Tissue Inhibitor Of Metalloproteinase-1 Levels Research Articles

Differential Effects of Sertraline and Penfluridol on EMT and ECM Remodeling in Glioblastoma Cell Lines

Background and Purpose: Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis due to rapid recurrence, chemoresistance, and limited efficacy of standard therapies. Epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling are critical processes in GBM progression and metastasis. The aim of this study is to examine the potential effects of sertraline and penfluridol on the EMT process and gelatinase activity in human glioblastoma cell lines. Methods: U87 and U251 human glioblastoma cells were treated with sertraline and penfluridol at previously identified IC50 doses. Protein levels of EMT markers, E-cadherin, vimentin, Snail, Slug, Twist1, phospho-Akt (p-Akt), and tissue inhibitor of metalloproteinases-2 (TIMP-2), were evaluated using Western blotting. Additionally, the impact of sertraline and penfluridol on the release and activity of MMP-2 and MMP-9 were assessed through gelatin zymography. Results: Both sertraline and penfluridol significantly reduced vimentin expression in U251 cells, indicating inhibition of the mesenchymal phenotype. Conversely, these drugs increased vimentin levels in U87 cells, highlighting cell line-specific differences. Sertraline and penfluridol also increased TIMP-2 levels in U251 cells but not in U87 cells. Neither drug altered MMP-2 or MMP-9 activity in either cell line, suggesting that their effects on ECM remodeling may be mediated through TIMP-2 upregulation rather than direct modulation of gelatinase activity. Conclusion: These findings suggest that sertraline and penfluridol potentially inhibit EMT and reduce ECM degradation in U251 cells but exert contrasting effects in U87 cells. This highlights the heterogeneity of GBM tumors and the importance of personalized therapeutic approaches.

Osthole Ameliorates Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition via PI3K/Akt/NF-κB Pathway in Chronic Rhinosinusitis with Nasal Polyps

Introduction: Osthole, a naturally occurring coumarin derivative, has been isolated from the traditional Chinese medicinal herb Cnidium monnieri. This compound exhibits a range of pharmacological properties, including anticancer, antioxidant, anti-inflammatory, and immunomodulatory effects. The objective of this study was to investigate the role of osthole in tissue remodeling in chronic rhinosinusitis with nasal polyp (CRSwNP). Methods: The effects of osthole on nasal polyp (NP) formation were examined within a mouse model of NPs induced by cigarette smoke (CS). The detection of polypoid changes and goblet cell metaplasia was achieved through the use of hematoxylin-eosin and periodic acid-Schiff staining, respectively. The levels of TGF-β1, matrix metalloproteinases 2, 7, 9, and 12 (MMP2, MMP7, MMP9, MMP12), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1) in nasal lavage fluid were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was employed to ascertain the expression of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, ZO-1, α-SMA, and vimentin), as well as the activity of the PI3K/AKT/NF-κB pathway. The expression of E-cadherin in nasal epithelium was determined through immunohistochemistry. Results: In the OVA+SEB or CS-exposed NP mouse model, osthole was observed to reduce the incidence of polypoid changes and goblet cells, while simultaneously increasing the expression of E-cadherin in the epithelium when compared to the CS-treated group. After treatment with osthole, the levels of TGF-β1, MMP2, MMP7, MMP9, and MMP12 in nasal lavage fluid were observed to decrease, while the levels of TIMP-1 were found to increase. In vitro, cigarette smoke extract was observed to downregulate the expression of E-cadherin and ZO-1, while simultaneously upregulating the expression of α-SMA and vimentin. Moreover, osthole upregulated the expression of E-cadherin and ZO-1 while downregulating the expression of α-SMA and vimentin. This effect of osthole was reversed by PI3K/AKT/NF-κB pathway agonists. Conclusion: Osthole attenuates CS exposure-induced EMT via the PI3K/AKT/NF-κB pathway, providing a theoretical and experimental basis for its clinical application in the treatment of CRSwNP.

