirmed by the overexpression of Myb in calvarial-derived cells causing upregulation of Mmp13. Expression of Mmp13 in the context of other Mmps during mandibular/alveolar bone development was followed in vivo along with Myb, Sp7 and Runx2. The most significant changes were observed in the expression of Mmp9 and Mmp13. These MMPs and MYB were further localized in situ by immunohistochemistry and were identified in pre/osteoblastic cells as well as in pre/osteocytes. In conclusion, these results provide a comprehensive insight into the expression dynamics of bone related Mmps during mandibular/alveolar bone formation and point to Myb as another potential regulator of Mmp13.

ABSTRACT Currently, the market offers a wide variety of suture threads, made of materials with different structural and chemical properties. Among many other characteristics, they vary in origin, absorption or degradation, and structure. From this variety, the clinical doubt arises as to which material provides the patient with the best healing quality. Objective: This study aims to comparatively evaluate two different types of suture threads-Monocryl® (polyglycaprone 25) and Ethilon® (nylon)-regarding their ability to aid in tissue regeneration by a histological and immunohistochemical analysis of the skin of rats sutured with the aforementioned materials. Methods: This basic experimental study used 12 adult Wistar rats, randomly divided into three groups with four animals each and subjected to four longitudinal incisions under anesthesia. Each group corresponded to a postsurgical evaluation date (one, seven, and 14 days). Results: At 14 postoperative days, the studied groups had no histological difference. However, the use of nylon thread showed greater evidence of earlier fibrotic union. Conclusion: This study found no histological difference in healing 14 days after surgery among the techniques and the types of suture threads. Level of Evidence II, Therapeutic Studies.

Programmed cell death 1 ligand 1 (PD-L1) expressed in non-immune cells is involved in immune-mediated tissue damage in the context of inflammatory conditions and tumor immune escape. Emerging evidence suggests soluble (s)PD-L1 as a marker of inflammation. Based on well-established sex-specific differences in immunity, we tested the novel hypotheses that (i) endothelial cell PD-L1 is modulated by inflammatory cytokines and vascular endothelial growth factor (VEGF) in a sex-specific fashion, and (ii) the endothelium is a source of sPD-L1. After exposure of human umbilical vein endothelial cells (HUVECs) to lipopolysaccharide, interleukin (IL)1β or VEGF for 24 h, total PD-L1 levels were upregulated solely in cells from female donors, while being unchanged in those from male donors. Accordingly, exposure to synovial fluids from patients with inflammatory arthritis upregulated PD-L1 levels in HUVECs from female donors only. Membrane PD-L1 expression as measured by flow cytometry was unchanged in response to inflammatory stimuli. However, exposure to 2 ng/mL IL-1β or 50 ng/mL VEGF time-dependently increased sPD-L1 release by HUVECs from female donors. Treatment with the metalloproteinase (MMP) inhibitor GM6001 (10 μM) prevented IL-1β-induced sPD-L1 release and enhanced membrane PD-L1 levels. The anti-VEGF agents bevacizumab and sunitinib reduced both VEGF-induced PD-L1 accumulation and sPD-L1 secretion. Thus, inflammatory agents and VEGF rapidly increased endothelial PD-L1 levels in a sex-specific fashion. Furthermore, the vascular endothelium may be a sPD-L1 source, whose production is MMP-dependent and modulated by anti-VEGF agents. These findings may have implications for sex-specific immunity, vascular inflammation and response to anti-angiogenic therapy.

Abstract Background Adipose-derived stromal cells (ASCs) possess a multitude of regenerative capabilities, which include immunomodulation, angiogenesis, and stimulation of extracellular matrix (ECM) remodeling. However, the underlying mechanisms leading to ECM remodeling remain largely elusive and highlight the need for functional in vitro models for mode of action studies. Therefore, the purpose of this study was to develop an in vitro co-culture model to investigate the capabilities of ASCs to modulate fibroblasts and ECM. Methods An ECM in vitro model with ASCs and normal human dermal fibroblasts (NHDFs) was established utilizing macromolecular crowding, ascorbic acid, and TGF-β stimulation. Paracrine and juxtacrine co-cultures were created using transwell inserts and cell cultures with direct cell–cell contacts. The cultures were screened using RT2 PCR Profiler Arrays; the protein levels of myofibroblast differentiation marker alpha smooth muscle actin (αSMA) and ECM remodeling enzymes were analyzed using western blot on cell lysates; the formation of collagen type I, III, VI, and fibronectin was investigated using ELISA on culture supernatants; and the deposition of collagens was analyzed using immunocytochemistry. Results TGF-β stimulation of NHDF monocultures increased the expression of 18 transcripts relevant for ECM formation and remodeling, the protein levels of αSMA and matrix metalloproteinase-2 (MMP-2), the formation of collagen type I, III, VI, and fibronectin, and the deposition of collagen type I and VI and decreased the protein levels of MMP-14. Inclusion of ASCs in the ECM co-culture model increased the formation of collagen type I and III through paracrine mechanisms and the formation of collagen type VI through juxtacrine mechanisms. Conclusions The co-culture model provides effective stimulation of NHDF monocultures by TGF-β for enhanced formation and deposition of ECM. In the model, ASCs induce changes in ECM by increasing formation of collagen type I, III and VI. The obtained results could guide further investigations of ASCs’ capabilities and underlying mechanisms related to ECM formation and remodeling.

Osteoarthritis is one of the most common chronic diseases, which is characterized by the destruction of joint cartilage and leads to changes in the structure of other joint elements, the formation of osteophytes and the development of inflammation in the immediate area. Precise assessment of the frequency and distribution of the disease in the population may be difficult due to the inconsistent definition of the disease and the selected diagnostic criteria, but it is estimated that it may occur in up to 60% of the elderly population, more often in women than men. There are many documented risk factors for the occurrence of the disease, such as age or genetic predisposition, but the modifiable ones deserve special attention. Recently, great emphasis in the context of osteoarthritis has been put on the fight against obesity, which not only increases the mechanical load on the joints, but also intensifies the generalized inflammation in the cartilage and its surroundings. This is one of the reasons why non-pharmacological therapy, i.e. patient education and physiotherapy, is a basic element of management, both alone and in combination with pharmacological treatment. The most common drugs used in OA are non-opioid analgesics from the lowest level of the analgesic ladder - mainly NSAIDs, and their proven effectiveness is consistent with the current concept of inflammation as the main pathogenetic factor. As a second-line treatment, injections of glucocorticoids, hyaluronic acid (HA) and platelet-rich plasma (PRP) directly into the joint may be considered. Unfortunately, most randomized studies show that the administration of steroids is effective, but the effects are relatively short-lived, up to a few weeks, while more reliable scientific evidence is needed to confirm the effectiveness of other substances.

Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how the PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, that HC-descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, postnatal day 10 (p10) HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling, and consistent with the implied regulatory role, in Mmp14ΔHC mutants, PTH signaling is enhanced. We found that HC-derived osteoblasts contribute ~50% of osteogenesis promoted by treatment with PTH 1–34, and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non-HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated modulation of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation. [ABSTRACT FROM AUTHOR]

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2, which requires cleavage of its spike protein (S) at two sites: S1/S2 and S2′. This study investigates the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. The assays used were cell-to-cell fusion in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increased cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduced cell-to-cell fusion by promoting the cellular degradation of ACE2. SKI-1 activity led to enhanced S2′ formation, which was attributed to increased metalloprotease activity as a response to enhanced cholesterol levels via activated SREBP-2. However, high metalloprotease activity resulted in the shedding of S2′ into a new C-terminal fragment (S2″), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2″ formation abolished S2′ and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2″ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested the binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) represents the highest degenerative disorder. Because cartilage erosion is a common pathological alteration in OA, targeting some key metalloproteinases such as MMP-3, ADAMTS-5 besides their inhibitor TIMP-3 by natural products, could be an effective strategy to protect against osteoarthritis. Forty female Wister rats were categorized into five equal groups. Control, osteoarthritic (OA) (monosodium iodoacetate (MIA) 2 mg/50 µL saline, single intra-articular injection), OA+ indomethacin (2 mg/kg/daily/orally), OA+ nano-naringenin (25 mg/kg/daily/orally), and OA+ Amphora coffeaeformis (772 mg/kg/daily/orally). Treatments were initiated on the 8th day after osteoarthritis induction and continued for 28 days thereafter. Finally, blood and knee joint samples were collected from all rats for biochemical and histopathological evaluations. The current study showed that MIA induced oxidative stress, which resulted in changes in the inflammatory joint markers associated with increased right knee diameter and higher clinical scores for lameness. Amphora coffeaeformis followed by nano-naringenin exhibited a potential anti-arthritic activity by reducing the concentrations of serum MMP-3, ADAMTS-5, and joint MDA and increasing the levels of serum TIMP-3 and joint GSH, similar to indomethacin. The histopathological results confirmed these outcomes. In conclusion, Amphora coffeaeformis and nano-naringenin can be considered as natural therapeutic agents for osteoarthritis owing to their antioxidant and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

We analyzed the associations of the mechanical strength of dilated ascending aorta wall (intraoperative samples from 30 patients with non-syndromic aneurysms) with tissue MMPs and the cytokine system. Some samples were stretched to break on an Instron 3343 testing machine and the tensile strength was calculated; others were homogenized and the concentrations of MMP-1, MMP-2, MMP-7, their inhibitors (TIMP-1 and TIMP-2), and pro- and anti-inflammatory cytokines were determined by ELISA. Direct correlations between aortic tensile strength and concentrations of IL-10 (r=0.46), TNFα (r=0.60), and vessel diameter (r=0.67) and an inverse correlation with patient's age (r=-0.59) were revealed. Compensatory mechanisms supporting the strength of the ascending aortic aneurysm are possible. No associations of MMP-1, MMP-7, TIMP-1, and TIMP-2 with tensile strength and aortic diameter were found. [ABSTRACT FROM AUTHOR]

During tuberculosis (TB) infection, B-lymphocytes migrate to the lungs and form B-cell follicles (BCFs) in the vicinity of TB granulomata. B-cell-lacking mice display enhanced susceptibility to TB infection, and early B-cell depletion in infected non-human primates alters T-lymphocyte cytokine responses and increases bacterial burdens in the lungs. However, the role of B cells during late TB stages remained unaddressed. Here, we demonstrate that B cells and BCFs persist up to weeks 25–45 post-challenge in the lungs of TB-resistant C57BL/6 (B6) mice. In hyper-susceptible I/St mice, B-cell content markedly drops between weeks 12–16 post-infection, paralleled by diffuse lung tissue inflammation and elevated gene expression levels for pro-inflammatory cytokines IL-1, IL-11, IL-17a, and TNF-α. To check whether B-cells/BCFs control TB infection at advanced stages, we specifically depleted B-cells from B6 mice by administrating anti-CD20 mAbs at week 16 post-infection. This resulted in more rapid cachexia, a shortened lifespan of the infected animals, an increase in (i) lung-infiltrating CD8+ T cells, (ii) IL-6 production by F4/80+ macrophages, (iii) expression levels of genes for neutrophil-attracting factors CXCL1 and IL-17, and tissue-damaging factors MMP8, MMP9, and S100A8. Taken together, our results suggest that lung B cells and BCFs are moderately protective against chronic TB infection. [ABSTRACT FROM AUTHOR]

The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of the MMP profile in cardiac surgery. All studies meeting the inclusion criteria (i.e., those reporting detailed data about MMP release during and after CPB) were selected after screening the literature published between July 1975 and August 2022. Fifteen trials that enrolled a total of 431 participants were included. MMP levels were found to be significantly correlated with CPB in all included studies. The gelatinases MMP-2 and MMP-9 were highly released in cardiac surgery with CPB. MMP-9 levels were found to be increased after CPB start and during the duration of CPB. Particularly, it is overexpressed both in the myocardial tissue and circulating in the bloodstream. Also, MMP-2 levels increased after CPB both in plasma and in myocardial tissue. MMP-7, MMP-8, and MMP-13 levels increased after CPB start and remained elevated up to 6 h later. Increased levels of MMPs were associated with adverse post-operative outcomes. Conversely, TIMP-1 decreased with CPB. Mechanical and pharmacological strategies were applied in two studies to analyze their effect on the inflammatory response to cardiac surgery and CPB and on postoperative outcomes. New targeted MMP inhibitor therapies could protect against systemic inflammatory response syndrome after CPB and should be the subject of future large prospective multicenter randomized clinical trials. [ABSTRACT FROM AUTHOR]

