Tissue Inhibitor Of Metalloproteinase Research Articles

Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes.

To explore whether the regulation of matrix metalloproteinase 9 (MMP-9)/ tissue inhibitors of MMPs (TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture (EA) protects blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) rat model. Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA (MEA) group, and the MCAO + EA + HAT inhibitor (HATi) group. The MCAO model was generated by blocking the middle cerebral artery. EA was applied to Baihui (GV20). Samples were collected 1 or 3 d after reperfusion. Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury. The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and chromatin immunoprecipitation (ChIP). Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption. The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression, but HATi reversed these effects of EA. In addition, ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter. EA treatment at Baihui (GV20) regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke, which preserves the structural integrity of the BBB in MCAO rats. These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.

Effect of nonsurgical periodontal therapy with additional photodynamic therapy on the level of MMP-9 and TIMP-1 in GCF in chronic periodontitis patients-a preliminary pilot study

PurposeMatrix metalloproteinases (MMPs) catalyze degradation of extracellular matrix proteins. The activity of MMPs is controlled by tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the MMP-9/TIMP-1 ratio has been linked with chronic periodontitis (CP). Photodynamic therapy (PDT) uses visible light, photosensitizer and oxygen to eradicate pathogens. The aim of the study was to evaluate the presence of MMP-9 and TIMP-1 in gingival crevicular fluid (GCF) in chronic periodontitis patients before and after nonsurgical periodontal therapy with additional PDT. MethodsNineteen patients, each with CP, were included in the study. After periodontal examination one site with a probing depth (PD) ​≥ ​4 ​mm was selected. The patients received scaling and root planing (SRP) with additional PDT by means of HELBO® diode minilaser. Prior to treatment, and after 3 and 6 months, the following parameters were estimated from the same site: PD, gingival recession (GR), clinical attachment level (CAL), plaque index (PI), bleeding on probing (BOP) and sulcus fluid flow rate (SFFR). The levels of MMP-9 and TIMP-1 in GCF were determined. ResultsCompared to baseline, the levels of MMP-9 and TIMP-1 did not show statistically significant differences after 3 and 6 months. According to Spearman's rank correlations, MMP-9 was positively correlated with SFFR at all time points. PD, CAL and PI showed a statistically significant decrease compared to baseline (p ​< ​0.001). SFFR decreased but not significantly. ConclusionNonsurgical periodontal therapy in conjunction with PDT was clinically effective but it had no effect on the levels of MMP-9 and TIMP-1 in GCF.

Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.

Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we computed polygenic scores as proxies for plasma protein levels and validated their prediction accuracy in two independent cohorts. Association models between genetic proxies and cognitive performance highlighted the significance of TIMP2, also when the models were stratified by sex, APOE -ε4, and Aβ42 status. This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.

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.

Pirfenidone Alleviates Inflammation and Fibrosis of Acute Respiratory Distress Syndrome by Modulating the Transforming Growth Factor-β/Smad Signaling Pathway.

Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-β1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-β1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.

Ficus pumila fruit polysaccharide attenuate ovalbumin-induced allergic asthma in mice associated with changes in microbiota involving the lung-intestinal axis

Allergic asthma accounts for more than 50 percent of adult asthma in life. Glucocorticoids and leukotriene receptor antagonists are commonly used to treat asthma, but these drugs not only have high side effects but also cannot cure the disease. In contrast, natural active ingredients are relatively safe to the organism and show great potential for improving the organism. Polysaccharides, as the main active ingredient in aqueous extract, may be equally beneficial for biological activity. The aim of this study is to investigate the alleviating effect and mechanism of action of Ficus pumila fruit polysaccharide (FPP) and aqueous extract of Ficus pumila fruit (FPW) on mice with allergic asthma. The results showed that FPP and FPW could regulate the secretion of the cytokines IL-4, IL-5, IL-13, and IFN-γ. FPP and FPW also reduced the inflammation, mucus secretion, and collagen deposition in mouse lung tissue, and down-regulated the expression of matrix metallopeptidase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) proteins. In addition, FPP and FPW modulated the intestinal microbiota by augmenting the alpha diversity and adjusting the taxonomic composition at the phylum and family levels, thereby ensured the sustenance of regular physiological processes in the body. This study demonstrated that FPP and FPW may attenuate asthma by inducing beneficial microbiota in the gut-lung axis and provide an effective basis for the future clinical treatment of allergic asthma with Ficus pumila and the development and utilization of new anti-asthma drugs.