Predictive Value of Urinary KIM-1, TIMP-2 and sTREM-1 for Contrast-Induced Acute Kidney Injury in Elderly Patients After Percutaneous Coronary Intervention.

We aimed to address the predictive value of urinary kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinases-2 (TIMP-2) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for contrast-induced acute kidney injury (CI-AKI) in elderly patients after percutaneous coronary intervention (PCI). One hundred thirty-six patients who underwent PCI were separated into the CI-AKI group (n = 36) and the non-CI-AKI group (n = 100) based on CI-AKI occurrence after operation, and their general data were collected. Blood and urine specimens were collected before operation (at the time of admission) and 6h, 12h, 24h and 48h after the operation and preserved for future use. Serum creatinine (Scr) levels were tested and an estimated glomerular filtration rate (eGFR) was counted. Urinary KIM-1, TIMP-2 and sTREM-1 levels were assessed and the preoperative and general data as well as postoperative urinary KIM-1, TIMP-2 and sTREM-1 levels were compared. The early diagnostic value of urinary KIM-1, TIMP-2 and sTREM-1 at 6hours postoperatively for CI-AKI was analyzed by receiver operating characteristic (ROC) curve. After 48h of operation, Scr in the CI-AKI group was higher versus the non-CI-AKI group. At 24h and 48h postoperatively, eGFR in the CI-AKI group was lower versus the non-CI-AKI group; urinary KIM-1 and sTREM-1 in the CI-AKI group were higher in contrast to the non-CI-AKI group; TIMP-2 in the CI-AKI group was higher versus that in the non-CI-AKI group. ROC curve analysis showed that the areas under the curve (AUCs) for urine KIM-1, TIMP-2, and sTREM-1 in diagnosing CI-AKI at 6hours postoperatively were 0.852 (95% CI: 0.768-0.936), 0.810 (95% CI: 0.723-0.898), and 0.874 (95% CI: 0.804-0.943), and the cut-off values were 45.93 ng/L, 1.63 ng/mL, and 61.48 ng/L, respectively, with sensitivities of 66.70%, 58.30%, and 72.20%, and specificities of 95.00%, 93.00%, and 91.00%, respectively (all P < 0.05). Urinary KIM-1, TIMP-2 and sTREM-1 can respond to early changes in renal function after PCI and have good application value in the early diagnosis of CI-AKI.

Tissue inhibitor of metalloproteinase-1 and fibroscan as predictors for nonalcoholic fatty liver disease in chronic kidney disease patients attending Assiut University Hospitals

Background Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share mechanistic pathways related to metabolic dysfunction. The aim of this study was assessing prevalence of nonalcoholic liver disease among patients with CKD. in addition to, determine the relationship between the severity of fatty liver in nonalcoholic liver disease assessed by liver enzymes and tissue inhibitor of metalloproteinase-1 (TIMP-1). Patients and methods The current study enrolled a total of 80 patients with different stages of CKD. It was conducted in the period between March 2020 and March 2021. All patients were subjected to thorough medical history, clinical examination, baseline laboratory data, ultrasound, fibroscan, and also, the level of TIMP-1 was assessed. Results A total of 15 (18.8%) patients with CKD had NAFLD while the other 65 (81.2%) patients did not have NAFLD. Patients with NAFLD had significantly higher BMI and TIMP-1. There was a positive correlation between the grade of NAFLD as detected by fibroscan and the stage of CKD. Also, the NAFLD group had a significant difference as regard liver stiffness where the majority (84.6%) of patients without NAFLD had f0 and the majority (73.3%) of those with NAFLD had f1. Predictors for the development of NAFLD among patients with CKD were; TIMP-1, estimated glomerular filtration rate, and degree of fibrosis. TIMP-I at cutoff point greater than 21, has 97.2% accuracy for prediction of NAFLD in patients with CKD while f1 degree of fibroscan has 89.7% accuracy for prediction of NAFLD in patients with CKD. Conclusion Patients with CKD are vulnerable to develop NAFLD. Early detection of those patients may help in improving their outcomes. Also, TIMP-1 is considered as a novel biomarker for early diagnosis of NAFLD in patients with CKD. fibroscan is considered an available, cheap, and noninvasive method for assessment of NAFLD severity.

