Tissue Inhibitor Of Metalloproteinase-1 Levels Research Articles

MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity

The association between matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and obesity as well as obesity-related disease including metabolic syndrome is not fully explored. Our aims are that: (i) to evaluate the plasma levels of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and their ratios in non-obese people, overweight and obese people with or without metabolic syndrome, (ii) to investigate correlations between MMPs or TIMPs levels and several anthropometric parameters, blood pressure, endothelial function. Anthropometric and biochemical parameters were determined in 479 randomly selected participants, subdividing according to body mass index (BMI) and metabolic syndrome status. Plasma MMPs and TIMPs levels were measured. The assessment of endothelial function was characterized in people with obesity, overweight and non-obese, using laser Doppler Flowmetry. Obese people have elevated MMP-1, MMP-2, TIMP-1, TIMP-2 levels and decreased MMP-3/TIMP-1 and MMP-9/TIMP-1 ratios compared with non-obese people. MMP-1 levels and MMP-1/TIMP-1 ratio were positively correlated with BMI and waist circumference (WC) while MMP-2 levels were negatively correlated with BMI and WC values in obese people. MMP-3 levels and MMP-3/TIMP-1 ratio were positively correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in obese and metabolic syndrome people. Additionally, MMP-9 levels and MMP-9/TIMP-1 ratio were negatively correlated with endothelium-dependent response in obese and metabolic syndrome people. MMP-1, MMP-2, TIMP-1, TIMP-2 levels were increased in obese subjects. Significant correlations between anthropometric parameters and MMP-1 as well as MMP-1/TIMP-1 ratio supported these results. MMP-3 and -9 levels as well as their ratios with TIMP-1 were associated with blood pressure and endothelial-dependent response, respectively. In conclusion, our results demonstrated that MMP-1, MMP-3 and MMP-9 levels were correlated with several obesity-related parameters including BMI, WC, blood pressure and endothelial-dependent response. Our findings will hopefully provide new aspects for the use of MMPs and TIMPs as clinical biomarkers in obesity-related cardiovascular diseases such as metabolic syndrome and hypertension. The lack of measure of MMPs activity in plasma and relevant organs/tissues in obesity and metabolic syndrome is considered as a limitation in this report.

TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.

Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine.

Tissue Inhibitor of Metalloproteinase-1 Is Increased in Chagasic Cardiomyopathy

Chagas disease (CD) mainly conveys stroke risk through structural cardiac disease. However, stroke and cognitive impairment are seen in CD independently of cardiac disease severity. Chronic inflammation may be an explanation for this association, because inflammation plays an important role in the pathogenesis of acute ischemic stroke and dementia. In the present study, we selected five candidate biomarkers for Chagas disease: interleukin-6, membrane metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP1), orosomucoid, and neprilysin. We sought to determine if mean levels of proinflammatory biomarkers are higher in patients with heart failure (HF) associated with Chagas disease when compared with other etiologies of HF. Patients were consecutively enrolled from subspecialty HF outpatient clinics at two university-based hospitals. Serum biomarker levels from blood samples were analyzed by ELISA. Severity of HF on echocardiography was worse in non-CD when compared with CD patients. No significant difference was observed in the levels of candidate biomarkers between the CD and non-CD groups. We found a significantly 2.2 ng/mL higher level of TIMP1 in CD when compared with non-CD patients with HF after adjustment for age and gender (95% confidence interval = 0.1 to 4.5, P = 0.037). In patients with heart failure, serum TIMP1 is increased in Chagas patients despite a lower myocardial disease severity on echocardiography when compared with non-Chagas patients. TIMP1 is probably one of multiple mediators of inflammatory injury.