Platelet-specific collagen receptor glycoprotein (GP)VI is stable on the surface of circulating platelets but undergoes ectodomain cleavage on activated platelets. Activation-dependent GPVI metalloproteolysis is primarily mediated by A Disintegrin And Metalloproteinase (ADAM) 10. Regulation of platelet ADAMs activity is not well-defined however Tissue Inhibitors of Metalloproteinases (TIMPs) may play a role. As levels of TIMPs on platelets and the control of ADAMs-mediated shedding by TIMPs has not been evaluated, we quantified the levels of TIMPs on the surface of resting and activated platelets from healthy donors by flow cytometry and multiplex ELISA. Variable levels of all TIMPs could be detected on platelets. Plasma contained significant quantities of TIMP1 and TIMP2, but only trace amounts of TIMP3 and TIMP4. Recombinant TIMP3 strongly ablated resting and activated platelet ADAM10 activity, when monitored using a quenched fluorogenic peptide substrate with ADAM10 specificity. Whilst ADAM10-specific inhibitor GI254023X or ethylenediamine tetraacetic acid (EDTA) could modulate ligand-initiated shedding of GPVI, only recombinant TIMP2 achieved a modest (~20%) inhibition. We conclude that some platelet TIMPs are able to modulate platelet ADAM10 activity but none strongly regulate ligand-dependent shedding of GPVI. Our findings provide new insights into the regulation of platelet receptor sheddase activity. What do we know? Platelet receptor GPVI initiates platelet adhesion and aggregation and is proteolytically cleaved from the activated platelet surface The metalloproteinases responsible belong to the ADAMs family of enzymes which are inhibited by TIMPs What did we discover? Plasma contains significant amounts of TIMP1 and TIMP2 Circulating platelets bear significant amounts of TIMPs 1, 2, and 3 Recombinant TIMP3 strongly inhibits resting and activated platelet ADAM10 activity Exogenous addition of TIMP2 mildly blocked ligand-initiated shedding of GPVI What is the impact? TIMPs may modulate ADAM10 activity under resting conditions and stabilize GPVI levels in response to platelet activation Anti-GPVI agents are being evaluated as anti-thrombotic agents, however, acute loss of GPVI in trauma or settings of thrombocytopenia is linked with clinical bleeding Understanding how GPVI levels are regulated is important as agents that modulate GPVI function are emerging as important therapeutics for clinical applications in Thrombosis and Hemostasis fields [ABSTRACT FROM AUTHOR]

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Introduction: In the course of evolution, humans developed a number of complex multi-step wound healing mechanisms which limit the infectious agents access to the bloodstream, protect the organism from blood loss, and restore skin integrity. The process of skin wound healing includes the following stages: haemostasis, inflammation, proliferation, and remodeling. These processes are possible because of modulators, growth factors, cytokines, matrix metalloproteinases and cellular receptors, as well as some trace elements like zinc. Materials and Methods: The presented data was analyzed and compiled using all relevant articles describing the role of zinc in blood coagulation, proliferation, damaged tissues regeneration and angiogenesis. Results and Discussion: There are some on-going studies about zinc effects on blood coagulation, proliferation, damaged tissues regeneration and angiogenesis. However, molecular mechanisms of these processes are not yet fully understood and require further study. The analysis of scientific efforts to investigate the role of zinc in wound healing molecular mechanisms is especially relevant to the understanding of treatment of skin wound injuries. Conclusion: Wound healing is a complex multi-phase process consisting of several phases. Each stage involves metal ions, primarily zinc, which stimulates re-epithelialization, decreases inflammation and bacterial growth. The use of known zinc-based drugs is accompanied by side effects and low efficacy due to low skin absorption. These factors significantly limit use of such drugs and highlight the urgency of finding new, more effective and safe treatment. The emerging field of nanobiotechnology may provide an alternative platform to develop new therapeutic agents for the wound healing process. [ABSTRACT FROM AUTHOR]

Metalloproteinases (MPs) is a large family of proteinases with metal ions in their active centers. According to the different domains metalloproteinases can be divided into a variety of subtypes mainly including Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteases (ADAMs) and ADAMs with Thrombospondin Motifs (ADAMTS). They have various functions such as protein hydrolysis, cell adhesion and remodeling of extracellular matrix. Metalloproteinases expressed in multiple types of cancers and participate in many pathological processes involving tumor genesis and development, invasion and metastasis by regulating signal transduction and tumor microenvironment. In this review, based on the current research progress, we summarized the structure of MPs, their expression and especially immunomodulatory role and mechanisms in cancers. Additionally, a relevant and timely update of recent advances and future directions were provided for the diagnosis and immunotherapy targeting MPs in cancers. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (KIRC) is the most common and aggressivemalignancy subtype of renal neoplasm that arises from proximal convoluted tubules. It is characterized by poor clinical outcomes and high mortality of patients due to the lack of specific biomarkers for varying stages of the disease and no effective treatment. Proteases are associated with the development of several malignant tumors in humans by their ability to degrade extracellular matrices, facilitating metastasis. Herein, differentially expressed genes in KIRC cases compared to healthy kidneys were screened out from the Gene Expression Profiling Interactive Analysis (GEPIA) database. This data was applied to determine the most elevated protease in KIRC and as a result, A Disintegrin and Metalloproteinase Domain-Like Protein Decysin-1 (ADAMDEC1) was selected. This expression pattern was exclusive for KIRC and not observed for papillary and chromophobe renal cell carcinomas, in which ADAMDEC1 was at the same level in tumors and non-cancer specimens. Furthermore, the ADAMDEC1 significant increase was detected in the fourteen other human malignancies compared to healthy samples, which suggested its strong involvement in cancer development. Next, GEPIA and Pathology Atlas correlated ADAMDEC1 high expression with more advanced tumor grade and shorter survival of KIRC patients. Xena Functional Genomics Explorer presented that ADAMDEC1 could be hypermethylated in some tumor cases and one somatic mutation in the gene sequence was detected. Finally, a Search Tool for the Retrieval of Interacting Genes/Proteins; STRING base was utilized to predict the interactions of ADAMDEC1 with other molecules and construct the signaling network. In summary, ADAMDEC1 showed the tremendous potential to be the predictive marker for the KIRC and its development. Therefore, this review with data analysis can be a good base for further in vitro and in vivo research that experimentally can confirm the ADAMDEC1 as prognostic biomarkers and therapeutic target of KIRC. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) play a crucial role in the degenerative course of rheumatic disorders. They are responsible for cartilage and other joint-associated tissues breakdown. Amid arthritis treatments, photobiostimulation (PBM), a non-thermal and non-invasive low-power laser application, appears to be an outstanding therapy alternative once it has succeeded in MMPs modulation. Thus, this study aimed to evaluate the PBM effects of low infrared laser (830 nm), testing two different energy densities (3 and 30 Jcm−2) in MMP-2, MMP-9, MMP-13, and MMP-14 as well as the inhibitor TIMP-2 expressions using zymosan-induced arthritis model. C57BL/6 mice were distributed into four groups (n = 8): zymosan-induced arthritis without treatment; zymosan-induced arthritis and dexamethasone-treated; zymosan-induced arthritis and PBM at energy density of 3 Jcm−2 treated; and zymosan-induced arthritis and PBM at energy density of 30 Jcm−2 treated. MMPs and TIMP-2 mRNA relative levels by qRT-PCR and proteins expression by immunohistochemical and Western blotting techniques were performed after PBM treatment in the inflamed joint. Our results demonstrated PBM could modulate both mRNA relative levels and proteins expression of the MMP-2, -9, -13, -14, and TIMP-2 in joint tissues, decreasing MMP-9 protein expression and increasing TIMP-2 protein expression. PBM promotes a better arthritis prognostic, modulating metalloproteinase and its inhibitor, especially MMP-9 and TIMP-2 protein expression that is important inflammatory markers. These findings may also corroborate that PBM may regulate MMPs expression using different pathways. [ABSTRACT FROM AUTHOR]

Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis (HGA), is an obligate intracellular bacterium transmitted by the bite of black-legged ticks, Ixodes scapularis. The main host cells in vertebrates are neutrophils. However, the first site of entry is in the skin during tick feeding. Given that the initial responses within skin are a crucial determinant of disease outcome in vector-borne diseases, we used a non-biased approach to characterize the transcriptional changes that take place at the bite during I. scapularis feeding and A. phagocytophilum transmission. Experimentally infected ticks were allowed to feed for 3 days on C57BL/6J mice to allow bacterial transmission and establishment. Skin biopsies were taken from the attachment site of uninfected ticks and A. phagocytophilum-infected ticks. Skin without ticks (intact skin) was used as baseline. RNA was isolated and sequenced using next-generation sequencing (NGS). The differentially expressed genes were used to identify over-represented pathways by gene ontology (GO) and pathway enrichment (PE). Anaplasma phagocytophilum transmission resulted in the activation of interferon signaling and neutrophil chemotaxis pathways in the skin. Interestingly, it also led to the downregulation of genes encoding extracellular matrix (ECM) components, and upregulation of metalloproteinases, suggesting that A. phagocytophilum delays wound healing responses and may increase vascular permeability at the bite site. [ABSTRACT FROM AUTHOR]

• Overexpression of ADAMTS6 results in an increase in TGFβ activation, when active TGFβ is added, and this increase is linked to the catalytic activity of ADAMTS6. • ADAMTS6 binds and cleaves LTBP3, as previously shown with LTBP1, which would disrupt the LLC and release active TGFβ. • ADAMTS10 and ADAMTSL2 also increase TGFβ activation but using a non-catalytic method. • ADAMTS6, ADAMTS10 and ADAMTSL2 all increase the mechanotension of the cell, which has been shown to aid the release of active TGFβ from its latent complex. The ADAMTS superfamily is composed of secreted metalloproteases and structurally related non-catalytic ADAMTS-like proteins. A subset of this superfamily, including ADAMTS6, ADAMTS10 and ADAMTSL2, are involved in elastic fiber assembly and bind to fibrillin and other matrix molecules that regulate the extracellular bioavailability of the potent growth factor TGFβ. Fibrillinopathies, that can also result from mutation of these ADAMTS/L proteins, have been linked to disrupted TGFβ homeostasis. ADAMTS6 and ADAMTS10 are homologous metalloproteases with poorly characterized substrates where ADAMTS10 is thought to process fibrillin-2 and ADAMTS6 latent TGFβ-binding protein (LTBP)-1. In order to understand the contribution of ADAMTS6, and these other members of the ADAMTS/L family, to TGFβ homeostasis, we have analyzed the effects of ADAMTS6, ADAMTS10 and ADAMTSL2 expression on TGFβ activation. We found that their expression increases TGFβ activation in a dose dependent manner, following stimulation with mature TGFβ1. For ADAMTS6, the catalytically active protease is required for effective TGFβ activation, where ADAMTS6 cleaves LTBP3 as well as LTBP1, and binds to the large latent TGFβ complexes of LTBP1 and LTBP3. Furthermore, ADAMTS6 expression increases the mechanotension of cells which results in inactivation of the Hippo Pathway, resulting in an increased translocation of YAP/TAZ complex to the nucleus. Together these findings suggest that when the balance of TGFβ is perturbed ADAMTS6 can influence TGFβ activation via two mechanisms. It directly cleaves the latent TGFβ complexes and also acts indirectly, along with ADAMTS10 and ADAMTSL2, by altering the mechanotension of cells. Together this increases activation of TGFβ from large latent complexes which may contribute to disease pathogenesis. [ABSTRACT FROM AUTHOR]

Study Question: Does basigin (BSG) regulate human endometrial stromal cell (HESC) decidualization in vitro?Summary Answer: BSG regulates HESCs proliferation and decidualization.What Is Known Already: Studies have shown that in the human endometrium, BSG expression is menstrual-cycle dependent and its expression was significantly lower in uterine endometrium during the luteal phase of women experiencing multiple implantation failures after IVF than in women with normal fertility.Study Design, Size, Duration: We utilized a telomerase-immortalized HESCs in an in vitro cell culture model system to investigate whether BSG regulates decidualization of stromal cells. Further, we used microarray analysis to identify changes in the gene expression profile of HESCs treated with BSG small interfering RNA (siRNA). All experiments were repeated at least three times.Participants/materials, Setting, Methods: The effect of BSG knockdown (using siRNA) on HESC proliferation was determined by counting cell number and by tritiated thymidine incorporation assays. The effect of BSG on decidualization of HESCs was determined by RT-qPCR for the decidualization markers insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL). Immunoblotting was used to determine the effect of BSG siRNA on the expression of MMP-2,3. Microarray analysis was used to identify BSG-regulated genes in HESCs at Day 6 of decidualization. Functional and pathway enrichment analyses were then carried out on the differentially expressed genes (DEGs). The STRING online database was used to analyze protein-protein interaction (PPI) between DEG-encoded proteins, and CytoScape software was used to visualize the interaction. MCODE and CytoHubba were used to construct functional modules and screen hub genes separately. Several BSG-regulated genes identified in the microarray analysis were confirmed by qPCR.Main Results and the Role Of Chance: Knockdown of BSG expression in cultured stromal cells by siRNA significantly (P < 0.05) inhibited HESC proliferation, disrupted cell decidualization and down-regulated MMP-2 and MMP-3 expression. Microarray analysis identified 721 genes that were down-regulated, and 484 genes up-regulated with P < 0.05 in BSG siRNA treated HESCs. GO term enrichment analysis showed that the DEGs were significantly enriched in cell communication, signaling transduction and regulation, response to stimulus, cell adhesion, anatomical structure morphogenesis, extracellular matrix organization, as well as other functional pathways. KEGG pathway analysis identified upregulated gene enriched in pathways such as the MAPK signaling pathway, colorectal cancer, melanoma and axon guidance. In contrast, downregulated genes were mainly enriched in pathways including ECM-receptor interaction, PI3K-Akt signaling pathway, pathways in cancer, antigen processing, type I diabetes mellitus and focal adhesion. The top 10 hub nodes were identified using 12 methods analyses. The hub genes that showed up in two methods were screened out. Among these genes, upregulated genes included EGFR, HSP90AA1, CCND1, PXN, PRKACB, MGAT4A, EVA1A, LGALS1, STC2, HSPA4; downregulated genes included WNT4/5, FOXO1, CDK1, PIK3R1, IGF1, JAK2, LAMB1, ITGAV, HGF, MXRA8, TMEM132A, UBE2C, QSOX1, ERBB2, GNB4, HSP90B1, LAMB2, LAMC1 and ITGA1. Hub genes and module genes involved in the top three modules of PPI analysis were analyzed through the string database. Analysis showed that hub and module genes were related mainly to the WNT signaling pathway, PI3K-AKT signaling pathway and pathways in cancer.Large Scale Data: The microarray data set generated in this study has been published online at databank.illinois.edu.Limitations, Reasons For Caution: Most of the findings were obtained using an in vitro cell culture system that may not necessarily reflect in vivo functions.Wider Implications Of the Findings: Our results demonstrate that BSG plays a vital role in decidualization and that downregulation of BSG in the uterine endometrium may be associated with infertility in women. The identified hub genes and pathways increase our understanding of the genetic etiology and molecular mechanisms underlying the regulation of decidualization by BSG.Study Funding/competing Interest(s): This work was supported by the NIH U54 HD40093 (R.A.N.). The authors have no competing interests to declare. [ABSTRACT FROM AUTHOR]