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells

ObjectivesMutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis. MethodsQuantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P < 0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U–13C6] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U–13C6] glucose and [U–13C5] glutamine isotopic tracing in SFD iRPE cells. ResultsQuantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U–13C6] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U–13C6] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U–13C5] glutamine tracing found evidence of altered malic enzyme activity. ConclusionsThis study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Chronic liver disease and fibrosis: A review of emerging biomarkers and therapeutic targets

Chronic liver disease (CLD) and fibrosis represent a significant global health burden, driven by a range of etiologies including viral hepatitis, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD). These conditions often progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC), underscoring the urgent need for effective diagnostic and therapeutic strategies. Emerging biomarkers and therapeutic targets offer promising avenues for early diagnosis and intervention in CLD and fibrosis. Biomarkers are crucial for the early detection and monitoring of CLD and fibrosis, allowing for timely therapeutic intervention. Serum biomarkers such as liver enzymes (ALT, AST), bilirubin, and platelet count have traditionally been used, but they lack specificity and sensitivity. Recent advances have identified novel biomarkers with improved diagnostic performance. For instance, serum levels of fibrosis markers like hyaluronic acid, procollagen type III N-terminal peptide (P3NP), and tissue inhibitor of metalloproteinases-1 (TIMP-1) have shown potential in assessing liver fibrosis. Additionally, non-invasive imaging techniques such as transient elastography and magnetic resonance elastography provide quantitative measures of liver stiffness, correlating with fibrosis stage. The pathogenesis of liver fibrosis involves complex interactions between hepatocytes, hepatic stellate cells (HSCs), and the extracellular matrix (ECM). HSCs play a central role in fibrogenesis by transforming into myofibroblasts that secrete collagen and other ECM components. Targeting the activation and proliferation of HSCs has emerged as a promising therapeutic strategy. Small molecule inhibitors, such as those targeting the PDGF and TGF-? signaling pathways, have shown efficacy in preclinical models. Furthermore, antifibrotic agents like simtuzumab, an anti-LOXL2 monoclonal antibody, are being evaluated in clinical trials for their potential to halt or reverse fibrosis progression. Another promising approach involves the modulation of the gut-liver axis. Dysbiosis and increased intestinal permeability contribute to liver inflammation and fibrosis. Probiotics, prebiotics, and fecal microbiota transplantation (FMT) are being explored for their potential to restore gut homeostasis and mitigate liver injury. Additionally, the role of the immune system in fibrosis has gained attention, with immune checkpoint inhibitors and anti-inflammatory agents being investigated for their ability to modulate immune responses and reduce fibrosis. Keywords: Chronic Liver Disease, Fibrosis, Biomarkers, Therapeutic Targets.

Assessment of cell cycle arrest biomarkers and neutrophil gelatinase-associated lipocalin to distinguish acute kidney injury from other diseases in dogs.

Cell cycle arrest biomarkers (tissue inhibitor of metalloproteinase-2 [uTIMP-2] and insulin-like growth factor binding protein 7 [uIGFBP7]), and neutrophil gelatinase-associated lipocalin (NGAL) variables are valuable biomarkers for early diagnosis of acute kidney injury (AKI) in people. To evaluate uTIMP-2, uIGFBP7, fractional excretion of NGAL (FeNGAL), and urinary to serum NGAL ratio (u/sNGAL) in healthy dogs, dogs with AKI, dogs with chronic kidney disease (CKD), and critically ill (CI) dogs. Forty-two client-owned dogs (healthy, n = 10; AKI, n = 11; CKD, n = 11; CI, n = 10). Prospective, observational study. After assessment of routine renal biomarkers, stress (uTIMP-2, uIGFBP7) and damage (NGAL) biomarkers were measured, using ELISA kits, and normalized to urinary creatinine (uCr). Normalized uTIMP-2 and [uTIMP-2] × [uIGFBP7]/uCr were significantly higher in the AKI group (median 151.9 [range, 2.2-534.2] and 62.9 [1.1-266.8] pg/mL respectively), compared to healthy dogs (0.3 [0.2-74.7]; P < .001 and 0.16 [0.1-58.1] pg/mL; P < .001), dogs with CKD (0.7 [0.3-742.5]; P = .04 and 0.37 [0.2-180.1] pg/mL; P = .03) and CI dogs (1.9 [0.2-37.0]; P = .03 and 0.8 [0.1-16.1] pg/mL; P = .02). Fractional excretion of NGAL was significantly higher in dogs with AKI (54.17 [7.93-155.32] %), than in healthy (0.03 [0.01-0.21] %; P < .001) and CI dogs (3.05 [0.05-28.86] %; P = .02). Normalized uTIMP-2, [uTIMP-2] × [uIGFBP7]/uCr, and FeNGAL can be valuable renal biomarkers for early diagnosis of AKI in dogs.