Serum matrix metallopeptidase-9 and tissue inhibitor of metalloproteinase-1 levels may predict response to adrenocorticotropic hormone therapy in patients with infantile spasms

ObjectiveTo evaluate whether serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels predict response to adrenocorticotropic hormone (ACTH) therapy in patients with infantile spasms. MethodsWe prospectively evaluated patients with infantile spasms who were referred to Saitama Children’s Medical Center from January 2011 to December 2020. We measured Q-albumin and serum MMP-9 and TIMP-1 levels before ACTH therapy. Patients were divided into three groups based on the etiology of their infantile spasms: those with an unknown etiology and normal development (unknown-normal group); those with a structural and acquired etiology (structural-acquired group); and those with a structural and congenital, genetic, metabolic, or unknown etiology with developmental delay (combined-congenital group). Responders were defined as those having complete cessation of spasms for more than 3 months with the resolution of hypsarrhythmia on electroencephalography during ACTH therapy. ResultsWe collected serum from 36 patients with West syndrome and five patients with infantile spasms without hypsarrhythmia before ACTH therapy. Twenty-three of 41 patients (56.1%) were responders, including 8/8 (100%) in the unknown-normal group, 6/9 (66.7%) in the structural-acquired group, and 9/24 (37.5%) in the combined-congenital group. The serum MMP-9 level and MMP-9/TIMP-1 ratio were significantly higher in responders than in nonresponders (P = 0.001 for both). ConclusionA therapeutic response to ACTH was associated with a higher serum MMP-9 level and higher MMP-9/TIMP-1 ratio in patients with infantile spasms. Therefore, these biomarkers may predict responses to ACTH therapy in this patient population.

Clinical significance of serum matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in the first phase of burn trauma evolution.

No prospective study has specifically examined the serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the early shock phase of burn-injured patients. Thus, we aimed to detect early changes, activity dynamics, and the predictive value of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio to better understand the early repair mechanisms for the development of future therapies for patients with thermal burns. Twenty-five patients with a total body surface area (TBSA) affected by burn <25%, and 30 healthy subjects were enrolled in the study. Serum levels of MMP-9 and TIMP-1 were determined by the ELISA method. Our results showed that MMP-9 concentrations increased immediately after injury and remained on a plateau. In contrast, TIMP-1 showed an upward trend throughout the 7-day study period, and the time course of the MMP-9/TIMP-1 ratio followed the inverse dynamics of TIMP-1. Analysis of the areas under the receiver operating characteristic (ROC) curves (AUC) showed that patients with burn wounds tended to have a MMP-9 value higher than 421.5 ng/ml (AUC=0.979), TIMP-1 value higher than 231.6 ng/ml (AUC=0.908), and MMP-9/TIMP-1 ratio higher than 2.31 (AUC=0.959) (P<0.001). Our findings suggest that although the variations in the two biomarkers were different regarding the time of the initial insult, their ratio is a specific and sensitive indicator of burn evolutivity in patients with a TBSA affected by a burn <25%.

Blood-based biomarkers in patients with platinum-sensitive and resistant ovarian cancer treated with olaparib and cediranib: results from the UM9825 trial

