Tissue Inhibitor Of Metalloproteinase Research Articles

Role of viral load and host cytokines in determining the disease severity of Respiratory Syncytial Virus associated acute lower respiratory tract infections in children.

Respiratory syncytial virus disease (RSV) is an important cause of acute lower respiratory tract infection. This study aimed to evaluate the role of viral load and cytokines, including MMP-9 and TIMP-1, in determining the severity of RSV disease and to identify potential biomarkers of disease severity. 142 patients of RSV (>2 months to <5 years of age) presenting with acute lower respiratory tract infection (ALRTI) between December 2013 to March 2016 were enrolled. Their nasopharyngeal aspirate was subjected to RSV viral load quantification and local cytokine levels of IL-6, TNF, IL-17A, IFN-Ƴ and IL-10 as determined using cytokine bead array. Levels of MMP-9 and TIMP-1 were calculated using Quantikine ELISA on 109 aspirates. These parameters were compared against different categories of disease severity. A higher viral load and increased levels of TNFα, MMP-9 and MMP-9:TIMP-1 were associated with greater severity of disease; while levels of IL-17a, IFN-Ƴ, and IFN-Ƴ:IL-10 were associated with disease resolution. In defining transition from non-severe to severe disease, MMP-9 had a sensitivity and specificity of 89.7% and 85.4%, respectively and MMP-9:TIMP-1 had a sensitivity and specificity of 87.2% and 76.8% respectively. Hence, MMP-9, MMP-9:TIMP-1, TNFα and IL-10 could serve as potential biomarkers for disease progression in RSV-infected children.

SIGNIFICANCE OF TISSUE INHIBITOR METALLOPROTEINASE-1 IN THE PATHOGENESIS BREAST CANCER

Tissue metalloproteinase inhibitors (MPTIs) play an important role in the pathogenesis of breast cancer (BC). Although recent studies have shown the dual role of MPTIs in the development of this pathology, it has been proven that they inhibit the activity of metalloproteinases prevent invasiveness and tumor recurrence. Conducting extensive research towards studying the antitumor effect of these protease inhibitors, especially MPTI-1, may allow the development of new drugs for the treatment of breast cancer.

PDE-5-Inhibited BMSCs Alleviate High Glucose-Induced Myocardial Fibrosis and Cardiomyocyte Apoptosis by Activating the cGMP/PKG Pathway.

Phosphodiesterase-5 (PDE-5) inhibitors have been found to play an important cardio-protective role. This study aimed to clarify the inhibitory effects of PDE-5-silenced bone marrow mesenchymal stem cells (BMSCs) on high glucose-induced myocardial fibrosis and cardiomyocyte apoptosis. Cardiomyocytes and fibroblasts of neonatal rats were treated with high glucose (HG), and co-cultured with PDE-5-overexpressed or -knocked down BMSCs. The viability and apoptosis as well as the levels of cytokines, Cardiac troponin I and Vimentin of cardiomyocytes and fibroblasts were studied. The expressions of PDE-5, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG), in both cells were evaluated. BMSCs that silenced PDE-5 facilitated the viability of cardiomyocytes, decreased the viability of fibroblasts, and inhibited the apoptosis of cardiomyocytes and fibroblasts. The contents of collagen-I, collagen-III, tissue inhibitor of metalloproteinase (TIMP)-1 and Dermin in fibroblasts were decreased by the PDE-5 inhibitor, but the levels of matrix metalloproteinase (MMP)-1 in fibroblasts and troponin-I in cardiomyocytes were increased by the PDE-5 inhibitor. PDE-5 inhibitor also suppressed the expression of PDE-5 but up-regulated cGMP and PKG expression in cardiomyocytes and fibroblasts. PDE-5-inhibited BMSCs can decrease HG-induced myocardial fibrosis and cardiomyocyte apoptosis by activating the cGMP/PKG pathway, and may play a role in the prevention and treatment of diabetic cardiomyopathy.

Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity.

Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor-kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.

Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue

Osteoarthritis is a chronic degenerative joint disease affecting millions of people worldwide, with no disease-modifying drugs currently available to treat the disease. Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a potential therapeutic target in osteoarthritis because of its ability to inhibit the catabolic metalloproteinases that drive joint damage by degrading the cartilage extracellular matrix. We previously found that suramin inhibits cartilage degradation through its ability to block endocytosis and intracellular degradation of TIMP-3 by low-density lipoprotein receptor-related protein 1 (LRP1), and analysis of commercially available suramin analogues indicated the importance of the 1,3,5-trisulfonic acid substitutions on the terminal naphthalene rings for this activity. Here we describe synthesis and structure–activity relationship analysis of additional suramin analogues using ex vivo models of TIMP-3 trafficking and cartilage degradation. This showed that 1,3,6-trisulfonic acid substitution of the terminal naphthalene rings was also effective, and that the protective activity of suramin analogues depended on the presence of a rigid phenyl-containing central region, with para/para substitution of these phenyl rings being most favourable. Truncated analogues lost protective activity. The physicochemical characteristics of suramin and its analogues indicate that approaches such as intra-articular injection would be required to develop them for therapeutic use.

Human Induced Hepatocytes-Derived Extracellular Vesicles Ameliorated Liver Fibrosis in Mice via Suppression of TGF-β1/Smad Signaling and Activation of Nrf2/HO-1 Signaling.

Liver fibrosis is a wound-healing response caused by persistent liver injury and often occurs in chronic liver diseases. Effective treatments for liver fibrosis are still pending. Recent studies have revealed that extracellular vesicles (EVs) derived from primary hepatocytes (Hep-EVs) have therapeutic potential for multiple liver diseases. However, Hep-EVs are difficult to manufacture in bulk because of the limited sources of primary hepatocytes. Human-induced hepatocytes (hiHep) are hepatocyte-like cells that can expand in vitro, and their cell culture supernatant is thus an almost unlimited resource for EVs. This study aimed to investigate the potential therapeutic effects of EVs derived from hiHeps. hiHep-EVs inhibited the expression of inflammatory genes and the secretion of inflammation-related cytokines, and suppressed the activation of hepatic stellate cells by inhibiting the TGF-β1/Smad signaling pathway. The anti-inflammatory and antifibrotic effects of hiHep-EVs were similar to those of mesenchymal stem cell (MSC)-EVs. Furthermore, the administration of hiHep-EVs ameliorated oxidative stress, inflammation, and fibrosis in a CCl4-induced liver fibrosis mouse model. The expression of α smooth muscle actin (α-SMA), collagen I, and collagen III was reduced, which may be attributed to the regulation of metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 by hiHep-EVs, and the protein expression of Nrf2, HO-1, and NQO1 was increased. Taken together, our results suggested that hiHep-EVs alleviated liver fibrosis by activating the Nrf2/HO-1 signaling pathway and inhibiting the TGF-β1/Smad signaling pathway. This study revealed the hepatoprotective effect of hiHep-EVs, and provided a new approach to treating liver fibrosis.

The activity of Matrix Metalloproteinase-2 (MMP-2) and Tissue Inhibitors of Metalloproteinase-2 (TIMP-2) that are associated with the degree of endometrioma tissue invasion transplanted onto the Chorioallantoic Membrane (CAM)