TLR2 and TLR4 Are Expressed in Epiretinal Membranes: Possible Links with Vitreous Levels of Complement Fragments and DAMP-Related Proteins.

Previous studies reported the expression of toll-like receptors (TLRs), merely TLR2 and TLR4, and complement fragments (C3a, C5b9) in vitreoretinal disorders. Other than pathogens, TLRs can recognize endogenous products of tissue remodeling as damage-associated molecular pattern (DAMPs). The aim of this study was to confirm the expression of TLR2 and TLR4 in the fibrocellular membranes and vitreal fluids (soluble TLRs) of patients suffering of epiretinal membranes (ERMs) and assess their association with disease severity, complement fragments and inflammatory profiles. Twenty (n = 20) ERMs and twelve (n = 12) vitreous samples were collected at the time of the vitrectomy. Different severity-staged ERMs were processed for: immunolocalization (IF), transcriptomic (RT-PCR) and proteomics (ELISA, IP/WB, Protein Chip Array) analysis. The investigation of targets included TLR2, TLR4, C3a, C5b9, a few selected inflammatory biomarkers (Eotaxin-2, Rantes, Vascular Endothelial Growth Factor (VEGFA), Vascular Endothelial Growth Factor receptor (VEGFR2), Interferon-γ (IFNγ), Interleukin (IL1β, IL12p40/p70)) and a restricted panel of matrix enzymes (Matrix metalloproteinases (MMPs)/Tissue Inhibitor of Metallo-Proteinases (TIMPs)). A reduced cellularity was observed as function of ERM severity. TLR2, TLR4 and myD88 transcripts/proteins were detected in membranes and decreased upon disease severity. The levels of soluble TLR2 and TLR4, as well as C3a, C5b9, Eotaxin-2, Rantes, VEGFA, VEGFR2, IFNγ, IL1β, IL12p40/p70, MMP7 and TIMP2 levels were changed in vitreal samples. Significant correlations were observed between TLRs and complement fragments and between TLRs and some inflammatory mediators. Our findings pointed at TLR2 and TLR4 over-expression at early stages of ERM formation, suggesting the participation of the local immune response in the severity of disease. These activations at the early-stage of ERM formation suggest a potential persistence of innate immune response in the early phases of fibrocellular membrane formation.

Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinases explored in relation to the severity and progression of diabetic retinopathy in patients with type 1 diabetes: baseline and prospective analyses

AimsTo explore whether circulating matrix metalloproteinase-2 (MMP-2), MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin, MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1), MMP-14, TIMP-2 and TIMP-3 were associated with the severity and progression of diabetic retinopathy...

Comprehensive bioinformatic profiling of matrix metalloproteinases and their inhibitors: Expression and interaction patterns in head and neck cancer toward predictive biomarkers and personalized therapies

ObjectiveMatrix metalloproteinases (MMPs) and Tissue inhibitors of metalloproteinases (TIMPs) are involved in the turnover of extracellular matrix (ECM) components. Overexpression of MMPs facilitates tumour progression by promoting ECM turnover, angiogenesis, and cell migration. Head and neck squamous cell carcinoma (HNSCC) exhibits significant upregulation of multiple MMPs and TIMPs, correlating with poor prognosis, using bioinformatics tools to analyse the expression profiles and prognostic significance of MMPs and TIMPs in HNSCC. Materials and methodsGEPIA and UALCAN databases were used to analyse the expression of MMPs and TIMPs in HNSCC tissues. Immunohistochemistry confirmed high protein levels of several MMPs in tumour samples. GeneMANIA, STRING, and Metascape analyses highlighted key functional relationships and pathways enriched in MMPs and TIMPs. Kaplan-Meier survival analyses were conducted to assess the prognostic significance of TIMPs in HNSCC. ResultsThe study found significant overexpression of MMP1, MMP2, MMP3, MMP9, and MMP14 in HNSCC tissues. Immunohistochemistry confirmed elevated protein levels of these MMPs in tumour samples. PPI network analyses indicated crucial interactions among MMPs and their regulatory pathways. TIMP1 was significantly upregulated in HNSCC, while TIMP3 downregulation correlated with increased MMP activity and tumour progression. According to Kaplan-Meier survival analyses, higher TIMP expression was associated with poor overall survival in HNSCC patients. ConclusionThis comprehensive study emphasises the dysregulation of MMPs and TIMPs in HNSCC, proposing them as potential biomarkers for early diagnosis and prognostic evaluation and suggesting them as therapeutic targets to improve clinical outcomes in HNSCC patients.