Objectives: We investigated prognostic associations between blood-based biomarkers and clinical outcomes as well as the change in biomarkers in response to treatment in the open-label phase II trial testing olaparib and cediranib in patients with recurrent ovarian, peritoneal, or tubal cancer (NCT02345265). Methods: Plasma samples collected at baseline, cycle 2 day 1 (C2D1), and end-of-treatment (EOT) were analyzed via multiplex ELISA for 25 angiogenic and inflammatory circulating protein biomarkers (the Angiome). The prognostic values of each marker for progression-free survival (PFS) and response rate (RR) were tested using Cox proportional hazards regression models, unadjusted and adjusted for performance status, platinum sensitivity, and homologous recombination repair gene mutation (HRRm) status. The Wald test P-values and Q-values, to account for multiple testing, were calculated. Wilcoxon rank sum tests were performed to evaluate biomarker change in response to treatment. Results: Samples for analysis included: baseline (n=70), C2D1 (n=62), and EOT (n=35). The median age was 62; 50% were platinum resistant; 41.4% had HRRm+ tumors. Four markers (osteopontin (OPN), interleukin-6 (IL-6), tissue inhibitor of metalloproteinase-1 (TIMP-1), and angiopoietin-2 (Ang-2) were negatively prognostic of PFS with or without adjusting for covariates (see Table). Patients were stratified as responders (complete responders (CR), n=6; partial responders (PR), n=34) and non-responders (stable disease (SD), n=23; progressive disease (PD), n=4). Baseline levels of TIMP-1 (p=0.005; q=0.1) and intercellular adhesion molecule-1 (ICAM-1) (p=0.04; q=0.4) were lower in responders compared to non-responders. Lower expression of OPN was also noted in responders, but the difference did not reach statistical significance (p=0.07). Five biomarkers were upregulated at C2D1 and EOT: hepatocyte growth factor (HGF) (1.5 and 2.7-fold); IL-6 (1.9, 2.0); vascular endothelial growth factor (VEGF)-A (5.4, 3.9); placental growth factor (PlGF) (6.0, 3.9); and VEGFR1 (1.6, 2.3). Graphical Abstract View Large Image Figure Viewer Download Hi-res image Conclusions: In this exploratory analysis, OPN, IL-6, TIMP-1, and Ang-2 were consistently observed to be negatively associated with PFS in patients receiving combination olaparib and cediranib. The Angiome will be further assessed in the upcoming NRG Oncology GY004 and GY005 studies comparing olaparib and cediranib to stand-ard-of-care therapies. Further evaluation is needed to explore clinical implications and potential value of these candidate biomarkers. We investigated prognostic associations between blood-based biomarkers and clinical outcomes as well as the change in biomarkers in response to treatment in the open-label phase II trial testing olaparib and cediranib in patients with recurrent ovarian, peritoneal, or tubal cancer (NCT02345265). Plasma samples collected at baseline, cycle 2 day 1 (C2D1), and end-of-treatment (EOT) were analyzed via multiplex ELISA for 25 angiogenic and inflammatory circulating protein biomarkers (the Angiome). The prognostic values of each marker for progression-free survival (PFS) and response rate (RR) were tested using Cox proportional hazards regression models, unadjusted and adjusted for performance status, platinum sensitivity, and homologous recombination repair gene mutation (HRRm) status. The Wald test P-values and Q-values, to account for multiple testing, were calculated. Wilcoxon rank sum tests were performed to evaluate biomarker change in response to treatment. Samples for analysis included: baseline (n=70), C2D1 (n=62), and EOT (n=35). The median age was 62; 50% were platinum resistant; 41.4% had HRRm+ tumors. Four markers (osteopontin (OPN), interleukin-6 (IL-6), tissue inhibitor of metalloproteinase-1 (TIMP-1), and angiopoietin-2 (Ang-2) were negatively prognostic of PFS with or without adjusting for covariates (see Table). Patients were stratified as responders (complete responders (CR), n=6; partial responders (PR), n=34) and non-responders (stable disease (SD), n=23; progressive disease (PD), n=4). Baseline levels of TIMP-1 (p=0.005; q=0.1) and intercellular adhesion molecule-1 (ICAM-1) (p=0.04; q=0.4) were lower in responders compared to non-responders. Lower expression of OPN was also noted in responders, but the difference did not reach statistical significance (p=0.07). Five biomarkers were upregulated at C2D1 and EOT: hepatocyte growth factor (HGF) (1.5 and 2.7-fold); IL-6 (1.9, 2.0); vascular endothelial growth factor (VEGF)-A (5.4, 3.9); placental growth factor (PlGF) (6.0, 3.9); and VEGFR1 (1.6, 2.3). In this exploratory analysis, OPN, IL-6, TIMP-1, and Ang-2 were consistently observed to be negatively associated with PFS in patients receiving combination olaparib and cediranib. The Angiome will be further assessed in the upcoming NRG Oncology GY004 and GY005 studies comparing olaparib and cediranib to stand-ard-of-care therapies. Further evaluation is needed to explore clinical implications and potential value of these candidate biomarkers.

Age-associated level of myocardial fibrosis markers and chemokines in patients with acute coronary syndrome