High-affinity ssDNA aptamer and chemiluminescent aptasensor for TIMP-1 detection in human serum

TIMP-1 (Tissue Inhibitor of Metalloproteinases-1) is a protein involved in regulating extracellular matrix (ECM) degradation. It is recognized as a significant biomarker for cancer diagnosis. This study aimed to develop and characterize a single-stranded DNA (ssDNA) aptamer targeting human TIMP-1 protein with high affinity and specificity. A magnetic beads-based SELEX process combined with qPCR was used to select aptamers over seven rounds. The enriched ssDNA library was analyzed using high-throughput sequencing to identify candidate sequences, and these sequences were characterized using surface plasmon resonance (SPR) and binding assays to evaluate their affinity and specificity. The selected ssDNA aptamer demonstrated a dissociation equilibrium constant (KD) of 0.41 nM and a very slow off-rate, enabling effective capture of TIMP-1 in serum samples. Furthermore, a chemiluminescent aptasensor was developed for TIMP-1 detection, which exhibited high specificity and a broad linear detection range from 1 to 500 ng/mL in human serum. The developed ssDNA aptamer targeting TIMP-1 shows high affinity and specificity, and the chemiluminescent aptasensor demonstrates promising potential for clinical diagnosis of TIMP-1 levels in human serum.Graphical abstract

PDGFRα-positive cell-derived TIMP-1 modulates adaptive immune responses to influenza A viral infection.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs), but little is known about the role of TIMP-1 in regulating the pathogenesis of influenza A virus (IAV) infection. Here, we performed both in vivo and in vitro experiments to investigate the regulation and function of TIMP-1 during IAV infection. Specifically, plasma levels of TIMP-1 are significantly increased in human subjects and wild-type (WT) mice infected with 2009 H1N1 IAV compared with levels in uninfected controls. Also, TIMP-1 is strikingly upregulated in PDGFRα positive (PDGFRα+) cells in IAV-infected murine lungs as demonstrated using conditional KO (cKO) mice with a specific deletion of Timp-1 in PDGFRα+ cells. Our in vitro data indicated that TIMP-1 is induced by transforming growth factor-β (TGF-β) during lipofibroblasts (lipoFBs)-to-myofibroblast (myoFB) transdifferentiation. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. IAV-infected Timp-1-deficient mice showed increased macrophages, and B and T cell counts in bronchoalveolar lavage (BAL) on day 7 postinfection (p.i.), but reduced BAL neutrophil counts. Increased Cxcl12 levels were detected in both BAL cells and lungs from Timp-1-deficient mice on day 3 p.i. Taken together, our data strongly link TIMP-1 to IAV pathogenesis. We identified that PDGFRα-lineage cells are the main cellular source of elevated TIMP-1 during IAV infection. Loss of Timp-1 attenuates IAV-induced mortality and promotes T and B cell recruitment. Thus, TIMP-1 may be a novel therapeutic target for IAV infection.NEW & NOTEWORTHY Our data strongly link tissue inhibitor of metalloproteinases-1 (TIMP-1) to influenza A virus (IAV) pathogenesis. TIMP-1 is highly increased in PDGFRα-lineage cells during IAV infection. Transforming growth factor-β (TGF-β) induces TIMP-1 during lipofibroblast (lipoFB)-to- myofibroblast (myoFB) transdifferentiation. Timp-1 deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. TIMP-1 may be a novel therapeutic target for IAV infection.

Transcoronary study of biomarkers in patients with heart failure: Insights into intracardiac production.