Background. One of the fundamental pathogenesis of endometriosis to grow and develop is to carry out a cellular invasion of the surrounding tissue where it attaches. The invasion process of endometriotic focus is linked with the activity of matrix metalloproteinases-2 (MMP-2) and tissue inhibitors of metalloproteinases-2 (TIMP-2). In this study, we used endometrioma tissue to be implanted in chick chorioallantoic membrane (CAM) as a medium culture model to reconstruct and evaluate the invasion process of endometriosis. Then the MMP-2, TIMP-2 and invasion pattern can be invitro observed. Methods. Endometrioma tissue fragments were taken from ovarian endometrioma patients, reproductive age, no medication and no malignancy who underwent laparoscopic surgery. Sample research was taken in consecutive and non-probability sampling. The tissue fragments were divided into 4-8 strips, each dimension of 2 x 2 mm2. Two strips were assessed for the activity of MMP-2. Two remaining strips were transplanted onto the CAM. After incubation for five days, the transplanted tissues were harvested for assessment of MMP-2 by gelatin zymography, TIMP-2 by western blot and histological assessment by hematoxylin-eosin staining. The assessment was carried out by two qualified biologists as an observer. Result. Twenty-four fragments of endometrioma have been collected from 24 endometrioma patients who underwent laparoscopy surgery. The average age was 31±5 years, the BMI was 22±3 kg/m2, the duration of infertility was 58 ± 3 months, and r-ASRM was 67±35. In CAM of transplanted endometriomas tissue, MMP-2 activity was positively correlated with TIMP-2 in a moderate relationship (rô = 0.56, p-value &lt; 0.05), very weak positive correlation with invasion level (rô = 0.08, p-value &gt;0.05). TIMP-2 expression was negatively correlated with invasion level in a strong relationship (rô = -0.35, p-value &lt;0.05). The ratio between MMP-2/TIMP-2 was positively correlated with invasion level in a very strong relationship (rô = 0.72, p-value &lt; 0.05). ICC (intraclass correlation coefficient) value was 0.96, and p-value= 0.01, CI 95%. It shows that there was high reliability between observers. Conclusion. The invasion level of endometrioma transplanted onto CAM was determined by the balance between MMP-2 and TIMP-2.

Identification the key factor of pulmonary fibrosis following silica nanoparticles exposure based on bioinformatics analysis

Objective: To investigate the main mechanisms of pulmonary fibrosis following silica nanoparticles (SiNPs) exposure through constructing the macrophage-fibroblast model in vitro, which simulated the process of pulmonary fibrosis. Methods: In January 2021, human mononuclear leukemia cells (THP-1) were treated with 0, 25, 50, 100 μg/ml SiNPs for 24 h. The supernatant of THP-1 cells was collected and applied to human embryonic lung fibroblast cells (MRC-5) which divided into control and low, medium and high dose groups at the logarithmic growth stage for 24 h. MRC-5 cell viability was detected by CCK8. The hydroxyproline (Hyp), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) expression were detected in the supernatants of MRC-5. The changed proteins were detected by liquid-phase mass spectrometry in high dose group. GeneCard database were applied to identity the differential pulmonary fibrosis proteins in high dose group. Gene Ontology (GO) was performed to identity the key biological process in differential pulmonary fibrosis proteins of high dose group. The String database was used to construct the protein-protein interactions (PPI) network of differential pulmonary fibrosis proteins. The APP of CytoHubba was applied to calculate the key protein of differential pulmonary fibrosis proteins in PPI network. Correlation coefficients between key differential pulmonary fibrosis proteins were calculated using Pearson correlation analysis. Western blotting was applied to detect the expression of key proteins of differential pulmonary fibrosis proteins in different groups. Results: CCK8 results showed that MRC-5 cell viability was increasing in low, medium and high dose groups compared with control group (P<0.05). The expression levels of Hyp and IL-1β in different group were increased compared with control group, the expression levels of IL-6 and TNF-α were increased in high dose group compared with control group (P<0.05). GeneCard database identified 26 differential pulmonary fibrosis proteins, which were mainly involved in extracellular matrix hydrolysis, cell inflammatory response, tissue repair, cell proliferation, inflammation response by GO analysis. The APP of CytoHubba was calculated that matrix metalloproteinase 9 (MMP9) and tissue inhibitor metalloproteinase 1 (TIMP1) played an important role in PPI network. The results of correlation analysis showed that MMP9 was correlated with the expression of matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 3 (MMP3), TIMP1 and epidermal growth factor receptor (EGFR) (r=0.97, 0.98, 0.94, 0.93, P<0.05). Western blotting results showed that TIMP1 protein expression was increased in low, medium and high dose groups, while MMP9 protein expression was increased only in high dose group (P<0.05) . Conclusion: Differential expression proteins related with pulmonary fibrosis in MRC-5 cells mainly regulate biological processes of extracellular matrix hydrolysis, tissue repair, and cellular inflammation response following SiNPs exposure. MMP9 and TIMP1 may be the key proteins, which affected the fibrosis process in vitro pulmonary fibrosis model.