Aim. To study age-related specifics of the concentration of fibrosis markers and monocyte chemotactic protein-1 (MCP-1) in patients with ST-segment elevation acute coronary syndrome (STE-ACS).Material and methods. A total of 140 STE-ACS patients were examined. Depending on the age, participants were divided into following groups: middle age — 42 patients, elderly — 50 patients, senile — 48 patients. The control group (CG) consisted of 20 people without cardiovascular disease. The level of matrix metallopeptidase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), MCP-1 was determined by enzyme immunoassay. Statistical processing was carried out using the MATLAB 2020software.Results. It was found that in STE-ACS patients, the MMP-9 level in middle-aged patients is 2,9 times higher than in the CG (p&lt;0,001), elderly — 4,1 times (p&lt;0,001), senile — 6 times (p&lt;0,001). A strong direct relationship was found between age and MMP-9 level (r=0,86088, p&lt;0,001). The TIMP-1 level was higher in all patients (p&lt;0,05) compared with CG. A strong direct relationship was found between levels of MMP-9 and TIMP-1 (r=0,7801; p&lt;0,01). The MMP-9/TIMP-1 ratio was higher in the group of middle-aged people by 85,7% (p&lt;0,05), elderly — 1,2 times (p&lt;0,001), senile — 2,3 times (p&lt;0,001) compared to CG. MCP-1 was elevated in all age groups (p &lt;0,001). A direct correlation was found between levels of MCP-1 and MMP-9 (r=0,726, p&lt;0,001).Conclusion. In STE-ACS patients, an age-associated increase in concentrations of MMP-9 and MMP-9/TIMP-1 ratio was found in comparison with CG, which indicates the predominance of intercellular matrix degradation marker in patients with ACS. At the same time, MMP-9 increase is possibly induced by MCP-1.

Helminth Coinfection Is Associated With Enhanced Plasma Levels of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Tuberculous Lymphadenitis.

Matrix metalloproteinases (MMPs) are crucial for tissue remodeling and repair and are expressed in diverse infections, whereas tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of MMPs. However, the interaction of MMPs and TIMPs in tuberculous lymphadenitis (TBL), an extra-pulmonary form of tuberculosis (EPTB) and helminth (Hel+) coinfection is not known. Therefore, this present study investigates the levels of circulating MMPs (1, 2, 3, 7, 8, 9, 12, 13) and TIMPs (1, 2, 3, 4) in TBL individuals with helminth (Strongyloides stercoralis [Ss], hereafter Hel+) coinfection and without helminth coinfection (hereafter, Hel-). In addition, we have also carried out the regression analysis and calculated the MMP/TIMP ratios between the two study groups. We describe that the circulating levels of MMPs (except MMP-8 and MMP-12) were elevated in TBL-Hel+ coinfected individuals compared to TBL-Hel- individuals. Similarly, the systemic levels of TIMPs (1, 2, 3, 4) were increased in TBL-Hel+ compared to TBL-Hel- groups indicating that it is a feature of helminth coinfection per se. Finally, our multivariate analysis data also revealed that the changes in MMPs and TIMPs were independent of age, sex, and culture status between TBL-Hel+ and TBL-Hel- individuals. We show that the MMP-2 ratio with all TIMPs were significantly associated with TBL-helminth coinfection. Thus, our results describe how helminth infection has a profound effect on the pathogenesis of TBL and that both MMPs and TIMPs could dampen the immunity against the TBL-Hel+ coinfected individuals.

Antibody microarray analysis of the amniotic fluid proteome for predicting the outcome of rescue cerclage in patients with cervical insufficiency.

Little is known about the biomarkers that can identify patient candidates suitable for rescue cerclage procedure. The purpose of the study was to identify novel biomarkers in amniotic fluid (AF) that can predict the outcome of rescue cerclage in patients with cervical insufficiency by using an antibody microarray. This case–control study was conducted using AF samples collected from singleton pregnant women who underwent rescue cerclage following a diagnosis of cervical insufficiency (19–25 weeks). Patients were divided into case (n=20) and control (n=20) groups based on the occurrence of spontaneous preterm delivery (SPTD) at <34 weeks of gestation after cerclage placement. The AF proteomes were analyzed using an antibody microarray for biomarker discovery work. Ten candidate biomarkers of interest were validated by enzyme-linked immunosorbent assay (ELISA). Thirty-one molecules studied showed significant intergroup differences (≥two-fold change in signal intensity). Validation by ELISA confirmed significantly higher levels of a proliferation-inducing ligand (APRIL), S100 calcium-binding protein A8/A9 complex (S100 A8/A9), tissue inhibitors of metalloproteinase-1 (TIMP-1), macrophage inflammatory protein-1α (MIP-1α), and interleukin-8 (IL-8) in women who had SPTD at <34 weeks. Of these, AF S100 A8/A9 and TIMP-1 levels were independent of other potentially confounding factors (e.g., cervical dilatation). S100 A8/A9 had the highest area under the curve (AUC) at 0.857. Using protein–antibody microarray technology, we identified differentially expressed proteins (DEPs) and several novel biomarkers (APRIL, IL-8, MIP-1α, S100 A8/A9, and TIMP-1) in AF from women who had SPTB at <34 weeks after cerclage for cervical insufficiency. These data can provide an insight into the molecular mechanisms underlying SPTD after rescue cerclage in patients with cervical insufficiency.