Background. Platelets play a fundamental role in myocardial infarction and the pathogenesis of ischemia/reoxygenation (I/R) injuries. They contain matrix metalloproteinases (MMPs) that are involved in arterial thrombosis. The MMP inhibitor doxycycline has been shown to exert protective effects in I/R injuries involving various organs and mechanisms. Objectives. To explore the influence of doxycycline on platelet activation and MMP-2 activity during I/R. Materials and methods. Platelets isolated from the blood of healthy human volunteers were subjected to chemical I/R conditions. The study included aerobic controls (AERO), I/R platelets and I/R platelets pretreated with doxycycline (I/R+D). The concentration of doxycycline used was standardized to 10 µM. The analysis of platelet activation markers and platelet microvesicles (PMVs) was performed using flow cytometry. Adenosine diphosphate (ADP)-induced and collagen-induced aggregation, as well as MMP-2 activity and its concentration in platelets were evaluated. Results. Doxycycline decreased the expression of activated glycoprotein IIb/IIIa on platelets (p = 0.043). Additionally, an increased expression of CD63 was observed in buffers containing PMVs after doxycycline administration (p = 0.043). The ADP-dependent aggregation of I/R platelets was significantly lower in comparison to AERO (p = 0.022). Furthermore, there was a stronger tendency of enhanced ADP-dependent aggregation in I/R platelets pretreated with doxycycline compared to platelets that underwent I/R without doxycycline. Higher MMP-2 activity was observed in I/R+D platelets compared to I/R platelets (p < 0.01). Conclusions. The inhibition of platelet MMP-2 by doxycycline attenuated platelet activation and protected platelets by preserving their aggregation ability. [ABSTRACT FROM AUTHOR]

Nature-based and sustainably sourced cosmetics have been dominating the area of skincare products worldwide. Due to their antioxidant and antiaging properties, compounds from cyanobacteria, such as carotenoids and phycobiliproteins, may replace synthetic ingredients in cosmetic formulations and may be used in products such as sunscreens, skincare creams, and makeup. In this study, we evaluated the potential of acetonic and aqueous extracts from cyanobacteria strains of the genera Cyanobium and Leptothoe and from strains within Synechococcales and Oscillatoriales orders, for use in cosmetics. Extractions were sequentially performed with acetone and water. Extracts were firstly analyzed for their toxicity to keratinocytes, fibroblasts, and endothelial cells (HaCAT, 3T3L1 and hCMEC/D3, respectively). The non-cytotoxic extracts were characterized in terms of total proteins, carotenoids, chlorophyll, phenols, phycobiliproteins, and analyzed for their antioxidant potential against the superoxide anion radical (O2•−), and for their ability to inhibit key enzymes associated with the skin aging process. Aqueous extracts were richer in total proteins and phycobiliproteins. The aqueous extracts of Synechococcales cyanobacterium LEGE 181157 and Synechococcales cyanobacterium LEGE 181150 showed the highest value for total proteins (760.81 and 695.25 μg BSA mL−1dry extract, respectively) and the best values regarding O2•− scavenging (IC50 = 63.24 and 112.18 μg mL−1dry extract, respectively) with a significant negative correlation observed (p < 0.01). Moreover, aqueous extracts of Synechococcales cyanobacterium LEGE 181150 and Synechococcales cyanobacterium LEGE 181157 inhibited hyaluronidase, (IC50 of 483.86 and 645.06 μg mL−1dry extract, respectively), with a significant negative correlation with total proteins (p < 0.05), pointing out the contribution of these compounds to the biological activities observed. Acetonic extracts were richer in carotenoids and phenols. Zeaxanthin and β-carotene were predominant among all strains, being present in higher amount in Cyanobium sp. LEGE 07175 (53.08 μg mg−1) and Leptothoe sp. LEGE 181156 (47.89 μg mg−1), respectively. The same strains also showed the highest values for collagenase inhibition at 750 μg mL−1dry extract (32.88 and 36.61%, respectively). Furthermore, Leptothoe sp. LEGE 181156 exhibited the lowest IC50 value for tyrosinase inhibition (465.92 μg mL−1dry extract) and Synechococcales cyanobacterium LEGE 181157 presented the best values for elastase inhibition (IC50 of 380.50 and IC25 of 51.43 μg mL−1dry extract). In general, cyanobacteria extracts demonstrated potential for being used for antiaging purposes, with aqueous extracts being more efficient at free radicals scavenging and acetonic ones at avoiding degradation of dermal matrix components. [ABSTRACT FROM AUTHOR]

The effect of photodynamic therapy (PDT) on the level of matrix metalloproteinases in squamous cell skin cancer (SCSC) was studied. The study involved 202 people, including 185 patients with SCSC, who were on outpatient and inpatient treatment in medical institutions of Engels and Saratov during the period from 2015 to 2019, and 17 donors. The study design included studies in three main groups. The first (intervention) group included 74 (36.6%) patients with SCSC who underwent combined treatment, including PDT at the first stage and surgical treatment at the second stage. The second group consisted of 111 (55.0%) patients with SCSC who underwent only surgical treatment. The third group consisted of 17 (8.4%) relatively healthy volunteer donors, comparable in age and sex with the patients of the main group. As a result of the study, it was found that the level of metalloproteinase-1 inhibitor (TIMP-1) in the blood serum of patients with SCSC was reduced compared with physiologically normal indicators, which led to a statistically significant increase in matrix metalloproteinases (MMPs) MMPs-2, MMPs-7 and MMPs-9. Performing only surgical treatment for this pathology does not lead to a complete recovery of these indicators. However, the use of combined treatment including PDT showed a statistically significant increase in the amount of TIMP-1 before the start of surgical treatment, which naturally led to a decrease in MMPs-2, MMPs-7 and MMPs-9. Later, after excision of the tumor, the patients of this group had a complete normalization of TIMP-1, which, in turn, contributed to a decrease and then restoration of the number of MMPs-2, MMPs-7 and MMPs-9 to physiologically normal values.