Assessing effects of mechanical stimulation of fluid shear stress on inducing matrix Metalloproteinase-9 in cultured corneal epithelial cells

Blinking is regarded as mechanical stimulation of fluid shear stress on the corneal epithelial cells. Therefore, we evaluated whether fluid shear stress affects matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cultured human corneal epithelial cells (HCECs). No other study has shown the influence of fluid shear stress on HCECs regarding mRNA expression and the protein levels of MMPs. Cultured HCECs were exposed to shear stress (0, 1.2, 12 dyne/cm2) for 12 and 24 h with the parallel-plate type of flow chamber. Gene expression of MMPs and TIMPs was measured by real-time polymerase reaction. Concentrations of MMP-1 and MMP-9 in cell lysates were determined using bead-based amplified luminescent proximity homogenous assay-linked immunosorbent assay. The expression of MMP-9 and MMP-1 in HCECs exposed to low and high flow for 12 and 24 h, respectively, increased significantly compared with those under static conditions. The expression of MMP-9 in the cells exposed to high flow for 24 h increased significantly compared with those under static and low flow conditions. Levels of MMP-9 in cell lysates exposed to fluid flow for 24 h were elevated significantly with increasing shear stress. Fluid shear stress exerted on HCECs affected MMPs, which was associated with inflammation and pathogenesis. Mechanical stress induced by blinking might influence expression of MMPs on the ocular surface. Further studies are warranted to establish the molecular mechanism of shear stress-induced alternations of MMPs.

The effect of laser and dynamic quadripolar radiofrequency therapies on the expression of collagenogenesis proteins in the vaginal epithelium and tissue elasticity in women with genital prolapse

Background. Genital prolapse dramatically affects the quality of life of patients. Various sources show that the relapse rate after surgical treatment is 30 to 60%.&#x0D; Aim. To determine and compare the expression levels of collagen metabolism proteins before and after exposure to laser and radio frequency in the postoperative period in postmenopausal patients and to compare ultrasound elastography data to justify using these exposure methods as a rehabilitation program.&#x0D; Materials and methods. Histological specimens were collected from 54 patients with postmenopausal POP-Q grade 3 genital prolapse, and an ultrasound examination was made before surgery and after rehabilitation therapy. A real-time polymerase chain reaction method was used to assess the expression level of type I collagen, matrix metalloproteinases (MMP-2, MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2). Ultrasound examination was performed using the technology of compression elastography with the analysis of the color scale and the coefficient of tissue deformation.&#x0D; Results. Data were obtained on the increase in the expression of TIMP-1 by 7 times and TIMP-2 by 4 times in the radiofrequency therapy group compared to the group before treatment, as well as a 64-fold decrease in TIMP-2 expression in the vaginal tissue of women in the group after laser therapy compared to the group before treatment. A significant increase in the expression of TIMP-1 and TIMP-2 genes in vaginal tissue after radiofrequency exposure and a decrease in TIMP-2 after laser exposure demonstrate the compensatory effect of biological markers in response to energy therapy, as well as the remodeling effect of these methods. According to ultrasound, tissue elasticity in patients increased after laser and radiofrequency exposure.&#x0D; Conclusion. The results support using radiofrequency and laser therapy in the postoperative period as rehabilitation methods.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1.