Biomarkers are pivotal in the management of heart failure (HF); however, their lack of cardiac specificity could limit clinical utility. This study aimed to investigate the transcoronary changes and intracardiac production of these biomarkers. Transcoronary gradients for B-type natriuretic peptide (BNP) and five novel biomarkers-galectin-3 (Gal-3), soluble suppression of tumourigenicity 2 (sST2), tissue inhibitor of metalloproteinase 1 (TIMP-1), growth differentiation factor 15 (GDF-15) and myeloperoxidase (MPO)-were determined using femoral artery (FA) and coronary sinus (CS) samples from 30 HF patients and 10 non-HF controls. Intracardiac biomarker production was assessed in an HF canine model using real-time quantitative PCR (qPCR) and western blot (WB) analysis. Compared with the control group, levels of all detected biomarkers were significantly elevated in the HF group, while transcoronary gradients were only observed for BNP, Gal-3 and TIMP-1 levels in the HF group (BNP: FA: 841.5±727.2ng/mL vs. CS: 1132.0±959.1ng/mL, P=0.005; Gal-3: FA: 9.5±3.0ng/mL vs. CS: 19.7±16.4ng/mL, P=0.002; and TIMP-1: FA: 286.7±68.9ng/mL vs. CS: 377.3±108.9ng/mL, P=0.001). Real-time qPCR and WB analysis revealed significant elevation of BNP, Gal-3 and TIMP-1 in the cardiac tissues of the HF group relative to other groups. This study provided evidence of transcoronary changes in BNP, Gal-3 and TIMP-1 levels in HF patients, offering insights into their intracardiac production. These findings enhance the understanding of the biology of these biomarkers and may inform their clinical application.

MMP-3 and TIMP-1 as prognostic biomarkers in VZV-induced retinal necrosis.

Acute retinal necrosis (ARN) caused by varicella-zoster virus (VZV) is associated with changes in specific proteins in the eye's fluid, particularly matrix metalloproteinase-3 (MMP-3), an enzyme that breaks down tissue structures, and tissue inhibitor of metalloproteinase-1 (TIMP-1), which regulates MMP activity. This study aims to investigate how these proteins correlate with the progression of ARN. We analyzed aqueous humor samples from 33 patients with ARN and 23 control patients with virus-negative uveitis. MMP-3 levels were measured using immunoturbidimetry, and TIMP-1 levels were determined using an enzyme-linked immunosorbent assay. We examined the relationships between these protein levels and clinical findings using statistical correlation methods. MMP-3, TIMP-1 were significantly higher in the aqueous humor of ARN patients compared to the controls (P<0.0001). Correlation analysis revealed a significant correlation between MMP-3 levels and TIMP-1 (r = 0.460, P = 0.007). The upregulation of MMP-3 and TIMP-1 was found to parallel VZV DNA load and IL-6 levels. Additionally, they exhibited negative correlation with best corrected visual acuity (BCVA) and positive correlation with the percentage of active retinal necrosis area.MMP-3 was markedly enhanced in all 14 cases of retinal detachment (RD), whereas TIMP-1 levels were significantly reduced in the same cohort of eyes. Patients with initial higher TIMP-1 levels have a significantly increased risk of developing RD, with a hazard ratio (HR) of 3.152 (95% CI, 1.082-9.18). The imbalance between MMP-3 and TIMP-1 may play a critical role in the development and severity of ARN. Measuring these proteins in the eye's aqueous humor could be valuable for assessing disease progression and guiding treatment strategies, potentially improving outcomes for patients with virus-induced retinal diseases.

Expression of MMP-2, MMP-9 and TIMP-2 in pituitary tumors and their relationship with cavernous sinus invasion.