TIMP1 Triggers Neutrophil Extracellular Trap Formation in Pancreatic Cancer.

Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The noncanonical signaling activity of TIMP1 is emerging as one basis for its contribution to cancer progression. However, TIMP1-triggered progression-related biological processes are largely unknown. Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene-set enrichment analysis of a human PDAC proteome dataset revealed that TIMP1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP1 significantly contributed to NET formation in tumors, and abrogation of TIMP1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP1 expression. Furthermore, TIMP1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of patients with PDAC. A combination of plasma levels of TIMP1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, because elevated systemic levels of TIMP1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases. SIGNIFICANCE: These findings highlight the prognostic relevance of TIMP1 and neutrophil extracellular traps in highly lethal pancreatic cancer, where a noncanonical TIMP1/CD63/ERK signaling axis induces NET formation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3568/F1.large.jpg.

Effects of ERα gene overexpression on bone mineral density and calcium and phosphorus metabolism inovariectomized osteoporosis mice

Objective: To investigate the effects of estrogen receptor α (ERα) gene overexpression on bone metabolism and calcium and phosphorus metabolism in ovariectomized osteoporosis mice, and to provide experimental basis for targeted gene therapy of osteoporosis. Methods: Thirty SPF female mice were randomly divided into sham operation group, model group and ERα overexpression group with 10 mice in each group. After the model was established, the ERα overexpression group was transfected with recombinant adenovirus vector carrying mouse ERα gene by intraspinal injection. The model group was transfected with empty virus, and the sham operation group was not treated. The expression of ERα gene in bone tissue of mice was detected by quantitative Real-time PCR (qRT-PCR). Bone mineral density (BMD) of mouse femur was measured after modeling. Trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular segregation (Tb.Sp), bone volume fraction (BV/TV) and biomechanical strength of femur were measured by micro-CT scanning. Serum levels of calcium (Ca), phosphorus (P), osteocalcin (BGP) and alkaline phosphatase (ALP) were measured by automatic biochemical analyzer. The expressions of tissue inhibitor of metalloproteinases 1 (TIMP-1) and monocyte chemotactic protein 1 (MCP-1) in bone homogenate were detected by Immunohistochemistry. Results: Compared with sham operation group, the expression level of ERα gene in bone tissue of model group was decreased significantly, the levels of BMD, BV/TV, Tb. Th, maximum load, rigidity coefficient, Ca and P were decreased, while the levels of Tb. Sp, BGP and ALP were increased significantly (P＜0.05). Compared with the sham operation group, the expression level of TIMP-1 protein in the bone tissue of the model group was significantly decreased, while that of MCP-1 protein was increased, while that of the ERα overexpression group was increased while that of MCP-1 was decreased (P＜0.05).The levels of ERα gene expression, BMD, BV/TV, TB. Th, maximum load, rigidity coefficient, Ca and P in the ERα overexpression group were significantly higher than those in the model group, while Tb. Sp, BGP and ALP were significantly lower (P＜0.05). Compared with the sham operation group, mean optical density of TIMP-1 in the bone tissue of the model group was significantly decreased, while that of MCP-1 was significantly increased, and that of the ERα overexpression group was significantly increased while that of MCP-1 was significantly decreased (P＜0.05). Conclusion: ERα gene overexpression can improve osteoporosis by regulating bone mineral density, bone parameters, bone metabolism, calcium and phosphorus metabolic indicators and the expression levels of TIMP-1 and MCP-1 in tissues.

Assessment of renal fibrosis and anti-fibrotic agents using a novel diagnostic and stain-free second-harmonic generation platform.