Abstract Background Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients. Methods Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls. Results After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan’s skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT. Conclusions Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.

The success in modern biology has significantly enriched scientific understanding of the pathogenetic basis underlying some diseases, including obstetric and gynecological practice. Despite this, the etiology and pathogenesis of some conditions are not yet fully elucidated. One of the approaches is to study metalloproteinases during pregnancy, particularly concerning occurrence of formidable complication such as preeclampsia, which diagnostics and significance have been continuously revised. Preeclampsia is a disease that leads altered course of pregnancy, and sometimes even to maternal and/or fetal death. Currently, no specific treatment for preeclampsia has been proposed, but early prognosis is crucial for a more favorable maternal and fetal outcome. Given that metalloproteinase activity is able to influence trophoblast invasion and remodeling of spiral arteries, insights into such processes are of high importance.

The article "Correction to: Anti-arthritic and immunomodulatory efficacy of Micromeria biflora Benth extract and its fractions in rats by restoring oxidative stress, metalloproteinases, pro-inflammatory and anti-inflammatory cytokines network" addresses an error in Figure 6 of the original publication. The mistake involved a cropped image in the panel labeled as MBAF, which was replaced with the correct image. The correction does not impact the study's overall conclusions or results. The authors express regret for any confusion caused and provide contact information for further inquiries. [Extracted from the article]

Skin aging and wrinkle formation are processes that are largely influenced by the overexpression of enzymes like tyrosinase, elastase, and collagenase. This study aimed to validate the skin anti-aging properties of phytochemicals from Peperomia pellucida (PP) as well as its attendant mechanism of action. Compounds previously characterized from PP were retrieved from the PubChem database and docked to the active sites of tyrosinase, elastase, and collagenase using Schrödinger’s Maestro 11.5 and AutoDock tools to predict compounds with the best inhibitory potential to block these enzymes in preventing skin aging. It was observed that our hit compounds had favorable affinity and displayed key interactions at the active sites of these enzymes similar to those of the standards. With elastase, we observed key interactions with the amino acids in the S1 sub-pocket (especially ALA-181), Zn chelation, and histidine residues, which are key for inhibitory activity and ligand stability. The hit compounds showed H-bonds with the key amino acids of collagenase, including LEU-185 and ALA-186; phlobaphene and patuloside B were found to have better docking scores and inhibition constants (Ki) (−12.36 Kcal/mol, 0.87 nM and −12.06 Kcal/mol, 1.45 nM, respectively) when compared with those of the synthetic reference compound (−12.00 Kcal/mol, 1.67 nM). For tyrosinase, our hit compounds had both better docking scores and Ki values than kojic acid, with patuloside B and procyanidin having the best values of −9.43 Kcal/mol, 121.40 nM and −9.32 Kcal/mol, 193.48 nM, respectively (kojic acid = −8.19 Kcal/mol, 898.03 nM). Based on this study, we propose that acacetin, procyanidin, phlobaphene, patulosides A and B, palmitic acid, and hexahydroxydiphenic acid are responsible for the anti-aging effects of PP on the skin, and that they work synergistically through a multi-target inhibition of these enzymes.

Healing of burn tissue is a complete process involving reepitelization, granulation tissue formation and extracellular matrix remodeling. Thermal injury produces profound systemic changes, such as oligemic shock, anemia, renal failure and metabolic disorders. This causes direct tissue damages: inflammation and infection reactions. The tissue lesion also leads to increased oxidative stress in cells, as it has been observed by the low activity of endogenous antioxidant enzymatic and nonenzymatic systems. In this context, tissue matrix metalloproteinases (MMP) plays a key role in normal physiology of conjunctive tissue during its development, morphogenesis or wound healing, having an irregular activity and being involved in the patho-physiological processes. The analysis of biological samples, MMP profiles contribute to the characterization of some processes involving tissue remodeling, processes related to wound or burn healing, possibly to the development of new therapies. In this context we studied the proliferative effect of levan, a polysaccharide produced by Gram negative bacteria, Zymomonas mobilis, a microorganism that plays an important role in modern biotechnology to produce substances of great interest in biotechnology, food industry or in biomedicine. Our studies focused on analysis of tissue MMPs profiles from Wistar rats with lesions caused by mechanic processes on skin (wounds) and thermal (burn), treated by hallotherapy in Cacica and Dej salt mines, before and after the treatment with levan. The results indicate that levan, a natural polysaccharide produced by wild type Z. mobilis NCIB 11163, as well as other bacterial strains, seems to have real value in the management of wounds and burns, applied individually or in combination with natural or artificial haloteraphy. The way that levan participates in the healing process is unknown, probably by activating the tissue metalloproteinases.

One of the inflammatory bowel diseases is Crohn’s disease. Although this term has been used in the medical community since 1932, a significant increase in the number of publications occurs at the end of the 20th century and the beginning of the 21st century. Crohn’s disease is a disease that cannot be fully cured. In many cases, it is chronic, i.e., recurrent. All preventive and therapeutic measures taken by doctors are aimed at inhibiting the development of the disease and minimizing the occurrence of any potential “side effects” resulting from the developing disease. One of the diagnostic methods is the qualitative and quantitative determination of metalloproteinases in inflammatory tissues and in the blood. The aim of the study was the quantitative and qualitative determination of metalloproteinases in inflammatory bowel tissues in patients diagnosed with Crohn’s disease. The in vitro study was performed on surgical tissues from patients diagnosed with Crohn’s disease. The results show that in inflammatory tissues the concentration of metalloproteinases -3, -7, -8, -9 was higher compared to tissues taken from the resection margin without signs of inflammation, defined as healthy. The experiment confirmed that the biochemical test, which is the determination of metalloproteinases in tissues, is a useful diagnostic tool to differentiate inflammatory from non-inflammatory tissues.

Crohn’s disease is a chronic inflammatory bowel disease that affects the ileum and/or large intestine. At the same time, it can also affect any other part of the human body, i.e., from the mouth to the anus. In Crohn’s disease, the physiology and functioning of the epithelial barrier are inhibited due to the correlation of various factors, such as the environment, genetic susceptibility or intestinal microbiota. The symptoms are very troublesome and cause a significant reduction in quality of life, sometimes occurring with paralyzing permanent damage to the digestive tract, requiring enteral or parenteral nutrition throughout life. In order to make a proper and accurate diagnosis, an appropriately selected diagnostic path in a given clinical entity is necessary. Standard diagnostic methods are: laboratory examination, histopathological examination, endoscopic examination, X-ray, computed tomography, ultrasound examination and magnetic resonance imaging. Medical biology and the analysis of metalloproteinases have also proved helpful in diagnosing changes occurring as a result of Crohn’s disease. Here we provide a thorough review of the latest reports on Crohn’s disease and its genetic conditions, symptoms, morphology, diagnosis (including the analysis of Crohn’s disease biomarkers, i.e., metalloproteinases) and treatment.

BackgroundVascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers.MethodsWe assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination.ResultsA total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465–832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314–546) and 427 (365–513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (−6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%).ConclusionCombining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.

New data have been obtained for assessing the expression of genes of metalloproteinases and their tissue inhibitors (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2) in the Ligamentum flavum in patients with lumbar stenosis of spinal canal and dural sac. The features of the metabolism of the extracellular matrix (ECM) were revealed, the data obtained were compared with those for previously studied candidate genes. The search for relationships with the features of the ECM metabolic characteristics was carried out.The aim. To study the expression of genes of metalloproteinases and their tissue inhibitors in intraoperative biopsies of the Ligamentum flavum of patients with lumbar stenosis of the spinal canal and dural sac.Materials and methods. A group of 33 people (17 women, 16 men) with lumbar stenosis of the spinal canal and dural sac was studied; the average age is 45.73 ± 1.95 years. RNA was isolated from intraoperative biopsies of the Ligamentum flavum, reverse transcription was performed, and PCR using specific primers was performed.Results. In Ligamentum flavum of patients with stenosing processes of the spinal canal and dural sac, an increased activity of MMP-1 and insufficient response of TIMP-1 and TIMP-2 were found; the expression of MMP-1 increased synchronously with Dio2, and both genes decreased their activity with increasing age of the patient. In patients with Ligamentum flavum ossification, the MMR-8 gene was more actively expressed, and the synthesis of the mRNA of the MMR-9 gene decreased compared to the subgroup without ossification.

Direct oral anticoagulants (DOACs) are currently recommended by European guidelines as the first line therapy for both stroke prevention in patients with atrial fibrillation (AF) and the prevention and the treatment of venous thromboembolism (VTE). Recently, it has been speculated that DOACs have anti-inflammatory capabilities in reducing the abnormal release of pro-inflammatory factors in addition to inhibiting the activation of factor X or factor II of the coagulation cascade. However, this hypothesis is based on limited pathophysiological data with small sample size, often on in vitro studies. Real-world, in vivo, and large clinical data are scarce. The aim of the present study was the evaluation of the possible anti-inflammatory and anti-proliferative effects of DOACs treatment in a cohort of patients affected by AF or VTE, by analyzing an extensive panel of cytokines and molecules involved in the process of vascular and tissue remodeling. Our data evidenced that DOACs treatment is associated with variations in systemic inflammation markers and in metalloproteinases. Further studies with larger number of patients are required to confirm these data.

The increasing industrial use of vanadium (V), as well as its recent medical use in various pathologies has intensified its environmental release, making it an emerging pollutant. The sea urchin embryo has long been used to study the effects induced by metals, including V. In this study we used an integrated approach that correlates the biological effects on embryo development with proteolytic activities of gelatinases that could better reflect any metal-induced imbalances. V-exposure caused morphological/morphometric aberrations, mainly concerning the correct distribution of embryonic cells, the development of the skeleton, and the embryo volume. Moreover, V induced a concentration change in all the gelatinases expressed during embryo development and a reduction in their total proteolytic activity. The presence of three MMP-like gelatinases (MMP-2, -9, and -14) was also demonstrated and their levels depended on V-concentration. In particular, the MMP-14-like protein modified its expression level during embryo development in a time- and dose-dependent manner. This enzyme also showed a specific localization on filopodia, suggesting that primary mesenchyme cells (PMCs) could be responsible for its synthesis. In conclusion, these results indicate that an integrated study among morphology/morphometry, proteolytic activity, and MMP-14 expression constitutes an important response profile to V-action. [ABSTRACT FROM AUTHOR]

As a type of metalloproteinase, matrix metalloproteinases (MMPs) can be divided into collagenase, gelatinase, stromelysins, membrane-type (MT)-MMPs and heterogeneous subgroups according to their structure and function. MMP contents in the human body are strictly regulated, and their synthesis, activation and inhibition processes should be kept in a certain balance; otherwise, this would result in the occurrence of various diseases. Rheumatoid arthritis (RA) is a known immune-mediated systemic inflammatory disease that is affected by a variety of endogenous and exogenous factors. In RA development, MMPs act as important mediators of inflammation and participate in the degradation of extracellular matrix substrates and digestion of fibrillar collagens, leading to the destruction of joint structures. Interestingly, increasing evidence has suggested that herbal medicines have many advantages in RA due to their multitarget properties. In this paper, literature was obtained through electronic databases, including the Web of Science, PubMed, Google Scholar, Springer, and CNKI (Chinese). After classification and analysis, herbal medicines were found to inhibit the inflammatory process of RA by regulating MMPs and protecting joint structures. However, further preclinical and clinical studies are needed to support this view before these herbal medicines can be developed into drugs with actual application to the disease. [ABSTRACT FROM AUTHOR]

The transmembrane zinc metalloprotease ZMPSTE24 works in cooperation with interferon-induced transmembrane protein 3 (IFITM3) to restrict entry of several enveloped viruses. We investigated the role of ZMPSTE24 in porcine reproductive and respiratory syndrome virus (PRRSV) replication. ZMPSTE24 overexpression significantly reduced PRRSV replication in MARC-145 cells. Interestingly, knockdown of endogenous ZMPSTE24 did not significantly impact virus replication. There was no significant difference in the percentage of PRRSV-positive cells and viral RNA copies at 3 hours postinfection (hpi) between cells transfected with ZMPSTE24-FLAG and the vector control. Our results suggest that ZMPSTE24 overexpression may restrict PRRSV replication at a post-entry step. [ABSTRACT FROM AUTHOR]

Background: Metalloproteinases are proteolytic enzymes that degrade dentin and periodontal collagen; therefore, it is of special interest that dental students know its mechanism of action and how its effects can be inhibited. Therefore, the aim of this research was to evaluate the level of knowledge about metalloproteinases in dental students close to graduate from three universities in Peruvian capital city. Materials and methods: In this analytical, observational, cross‐sectional and prospective study, 223 dental students close to graduate in three Peruvian universities were evaluated from September to November 2020. A questionnaire of 20 closed questions with three answers was validated and used to measure the level of general and dental knowledge about metalloproteinases. A logit model was used to evaluate the influence of the following variables: "gender" (X1), "type of university" (X2), "marital status" (X3) and "age group" (X4), in the knowledge levels of the students, considering a p‐value <.05. Results: Of the 223 dentistry students, it was obtained that the level of knowledge about metalloproteinases was predominantly low with 82.1%, (95% confidence interval (CI): 77.1%–87.1%) of the total. According to multivariate logistic regression analysis, "type of university" was the only variable that proved to have a significant influence (p =.022) on the level of knowledge about metalloproteinases with an odds ratio of (OR = 0.44; CI: 0.21–0.89), whilst the other variables "age group" (p >.05), "gender" (p =.058) and "marital status" (p =.114) were not considered influential factors. Conclusion: The majority of final year dental students in three Peruvian universities presented a low level of overall knowledge about metalloproteinases. In addition, private university students were 56% less likely to pass the subject knowledge test. On contrary, gender, age group and marital status did not significantly influence the level of knowledge of the students. [ABSTRACT FROM AUTHOR]