To evaluate the expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-2 (TIMP-2) in pituitary tumors and investigate their correlation with circulating plasma proteins and cavernous sinus invasion. In addition, the Ki-67 index was also assessed. Seventy-four patients (37 females) with pituitary adenomas were included, with preoperative peripheral blood collected in 29 cases. Tumor samples were evaluated for MMP-2, MMP-9, TIMP-2 and Ki-67 expression by immunohistochemistry. Protein plasma was semi-quantitatively detected using a commercial membrane antibody array. Sixteen patients presented tumors invading the cavernous sinus. MMP-2 and TIMP-2 were slightly increased in these tumors compared to the noninvasive group, but the difference was not statistically significant. MMP-9 and TIMP-2 plasma concentrations did not correlate with tumor protein expression and also did not differ between the two groups. MMP-2 was not detected in plasma in any case. No statistically significant difference was observed when different tumor subtypes were considered. A significant difference was observed in tumor size (3.4 cm (2.8-4.9) vs 1.9 cm (1.3-2.6); P < 0.001) and in the Ki-67 index (1.8% (0.3-2.5) vs 0.5% (0.2-1.0); P = 0.01) between the invasive and noninvasive groups. In this cohort, we found no significant correlation between tissue and plasma levels of MMP-2, MMP-9 and TIMP-2 and cavernous sinus invasion in pituitary tumors. Further investigation is needed to elucidate the potential role of these markers in the invasiveness of pituitary tumors.

Plasma levels of matrix metalloproteinases in early psychosis, anxiety and depression: Evidence from the ALSPAC cohort

BackgroundConverging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs’ functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood–brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). MethodsThe present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking. ResultsThere was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06–1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22–1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19–1.72). There was no evidence for an association between MMPs and psychotic disorders. ConclusionsThe study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.

Effects of Acute Maximum-Intensity Exercise on Matrix Metalloproteinase-2, -9, and Tissue Inhibitor of Metalloproteinase-1 Levels in Adult Males with Type 1 Diabetes Mellitus Treated with Insulin Pumps.

Background: Dysregulation of matrix metalloproteinases (MMPs) activity is considered one of the potential causes of vascular complications in diabetic patients. Since training volume may influence MMPs levels in varying ways, the aim of our study was to evaluate changes in MMPs levels following acute maximum-intensity exercise in male patients with type 1 diabetes mellitus (T1DM). Methods: This study included 24 male T1DM patients and 10 healthy controls. Aerobic capacity was evaluated with a treadmill test. Levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured both before the aerobic capacity test and 60 min after its completion utilizing enzyme-linked immunosorbent assay (ELISA) system kits. Results: Before the aerobic capacity test only, MMP-9 serum levels were significantly elevated in the T1DM group compared to the controls. Following maximum-intensity exercise, the levels of MMP-2, MMP-9, and TIMP-1 were significantly higher in T1DM patients than in the control group. Between-group comparisons revealed that maximum-intensity exercise induced a statistically significant increase in MMP-2 serum levels from baseline in T1DM patients compared to controls. Conclusions: Our findings suggest that high-intensity exercise in T1DM patients leads to dysregulation of MMPs, as manifested by a significant increase in MMP-2 levels. This dysregulation may play a role in the development of vascular complications in diabetic patients.

Endogenous Tissue Inhibitor of Metalloproteinase-2 Levels Are Associated With High-Quality Neat Semen but Unrelated to Sperm Cryoresistance in Bulls.

Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) is part of the tissue inhibitors of the metalloproteinases (TIMPs) family. Its primary function is to regulate the activity of matrix metalloproteinases (MMPs) across various tissues, including those of the reproductive system. This study aimed to quantify the natural levels of TIMP-2 in seminal plasma (SP) and sperm membrane (SM) of bulls, explore potential associations between TIMP-2 levels and semen quality parameters, and examine the relationship between TIMP-2 levels and sperm cryoresistance in bulls. Thirty semen samples from Frieswal breeding bulls were categorized into two groups based on their initial progressive motility (IPM): Good (IPM ≥ 70%; n = 21) and Poor (IPM ≤ 40%; n = 9). The samples were evaluated for their quality parameters at the fresh stage, and TIMP-2 levels were measured in SP and SM using a bovine-specific ELISA kit. Following cryopreservation of Good samples (n = 21), post-thaw motility (PTM) was used to further classify samples into Freezeable (PTM ≥ 50%; n = 14) and Non-Freezable (PTM < 50%; n = 7) groups. In frozen-thawed samples, sperm attributes, kinetics, and functional parameters were assessed, and the results were correlated with retrospective TIMP-2 levels of SP/SM. Our study revealed that the quantified levels of TIMP-2 ranged from 100.27 to 535.95 ng/L in SP and from 0 to 115.78 ng/10 million spermatozoa in SM. TIMP-2 levels in both SP and SM were significantly higher in Good ejaculates compared to Poor ejaculates (p < 0.01). Furthermore, total TIMP-2 levels in the SP/SM of semen samples from bulls showed a positive correlation with fresh semen attributes. However, SP/SM TIMP-2 levels in the Freezeable group did not show any significant differences compared to the Non-Freezable group in post-thaw semen quality attributes, kinetic parameters, and functional tests, except for a significant positive correlation (r = 0.530, p < 0.05) between sperm DNA integrity and SP-TIMP-2 levels. In conclusion, the findings suggested that TIMP-2 can be a positive regulator of semen quality at the neat stage. However, when it comes to the resilience of sperm to cryopreservation, the levels of TIMP-2 do not seem to exert any significant influence in breeding bulls.