Current histological measurement techniques for interstitial collagen, the basis of interstitial fibrosis, are semi-quantitative at best and only provide a ratio of collagen levels within tissues. The Genesis200 imaging system and supplemental image analysis software, FibroIndex from HistoIndex, is a novel, automated platform that uses second-harmonic generation (SHG) for imaging and characterization of interstitial collagen deposition and additional characteristics, in the absence of any staining. However, its ability to quantify renal fibrosis requires investigation. This study compared SHG imaging of renal fibrosis in mice with unilateral ureteric obstruction (UUO), to that of Masson's trichrome staining (MTS) and immunohistochemistry (IHC) of collagen I. Additionally, the platform generated data on collagen morphology and distribution patterns. While all three methods determined that UUO-injured mice underwent significantly increased renal fibrosis after 7 days, the HistoIndex platform additionally determined that UUO-injured mice had a significantly increased collagen-to-tissue cross reticulation ratio (all P<.001 vs sham group). Furthermore, in UUO-injured mice treated with the relaxin family peptide receptor-1 agonists, relaxin (0.5mg/kg/day) or B7-33 (0.25 mg/kg/day), or angiotensin converting enzyme-inhibitor, perindopril (1 mg/kg/day) over the 7-day period, only the HistoIndex platform determined that the drug-induced prevention of renal fibrosis correlated with significantly reduced collagen fiber thickness and collagen-to-tissue cross reticulation ratio, but increased collagen fiber counts. Relaxin or B7-33 treatment also increased renal matrix metalloproteinase-2 and reduced tissue inhibitor of metalloproteinase-1 levels (all P<.01 vs UUO alone). This study demonstrated the diagnostic value of the HistoIndex platform over currently used staining techniques.

Aromatase inhibitor anastrozole modifies cellular functions in gingival fibroblasts and endothelial cells: possible periodontal complications of aromatase inhibitor treatment.

Recent studies have shown that treatment with aromatase inhibitors contributes to an increased prevalence of periodontitis. In this study, we assessed effects of the aromatase inhibitor anastrozole on cellular function of human gingival fibroblasts (HGFs) and endothelial cells. Expression levels of collagen, extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were examined in HGFs exposed to anastrozole. Furthermore, inflammatory responses in HGFs cultured with anastrozole were evaluated in the presence of Porphyromonas gingivalis lipopolysaccharide. We also evaluated the vascular permeability and vascular endothelial (VE)-cadherin expression of endothelial cells exposed to anastrozole. Anastrozole enhanced expression levels of collagen, ECM proteins, TIMPs, and inflammatory cytokines in HGFs, as well as vascular permeability of endothelial cells. In addition, anastrozole reduced expression levels of MMPs in HGFs and VE-cadherin in endothelial cells. These results suggest that anastrozole modulates various cellular functions in HGFs and endothelial cells.

Loss of TIMP4 (Tissue Inhibitor of Metalloproteinase 4) Promotes Atherosclerotic Plaque Deposition in the Abdominal Aorta Despite Suppressed Plasma Cholesterol Levels.

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Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis

BackgroundWe previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy.MethodsThe relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study).ResultsIn the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months.ConclusionWe herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

Angiotensin-converting enzyme inhibitors increase anti-fibrotic biomarkers in African Americans with left ventricular hypertrophy.

Angiotensin‐converting enzyme inhibitors (ACEi) are part of the indicated treatment in hypertensive African Americans. ACEi have blood pressure‐independent effects that may make them preferred for certain patients. We aimed to evaluate the impact of ACEi on anti‐fibrotic biomarkers in African American hypertensive patients with left ventricular hypertrophy (LVH). We conducted a post hoc analysis of a randomized controlled trial in which hypertensive African American patients with LVH and vitamin D deficiency were randomized to receive intensive antihypertensive therapy plus vitamin D supplementation or placebo. We selected patients who had detectable lisinopril (lisinopril group) in plasma using liquid‐chromatography/mass spectrometry analysis and compared them to subjects who did not (comparison group) at the one‐year follow‐up. The pro‐fibrotic marker type 1 procollagen C‐terminal propeptide (PICP) and the anti‐fibrotic markers matrix metalloproteinase‐1 (MMP‐1), tissue inhibitor of metalloproteinases 1 (TIMP‐1), telopeptide of collagen type I (CITP), and N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) peptide were measured. Sixty‐six patients were included, and the mean age was 46.2 ± 8 years. No difference was observed in the number and intensity of antihypertensive medications prescribed in each group. Patients with detectable lisinopril had lower blood pressure than those in the comparison group. The anti‐fibrotic markers Ac‐SDKP, MMP‐1, and MMP‐1/TIMP‐1 ratio were higher in patients with detectable ACEi (all p < .05). In a model adjusted for systolic blood pressure, MMP‐1/TIMP‐1 (p = .02) and Ac‐SDKP (p < .001) levels were associated with lisinopril. We conclude that ACEi increase anti‐fibrotic biomarkers in hypertensive African Americans with LVH, suggesting that they may offer added benefit over other agents in such patients.