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Bee Honey Extract Attenuates Hyperglycemia in Induced Type 1 Diabetes: Impact of Antioxidant and Angiogenesis Activities on Diabetic Severity In Vivo

Background: Diabetes mellitus (DM) has become a disease prevalent worldwide. Honey, which comprises predominantly bioactive constituents, has anti-inflammatory, antioxidant, and immunomodulating properties. Aim: Recent developments and benefits of natural products in treating various diseases have caught the attention of researchers. This study aims to investigate the antidiabetic effect of bee honey extract on induced diabetic Swiss mice. Materials and Methods: Fifty Swiss male mice were randomly assigned to five groups of 10 mice each. Group I served as the negative control; in group II, the mice received 2 mg/kg/b.wt of honey extract only; and groups III, IV, and V received cyclosporine (CsA) (20 mg/kg/day, s.c.) daily for 10 days prior to receiving streptozotocin (STZ) inoculated at multiple low doses (MLDSTZ) (30 mg/kg/day, i.p.) for five consecutive days. Group IV was administered with insulin initiated at a dose of 0.5 U/kg/b.wt as a standard treatment (positive control). Group V was administered 2 mg/kg/b.wt of honey extract, while group III received no treatment. Results: The results showed a significant hypoglycemic effect, increased body weight, increased liver glycogen levels, and the amelioration of antioxidant activities in groups IV and V compared with the diabetic group III. Moreover, serum matrix metalloproteinase (MMP-9) concentrations were significantly reduced in the mice treated with the insulin and honey extract in groups IV and V and the tissue inhibitor metalloproteinase-1 (TIMP-1) levels were significantly higher than the serum levels in group III. Furthermore, the histopathological examination of groups IV and V revealed regenerative changes with the restoration of normal islet cell architecture, as compared to the diabetic mice in group III. Compared to group I, group II showed no changes and exhibited non-significant data. Conclusion: Honey extract plays an effective role in improving all biomarkers in treated group V. Furthermore, MMP-9 and TIMP-1 are considered prognostic markers in the progression, severity, diagnosis, and treatment of type 1 DM. This may play an important role for the treatment of individuals in the future.

Biomarkers for assessing disease progression and treatment outcomes of oral submucous fibrosis

Biomarkers for assessing disease progression and treatment outcomes of oral submucous fibrosis (OSMF) have gained significant attention in recent years. This review provides an overview of the current research on biomarkers in OSMF and their potential implications in clinical practice. The review focuses on the different categories of biomarkers that have shown promise in assessing disease progression and treatment outcomes in OSMF. Epithelial dysplasia markers, including Ki-67, p53, and cyclin D1, are discussed in relation to dysplastic changes observed in OSMF. Inflammatory and immune markers, such as cytokines, chemokines, and inflammatory mediators, are explored for their role in OSMF progression. The dysregulation of extracellular matrix remodelling is highlighted, with a discussion on matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as potential biomarkers. Furthermore, the review delves into biomarkers for treatment response and outcome prediction. Collagen turnover markers, including pro-collagen type I and MMPs, are examined as indicators of collagen synthesis and degradation. Oxidative stress markers, such as malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx), are evaluated for their ability to reflect oxidative stress and antioxidant status. The review also touches upon the potential of epigenetic markers, such as DNA methylation and histone modifications, in predicting treatment response and prognosis in OSMF. Additionally, the review explores the use of imaging techniques, including optical coherence tomography (OCT), autofluorescence imaging, and confocal microscopy, for assessing structural changes and biomarker expression in OSMF. It discusses the potential of molecular imaging modalities, such as positron emission tomography (PET) and molecular MRI, for visualizing specific biomarkers in OSMF. Moreover, the review highlights the importance of genomics approaches, including genomics, transcriptomics, proteomics, and metabolomics, in identifying novel biomarkers and unraveling molecular pathways in OSMF. We emphasize the potential of biomarkers in improving patient care and management in OSMF. It acknowledges the challenges in biomarker validation, standardization, and cost-effectiveness for widespread clinical use. The review calls for further research in emerging areas, such as non-coding RNAs, microRNA panels, and multi-modal biomarker approaches, to enhance our understanding of OSMF and facilitate personalized treatment strategies.

Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop drug-resistant and metastatic tumors. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a secreted protein with a tumor suppressor function due to its anti-proteolytic activity. Nevertheless, evidence indicates that TIMP-1 binds to the CD63 receptor and activates noncanonical oncogenic signaling in several cancers, but its role in mediating TNBC chemoresistance is still largely unexplored. Here, we show that mesenchymal-like TNBC cells express TIMP-1, whose levels are further increased in cells generated to be resistant to cisplatin (Cis-Pt-R) and doxorubicin (Dox-R). Moreover, public dataset analyses indicate that high TIMP-1 levels are associated with a worse prognosis in TNBC subjected to chemotherapy. Knock-down of TIMP-1 in both Cis-Pt-R and Dox-R cells reverses their resistance by inhibiting AKT activation. Consistently, TNBC cells exposed to recombinant TIMP-1 or TIMP-1-enriched media from chemoresistant cells, acquire resistance to both cisplatin and doxorubicin. Importantly, released TIMP-1 reassociates with plasma membrane by binding to CD63 and, in the absence of CD63 expression, TIMP-1-mediated chemoresistance is blocked. Thus, our results identify TIMP-1 as a new biomarker of TNBC chemoresistance and lay the groundwork for evaluating whether blockade of TIMP-1 signal is a viable treatment strategy.

The role of matrix metalloproteinases and their tissue inhibitors in the formation of hypertrophic skin scars with the use of a pulsed dye laser and Fermencol phonophoresis

BACKGROUND: An imbalance between matrix metalloproteinases (MMPs) expression and tissue inhibitors of MMP is considered as a possible mechanism for impaired collagen synthesis and degradation, which leads to the development of hypertrophic scars. The use of a vascular laser, in particular a pulsed dye laser, leads to coagulation of the vascular locus that feeds the hypertrophic skin scar, resulting in a decrease in extracellular matrix synthesis. The use of collagenase phonophoresis increases the effectiveness of laser therapy due to the destruction of the extracellular matrix.&#x0D; AIM: To study the role of matrix metalloproteinases and their tissue inhibitors in the pathogenesis of immature hypertrophic skin scars and to evaluate the dynamics of enzymes during the combined use of a pulsed dye laser and Fermenkol phonophoresis.&#x0D; MATERIAL AND METHODS: The study was performed with the participation of 125 patients aged 22 to 55 years with immature (up to 6 months) hypertrophic skin scars. All patients were divided into 4 groups according to the simple fixed randomization procedure. The first group (control, n=32) received course local compression therapy using silicone plates for 2 months. The second group (main group I, n=31) underwent two courses of Fermencol phonophoresis (5 daily procedures lasting 10 minutes each with a break of 34 weeks). The third group (main group II, n=31) underwent two pulsed dye laser procedures with an interval of 4 weeks. The fourth group (main III, n=31) received complex treatment, which included a combination of two pulsed dye laser procedures and two cycles of Fermenkol phonophoresis. The study of the clinical condition of patients was carried out according to the modified Vancouver scar scale (VSS). The content of MMP and tissue inhibitor of metalloproteinase-1 in blood serum was determined by enzyme immunoassay. Patients were examined twice: before the start and 2 weeks after the end of the course of treatment. To form a sample of reference values of MMPs and tissue inhibitors of metalloproteinases (TIMPs), a group of 20 somatically healthy individuals was used.&#x0D; RESULTS: Initially reduced levels of MMP-1 and MMP-9 were found in the blood serum of patients with immature hypertrophic skin scars, with high values of TIMP-1, which allows us to consider reduced expression as an important link in the pathogenesis of the fibroproliferative process in the skin, which causes excessive deposition of extracellular matrix components. The use of pulsed dye laser in combination with Fermencol phonophoresis was accompanied by an increase in the content of MMP in the blood serum of patients with immature hypertrophic skin scars, which positively correlated with the severity of the clinical result of treatment, assessed by VSS.&#x0D; CONCLUSION: A conclusion was made about the clinical and pathogenetic significance of MMPs and TIMPs in the development of fibroplastic processes, which allows us to consider these biochemical parameters as informative criteria for the effectiveness of the therapy.