Serum matrix metallopeptidase-9 levels in infantile epileptic spasms syndrome of unknown etiology

PurposeEpileptic spasms are the primary symptom of infantile epileptic spasms syndrome (IESS); however, their direct impact on blood–brain barrier (BBB) function is unknown. Matrix metallopeptidase-9 (MMP-9), degrades type IV collagen, a key component of the blood-brain barrier, while tissue inhibitor of metalloproteinase-1 (TIMP-1) suppresses its activity, protecting BBB integrity. This study aimed to assess serum MMP-9 and TIMP-1 levels in patients with IESS of unknown etiology. MethodsWe prospectively assessed serum MMP-9 and TIMP-1 levels prior to administering vigabatrin or adrenocorticotropic hormone therapy in patients with IESS of unknown etiology at Saitama Children’s Medical Center between February 2012 and December 2023. We compared these biomarkers between patients with epileptic spasms and age-matched controls and performed a curve regression analysis between the biomarkers and the frequency of epileptic spasms. Additionally, we assessed whether MMP-9 and TIMP-1 levels were diagnostic predictors of IESS. ResultsThis study included 22 patients with IESS (11 males) and 12 controls. Serum MMP-9 and MMP-9/TIMP-1 ratios were higher in patients with IESS than in controls (p < 0.001 and p = 0.002, respectively). A high frequency of epileptic spasms also led to higher serum MMP-9 levels (y = 0.0871x2 + 0.195x + 195.15, R² = 0.77, p < 0.001). Using MMP >188 ng/mL as the cutoff level, the sensitivity for diagnosing IESS was 95.5 %, the specificity was 75.0 %, the positive likelihood ratio was 3.82 (95 % confidence interval (CI) 1.43–10.22), and the relative risk was 8.75 (95 % CI 1.36–56.5). ConclusionPatients with IESS had elevated serum MMP-9 levels, suggesting an association between epileptic spasms and blood–brain barrier dysfunction. MMP-9 level measurement may be useful for diagnosing suspected patients.

Amelioration Potency of a Nano-Therapeutic Drug in Rats with Uninephrectomy and Cisplatin-induced Toxicity

While physicians describe drugs to treat diseases, these medications may have cytotoxic effects on certain organs, necessitating the use of some drugs to ameliorate such adverse effects. The study was conducted to investigate the protective behavior of nanoemulsified sodium salicylate on uninephrectomized rats injected with cisplatin to induce nephrotoxicity. Fifty adult male albino rats, aged five weeks and weighing approximately 100-120 g, were divided into five groups. The first group received 200 mg/kg/day i.p normal saline for 30 days. The second group was administrated 200 mg/kg/day of nanoemulsified salt of salicylic acid for 30 days. The third group, comprising uninephrectomized rats, was injected with two doses of cisplatin (20 mg/kg body weight) on alternate days from the start of the experiment to induce nephrotoxicity. The fourth group, also uninephrectomized, received 200 mg/kg/day i.p of nanoemulsified sodium salicylate for 30 days. The fifth group, uninephrectomized and treated with 200 mg/kg/day sodium salicylate nanoemlusion for 21 days, was subsequently injected with two doses of cisplatin, followed by continued nanoemulsified sodium salicylate treatment until day 30 from the start of the study. The results showed a significant increase in tissue inhibitor metalloproteinase 1 (TIMP-1), Hyaluronic acid (HA), malondialdehyde, kidney injury molecule -1(KIM-1), and nitric oxide in the nephrotoxic group injected with cisplatin compared to the control group. Additionally, there was an elevation in the mRNA expression of nephrotoxic group with uninephrectomy. However, nephrotoxic rats treated with nanoemulsified sodium salicylate exhibited only a modest increase in TIMP-1, HA, and KIM-1 levels, along with elevated expressions of podocin and nephrin compared to the healthy control group. These findings suggest that nanoemulsified sodium salicylate exerts a protective effect against cisplatin-induced nephrotoxicity in uninephrectomized.