Surface-bound matrix metalloproteinase-8 on macrophages: Contributions to macrophage pericellular proteolysis and migration through tissue barriers.

ABSTRACTObjectiveMMP‐8 binds to surface‐bound tissue inhibitor of metalloproteinase‐1 (TIMP‐1) on PMNs to promote pericellular proteolysis during the development of inflammatory diseases associated with tissue destruction. Little is known about the biology of MMP‐8 in macrophages. We tested the hypotheses that: (1) MMP‐8 and TIMP‐1 are also expressed on the surface of activated macrophages, (2) surface‐bound MMP‐8 on macrophages promotes TIMP‐resistant pericellular proteolysis and macrophage migration through tissue barriers, and (3) MMP‐8 binds to surface‐bound TIMP‐1 on macrophages.MethodsSurface MMP‐8 and TIMP‐1 levels were measured on human monocyte‐derived macrophages (MDM) and/or murine macrophages using immunostaining, biotin‐labeling, and substrate cleavage methods. The susceptibility of membrane‐bound Mmp‐8 on activated macrophages from wild‐type (WT) mice to TIMPs was measured. Migration of WT and Mmp‐8 −/− macrophages through models of tissue barriers in vitro and the accumulation of peritoneal macrophages in WT versus Mmp‐8 −/− mice with sterile peritonitis was compared. Surface levels of Mmp‐8 were compared on activated macrophages from WT and Timp‐1 −/− mice.ResultsLipopolysaccharides and a cluster of differentiation 40 ligand increased surface MMP‐8 and/or TIMP‐1 staining and surface type I collagenase activity on MDM and/or murine macrophages. Activated Mmp‐8 −/− macrophages degraded less type I collagen than activated WT macrophages. The surface type‐I collagenase activity on WT macrophages was resistant to inhibition by Timp‐1. Peritoneal macrophage accumulation was similar in WT and Mmp‐8 −/− mice with sterile acute peritonitis. However, Mmp‐8 −/− macrophages migrated less efficiently through models of tissue barriers (especially those containing type I collagen) than WT cells. Activated WT and Timp‐1 −/− macrophages had similar surface‐bound Mmp‐8 levels.ConclusionsMMP‐8 and TIMP‐1 are expressed on the surface of activated human MDM and murine macrophages, but Mmp‐8 is unlikely to bind to surface‐bound Timp‐1 on these cells. Surface‐bound MMP‐8 contributes to TIMP‐resistant monocyte/macrophage pericellular proteolysis and macrophage migration through collagen‐containing tissue barriers.

Plasma levels of tissue inhibitor of metalloproteinase-1 in patients with type 1 diabetes mellitus associate with early diabetic neuropathy and nephropathy.