Tendinopathy is a common tendon disorder that causes pain, loss of strength and function, and local inflammation mainly characterized by hypoxia, collagen degradation, and extracellular matrix (ECM) disorganization. Generally, ECM degradation and remodeling is tightly regulated; however, hyperactivation of matrix metalloproteases (MMPs) contributes to excessive collagenolysis under pathologic conditions resulting in tendon ECM degradation. This review article focuses on the production, function, and signaling of matrikines for tendon regeneration following injury with insights into the expression, tissue compliance, and cell proliferation exhibited by various matrikines. Furthermore, the regenerative properties suggest translational significance of matrikines to improve the outcomes post-injury by assisting with tendon healing. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles (SLNs) containing rutin were prepared to enhance their photochemopreventive effect on the skin. SLNs were produced by the hot melt microemulsion technique. Two 3D skin models: ex vivo skin explants and 3D tissue engineering skin were used to evaluate the photochemopreventive effect of topical formulations containing rutin SLNs, against ultraviolet B (UVB) radiation, inducing sunburn cells, caspase-3, cyclobutane pyrimidine dimers, lipid peroxidation, and metalloproteinase formation. The rutin SLNs presented average size of 74.22 ± 2.77 nm, polydispersion index of 0.16 ± 0.04, encapsulation efficiency of 98.90 ± 0.25%, and zeta potential of −53.0 ± 1.61 mV. The rutin SLNs were able to efficiently protect against UVB induced in the analysed parameters in both skin models. Furthermore, the rutin SLNs inhibited lipid peroxidation and metalloproteinase formation. These results support the use of rutin SLNs as skin photochemopreventive agents for topical application to the skin. [ABSTRACT FROM AUTHOR]

Background/Purpose: Localized scleroderma (LS) is a rare disease leading to progressive hardening and induration of the skin and subcutaneous tissues. LS is responsive to UVA‐1 phototherapy, though its exact mechanism of action dermal fibrosis is yet to be fully elucidated. We aimed to investigate the molecular changes induced by UVA‐1 rays in human primary fibroblasts cultures. Methods: A total of 16 LS patients were treated with medium‐dose UVA‐1 phototherapy. At baseline, during and after therapy, Localized Scleroderma Assessment Tool, Dermatology Life Quality Index and lesions' staging and mapping were performed along with high‐frequency ultrasound (HFUS) examination for dermal thickness assessment. Gene expression analysis for 23 mRNA transcripts, in vitro UVA‐1 irradiation and viability tests were realized on lesional fibroblasts' primary cultures, before and 3 months after therapy. Results: The dermal thickness, the LoSCAT and the DLQI progressively decreased starting from the last phototherapy session up to the 6 and 9 month follow‐ups (−57% and −60%, respectively). Molecular gene analysis (rt‐PCR) revealed that UVA‐1 phototherapy exerts multiple effects: the activation of specific anti‐fibrotic pathways (e.g., overexpression of CTHRC1 and metalloproteases 1, 2, 7, 8, 9, 12, suppression of TIMP‐1), the downregulation of peculiar pro‐fibrotic pathways (e.g., downregulation of TGF‐ß, TGF‐ßrII, Grb2, SMAD 2/3, TNRSF12A, CTGF) through a significant overexpression of IL‐1ß; the stabilization of collagen synthesis acting on genes COL1A1, COL3A1, COL8A1, COL10A1, COL12A1. Conclusion: UVA‐1 phototherapy adds significant benefits in local tissue remodeling, rebalancing the alteration between pro‐fibrotic and anti‐fibrotic pathways; these changes can be well monitored by HFUS. [ABSTRACT FROM AUTHOR]

Snakebite envenoming is a neglected tropical disease (NTD) that results from the injection of snake venom of a venomous snake into animals and humans. In Africa (mainly in sub-Saharan Africa), over 100,000 envenomings and over 10,000 deaths per annum from snakebite have been reported. Difficulties in snakebite prevention and antivenom treatment are believed to result from a lack of epidemiological data and underestimated figures on snakebite envenoming-related morbidity and mortality. There are species- and genus-specific variations associated with snake venoms in Africa and across the globe. These variations contribute massively to diverse differences in venom toxicity and pathogenicity that can undermine the efficacy of adopted antivenom therapies used in the treatment of snakebite envenoming. There is a need to profile all snake venom proteins of medically important venomous snakes endemic to Africa. This is anticipated to help in the development of safer and more effective antivenoms for the treatment of snakebite envenoming within the continent. In this review, the proteomes of 34 snake venoms from the most medically important snakes in Africa, namely the Viperidae and Elipdae, were extracted from the literature. The toxin families were grouped into dominant, secondary, minor, and others based on the abundance of the protein families in the venom proteomes. The Viperidae venom proteome was dominated by snake venom metalloproteinases (SVMPs–41%), snake venom serine proteases (SVSPs–16%), and phospholipase A2 (PLA2–17%) protein families, while three-finger toxins (3FTxs–66%) and PLA2s (16%) dominated those of the Elapidae. We further review the neutralisation of these snake venoms by selected antivenoms widely used within the African continent. The profiling of African snake venom proteomes will aid in the development of effective antivenom against snakebite envenoming and, additionally, could possibly reveal therapeutic applications of snake venom proteins. [ABSTRACT FROM AUTHOR]

Increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of snake venoms. However, the complexity of animal venoms and the extreme synergy of the venom components during envenomation calls for critical review and analysis. The epithelium is a primary target for injected viper venom's toxic substances, and therefore, is a focus in modern toxinology. We used the Vero epithelial cell line as a model to compare the actions of a crude Macrovipera lebetina obtusa (Levantine viper) venom with the actions of the same venom with two key enzymatic components inhibited (specifically, phospholipase A2 (PLA2) and metalloproteinases) in the bioenergetic cellular response, i.e., oxygen uptake and reactive oxygen species generation. In addition to the rate of free-radical oxidation and lipid peroxidation, we measured real-time mitochondrial respiration (based on the oxygen consumption rate) and glycolysis (based on the extracellular acidification rate) using a Seahorse analyzer. Our data show that viper venom drives an increase in both glycolysis and respiration in Vero cells, while the blockage of PLA2 or/and metalloproteinases affects only the rates of the oxidative phosphorylation. PLA2-blocking in venom also increases cytotoxic activity and the overproduction of reactive oxygen species. These data show that certain components of the venom may have a different effect within the venom cocktail other than the purified enzymes due to the synergy of the venom components. [ABSTRACT FROM AUTHOR]