Estrogen-dependent gene regulation: Molecular basis ofTIMP-1 as a sex-specific biomarker for acute lung injury.

Increased circulating tissue inhibitor of metalloproteinases-1 (TIMP-1) levels have been observed in patients with acute lung injury (ALI). However, the sex-specific regulation of TIMP-1 and the underlying molecular mechanisms have not been well elucidated. In this study, we found that plasma TIMP-1 levels were significantly higher in COVID-19 and H1N1 patients compared with those in healthy subjects (n = 25). TIMP-1 concentrations were significantly different between males and females in each disease group. Among female but not male patients, TIMP-1 levels significantly correlated with the PaO2/FiO2 ratio and hospital length of stay. Using the mouse model of ALI induced by the H1N1 virus, we found that TIMP-1 is strikingly induced in PDGFRα-positive cells in the murine lungs. Moreover, female mice showed a higher Timp-1 expression in the lungs on day 3 postinfection. Mechanistically, we observed that estrogen can upregulate TIMP-1 expression in lung fibroblasts, not epithelial cells. In addition, overexpression of estrogen receptor α (ERα) increased the TIMP-1 promoter activity. In summary, TIMP-1 is an estrogen-responsive gene, and its promoter activity is regulated by ERα. Circulating TIMP-1 may serve as a sex-specific marker, reflecting the severity and worst outcomes in female patients with SARS-CoV2- and IAV-related ALI.

Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

Characterization of oral biomarkers during early healing at augmented dental implant sites.

The aim of this study is to assess early wound healing expression of local angiogenic biomarkers following connective tissue graft (CTG) at dental implant sites. Twenty-eight subjects with single dental implants exhibiting a soft tissue dehiscence were included and randomly treated with CTG, either with coronally advanced flap (CAF) or with tunnel technique (TUN). Peri-implant crevicular fluid (PICF) was collected at the midfacial and midlingual aspect of the implant sites at baseline and at 3, 7, 14, 30, and 90 days after the surgical intervention. The expression of angiogenin (ANG), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinases-2 (TIMP-2), and vascular endothelial growth factor (VEGF) was investigated over a period of 3 months. Patient-reported outcomes, clinical measurements, and ultrasonography scans at multiple time points were also evaluated. The longitudinal regression revealed a significant difference in the expression of VEGF and TIMP-2 between CAF- and TUN-treated sites over 3 months (p = .033 and p = .004, respectively), whereas no significant differences were observed for ANG, FGF-2 and PDGF between the two groups. At 7 days, a direct correlation was observed between ANG levels and ultrasonographic color velocity in the CAF group (p < .001) and between ANG levels and ultrasonographic color power in the TUN group (p = .028). VEGF levels and ultrasonographic mean perfused area of the CTG were significantly correlated at the 7-day time point (p < .001 for both CAF and TUN). The expression of VEGF at 7 days was directly associated with mucosal thickness gain at 1 year (p < .001 for both groups). Early TIMP-2 expression showed an inverse correlation with time to recovery (p = .002). TIMP-2 levels at 3 months exhibited inverse correlations with mean dehiscence coverage (p = .004) and the rate of complete dehiscence coverage (p = .012). PICF biomarkers can be used to monitor early wound healing events following soft tissue grafting at implant sites. VEGF and TIMP-2 showed correlations with the 1-year clinical and volumetric outcomes, as well as with post-operative patient-reported outcomes and Doppler Ultrasonographic tissue perfusion-related parameters.