Background:Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been suggested as a marker for abnormal regulation of tissue remodelling in type 1 diabetes. Metalloproteinase-9 (MMP-9) has been associated with matrix turnover, and Neutrophil gelatinase associated lipocalin (NGAL) is a marker of tubular injury in diabetic nephropathy. The aim was to analyse these biomarkers to unmask early diabetic complications.Methods:Thirty-three type 1 diabetes patients, aged 20–35 years, and disease duration 20 ± 5.3 years were included. Along with clinical examination, neurophysiological measurements, routine biochemistry, plasma concentrations of TIMP-1, MMP-9 and NGAL were determined with immunoenzymatic techniques.Results:TIMP-1 correlated with abnormal unilateral and bilateral vibratory sense foot perception (r = −0.49 and r = −0.51, respectively), foot neuropathy impairment assessment score (NIA; r = −0.55), neuropathy symptom assessment score (r = 0.42), microalbuminuria (r = 0.50) and eGFR (r = −0.45). MMP-9 correlated with impaired foot NIA (r = 0.51). Multiple regression analysis showed an association for TIMP-1 (p = 0.004) with impaired neurophysiological examinations and renal dysfunction along with NGAL (p = 0.016 and p = 0.015 respectively).Conclusions:This study suggests that plasma levels of TIMP-1, MMP-9 and NGAL may serve as useful biomarkers in unravelling subclinical neuropathy and nephropathy in type 1 diabetes.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) as a prognostic biomarker in gastrointestinal cancer: a meta-analysis

BackgroundTissue inhibitor of metalloproteinase 1 (TIMP-1) has recently been shown to be dependent on or independent of Matrix metalloproteinases (MMPs) in its roles in tumorigenesis and progression. This appreciation has prompted various studies assessing the prognostic value of TIMP-1 in patients with gastrointestinal cancer, however, the conclusions were still inconsistent. The aim of this study was to assess the prognostic value of TIMP-1-immunohistochemistry (IHC) staining and pretreatment serum/plasma TIMP-1 level in gastrointestinal cancer survival as well as the association between TIMP-1 and clinicopathologic features.MethodsThe meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration NO. CRD42020185407) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A highly sensitive literature search was performed in electronic databases including PubMed, EMBASE and the Cochrane Library. Heterogeneity analysis was conducted using both chi-square-based Q statistics and the I2 test. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the prognostic value of TIMP-1 using the fixed-effects model. Odds ratios (ORs) with 95% CIs were calculated to evaluate the associations between TIMP-1 and clinicopathological characteristics. The meta-analysis was conducted using STATA 12.0 software.ResultsA total of 3,958 patients from twenty-two studies were included in the meta-analysis. Elevated TIMP-1 levels were significantly associated with poor survival in gastrointestinal cancer (TIMP-1-IHC staining: HR = 2.04, 95% CI [1.59–2.61], I2 = 35.7%, PQ = 0.156; pretreatment serum/plasma TIMP-1 levels: HR = 2.02, 95% CI [1.80–2.28], I2 = 0%, PQ = 0.630). Moreover, clinicopathological parameter data analysis showed that elevated TIMP-1 levels were significantly associated with lymph node metastasis (N1/N2/N3 vs N0: OR = 2.92, 95% CI [1.95–4.38]) and higher TNM stages (III/IV vs I/II: OR = 2.73, 95% CI [1.23–6.04]).ConclusionBoth TIMP-1-positive IHC staining and high serum/plasma TIMP-1 levels are poor prognostic factors for the survival of gastrointestinal cancer. In addition, TIMP-1 overexpression was correlated with more advanced clinicopathological features.

Regulative effect of Taohong Siwu decoction on extracellular matrix of endometrium in drug-induced abortion.

To explore the effects of Taohong Siwu decoction (, THSWD) on the extracellular matrix of endometrium in rats following drug-induced abortion. Thirty-six pregnant female rats were administered mifepristone and misoprostol to induce abortion, and amounts of uterine bleeding were recorded. Pathological damage and collagen accumulation were detected by hematoxylin-eosin staining and Masson's trichrome staining in uterus, respectively. Myeloperoxidase was evaluated by immunohistochemistry.The expression levels of fibronectin, laminin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were quantified using western blotting. THSWD could promote endometrial protection in rats following drug-induced abortion. The contents of cellulose and myeloperoxidase were significantly decreased in uterine tissue of THSWD-treated groups. Moreover, THSWD significantly decreased the expression levels of fibronectin, laminin, and TIMP-1. THSWD also significantly increased MMP-9 expression and the MMP-9/TIMP1 ratio. THSWD plays a critical role in endometrial protection by reducing extracellular matrix deposition and uterine fibrosis. These effects may have been achieved by increasing MMP-9, reducing TIMP-1, and/or altering the ratio of MMP-9/TIMP-1.