Metalloproteinases between History, Health, Disease, and the Complex Dimension of Social Determinants of Health

Metalloproteinases (MPs) belong to the superfamily of zinc endopeptidases, which are called metzincins. Three families of MPs have been studied in healthy and diseased conditions in humans. The first study on MPs was published in 1962, and following that, several studies characterized their activity and their effect on health and disease. Several diseases have been related to MPs, such as cardiovascular disease, cancer, inflammatory diseases, gynecological disorders, and others. Moreover, tissue inhibitors of metalloproteinases (TIMPs) have been widely studied, and drugs and artificial molecules that could target MP activity have been evaluated. MPs are relevant to public health because of their role in several diseases and, most of all, their role as biomarkers that also impact the quality of life and the psychosocial dimension of affected patients. In this context, new pathways to precision health and precision medicine have been opened in the area of MPs. This review describes, from the initial studies, the complex dimensions of MPs and related issues centered on health and disease dimensions.

Targeting of HBP1/TIMP3 axis as a novel strategy against breast cancer

Malignant proliferation and metastasis are the main causes of breast cancer death. The transcription factor high mobility group (HMG) box-containing protein 1 (HBP1) is an important tumor suppressor whose deletion or mutation is closely related to the appearance of tumors. Here, we investigated the role of HBP1 in breast cancer suppression. HBP1 enhances the activity of the tissue inhibitors of metalloproteinases 3 (TIMP3) promoter, thereby increasing protein and mRNA levels of TIMP3. TIMP3 increases the phosphatase and tensin homolog (PTEN) protein level by inhibiting its degradation and acts as a metalloproteinase inhibitor to inhibit the protein levels of MMP2/9. In this study, we demonstrated that the HBP1/TIMP3 axis plays a crucial role in inhibiting the tumorigenesis of breast cancer. HBP1 deletion interferes with the regulation of the axis and induces the occurrence and malignant progression of breast cancer. In addition, the HBP1/TIMP3 axis promotes the sensitivity of breast cancer to radiation therapy and hormone therapy. Our study opens new perspectives on the treatment and prognosis of breast cancer.

Inhibition of Monoacylglycerol Lipase Decreases Angiogenic Features of Endothelial Cells via Release of Tissue Inhibitor of Metalloproteinase-1 from Lung Cancer Cells.

Despite the well-described anticarcinogenic effects of endocannabinoids, the influence of the endocannabinoid system on tumor angiogenesis is still debated. In the present study, conditioned medium (CM) from A549 and H358 lung cancer cells treated with ascending concentrations of the monoacylglycerol lipase (MAGL) inhibitor JZL184 and 2-arachidonoylglycerol (2-AG), a prominent MAGL substrate, caused a concentration-dependent reduction in human umbilical vein endothelial cell (HUVEC) migration and tube formation compared with CM from vehicle-treated cancer cells. Comparative experiments with MAGL inhibitors JW651 and MJN110 showed the same results. On the other hand, the angiogenic properties of HUVECs were not significantly altered by direct stimulation with JZL184 or 2-AG or by exposure to CM of JZL184- or 2-AG-treated non-cancerous bronchial epithelial cells (BEAS-2B). Inhibition of HUVEC migration and tube formation by CM of JZL184- and 2-AG-treated A549 cells was abolished in the presence of the CB1 antagonist AM-251. Increased release of tissue inhibitor of metalloproteinase-1 (TIMP-1) from JZL184- or 2-AG-stimulated A549 or H358 cells was shown to exert an antiangiogenic effect on HUVECs, as confirmed by siRNA experiments. In addition, JZL184 caused a dose-dependent regression of A549 tumor xenografts in athymic nude mice, which was associated with a decreased number of CD31-positive cells and upregulation of TIMP-1-positive cells in xenograft tissue. In conclusion, our data suggest that elevation of 2-AG by MAGL inhibition leads to increased release of TIMP-1 from lung cancer cells, which mediates an antiangiogenic effect on endothelial cells.

TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone.

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)-regulators of ECM remodeling-for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs.

Urinary TIMP-2*IGFBP-7 to diagnose acute kidney injury in children receiving cisplatin.

Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers. We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). serum creatinine (SCr)-defined AKI (≥ stage 1). At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine)2/1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70). TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.