Correlation between matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 and white matter hyperintensities in patients with cerebral small vessel disease based on cranial magnetic resonance 3D imaging

ObjectiveThe objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). MethodsThis cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. ResultsThe sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. ConclusionSerum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.

Local proteolytic system indicators as suspective factors of keratolysis development after urgent keratoplasty

Purpose: to determine the concentration of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the tear of patients with cornea melting and to assess whether these factors can be used as prognostically significant biomarkers of keratolysis. Material and methods. 20 patients who underwent urgent penetrating keratoplasty were tested for cornea perforation (melting) before and after the procedure. For control, 12 healthy adults (24 eyes) were tested. The tear fluid was collected before the surgery and on the 7th day after it with the help of filtering paper. MMP-9 and TIMP-1 concentrations were determined by ELISA. The course of the early postoperative period was assessed according to the area of keratotransplant epithelization on the 7th day after surgery. Results. MMP-9 and TIMP-1 concentrations in the tears of all patients before the surgery were significantly higher than the ones of healthy controls. The patients who were supposed to have re-keratoplasty had a significantly higher MMP-9 concentration than the ones who expected the first keratoplasty. An uncomplicated early postoperative period showed a statistically significant decrease of MMP-9 and TIMP-1 concentrations, whilst the complicated one demonstrated a significant increase of both markers. The highest increase of both markers was shown by the patients who underwent re-keratoplasty. Conclusion. MMP-9 concentration in the tears is a valid marker of the clinical course of the early post-keratoplasty period. To ensure a successful donor cornea engraftment, the levels of MMP-9 and TIMP-1 in the tear must be high enough before the surgery and the concentration of the ferment should decrease timely after its main functions have been completed. A 2-fold (or greater) decrease of MMP-9 concentration in the tear on the 7th day after keratoplasty can be considered a marker of the favorable prognosis for engraftment.

Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) as a Prognostic Biomarker in Acute Kidney Injury: A Narrative Review.

Acute kidney damage (AKI) is a serious and common consequence among critically unwell individuals. Traditional biomarkers, such as serum creatinine, frequently fail to detect AKI in its early stages, necessitating the development of new accurate early biomarkers. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has emerged as a promising biomarker for predicting early AKI. The present narrative review investigates the role of TIMP-2 in AKI prediction in a variety of clinical scenarios. In the NephroCheck® test, TIMP-2 exceeds established biomarkers for the early identification of AKI in terms of sensitivity and specificity when combined with insulin-like growth factor-binding protein 7 (IGFBP-7). Elevated levels of these biomarkers can provide a warning signal for AKI two to three days before clinical symptoms appear. TIMP-2 and IGFBP-7 have high predictive values, with an area under the curve (AUC) typically above 0.8, indicating good predictive capacity. For example, the [TIMP-2] × [IGFBP-7] product produced an AUC of 0.85 in surgical patients at high risk. In critically ill patients, a threshold of 0.3 (ng/mL)2/1000 demonstrated 92% sensitivity and 72% specificity. Elevated TIMP-2 levels have been correlated with higher mortality rates and the need for renal replacement therapy (RRT). In sepsis-associated AKI (SA-AKI), TIMP-2 levels combined with clinical prognostic models improved predictive accuracy (AUC: 0.822). Furthermore, elevated urine TIMP-2 levels were good predictors of AKI in pediatric patients after cardiac surgery, with AUC-ROC values of up to 0.848. Urine output and the presence of concomitant disorders may influence the prognostic accuracy of these biomarkers; therefore, more research is needed to fully understand their utility. The predictive value of TIMP-2 could be strengthened by combining it with other clinical parameters, reinforcing its role in the early detection and treatment of AKI.