Expression of MMP2, MMP9, TIMP2 and TIMP3 genes in aortic dissection.

Thoracic aortic dissection (TAD) is a highly lethal disease occurring inside the aortic wall and is characterized by matrix degradation. Matrix metalloproteinases (MMPs) are members of a large endopeptidase family that function in the degradation of the extracellular matrix (ECM) proteins, the maintenance of the ECM, and the regulation of signaling in the aorta. MMPs are found in tissue with their natural inhibitors. Tissue inhibitors of metalloproteinases (TIMPs) are actively involved in both the activation and inhibition of MMPs. The present study was designed to determine the mRNA level gene expression differences of MMP2, MMP9, TIMP2 and TIMP3, which are considered to have an essential role in TAD, in aortic tissue and circulating monocyte cells. For the purpose of the present study, aortic vascular tissue and peripheral blood-derived monocyte cells were obtained from 10 patients with TAD and 10 control individuals. The gene expression levels of targeted genes (MMP2, MMP9, TIMP2 and TIMP3) were examined by droplet digital PCR. In research results, decreased expression of MMP9, TIMP2 and TIMP3 genes (P=0.043, P=0.009 and P=0.028, respectively) and increased ratio of MMP2/TIMP3 (P=0.012) were obtained in the aortic tissue. No changes were observed in terms of gene expression in monocyte cells. When the results obtained were evaluated within the framework of TAD pathogenesis, it was concluded that expression changes in MMP9, TIMP2 and TIMP3 genes may provide a sensitive environment in aortic tissue and may be associated with TAD formation. In addition, since the expression ratios of MMPs and TIMPs may reflect disease development, it was considered that the evaluation of MMPs along with TIMPs may be an appropriate and informative approach for future studies.

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study.

Epigenetic age estimators indicating faster/slower biological aging vs chronological age independently associate with several age-related outcomes; however, longitudinal associations with cognitive function are understudied. We examined associations of epigenetic age estimators with cognitive function measured annually. This longitudinal study consisted of older women enrolled in the Women's Health Initiative Memory Study with DNA methylation (DNAm) collected at baseline (1995-1998) from 3 ancillary studies and were followed up to 13 years. Global cognitive function was measured annually by Modified Mini-Mental State Examination (3MS; baseline-2007) and by modified Telephone Interview for Cognitive Status (TICS-m, 2008-2021). We calculated 5 epigenetic age estimators: extrinsic AgeAccel, intrinsic AgeAccel, AgeAccelPheno, AgeAccelGrim2, Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), and AgeAccelGrim2 components (DNA-based plasma protein surrogates). We estimated longitudinal epigenetic age estimator-cognitive function associations using linear mixed-effects models containing age, education, race or ethnicity, and subsequently alcohol, smoking, body mass index, and comorbidities. We examined effect modification by APOE ε4 carriage. A total of 795 participants were enrolled. The mean baseline age was 70.8 ± 4 years (10.7% Black, 3.9% Hispanic or Latina, 85.4% White), A 1-SD (0.12) increment in DunedinPACE associated with faster annual declines in TICS-m scores in minimally adjusted (β = -0.118, 95% CI -0.202 to -0.034; p = 0.0006) and fully adjusted (β = -0.123, 95% CI -0.211 to -0.036; p = 0.006) models. AgeAccelPheno associated with faster annual declines in TICS-m with minimal adjustment (β = -0.091, 95% CI -0.176 to -0.006; p = 0.035) but not with full adjustment. No other epigenetic age estimators associated with changes in 3MS or TICS-m. Higher values of DNAm-based surrogates of growth differentiation factor 15, beta-2 microglobulin, Cystatin C, tissue inhibitor metalloproteinase 1, and adrenomedullin associated with faster annual declines in 3MS and TICS-m. Higher DNAm log A1c associated with faster annual declines in TICS-m only. DunedinPACE associated with faster annual declines in 3MS among APOE ε4 carriers but not among noncarriers (p-interaction = 0.020). Higher DunedinPACE associated with faster declines in TICS-m and 3MS scores among APOE ε4 carriers. DunedinPACE may help identify older women at risk of future cognitive decline. Limitations include the ancillary studies that collected epigenetic data not designed to study epigenetics and cognitive function. We examined epigenetic age estimators with global cognitive function and not specific cognitive domains. Findings may not generalize to men and more diverse populations.

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.

Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension.

Matrix Metalloproteinases (MMPs) are drivers of many diseases including cancer and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are human proteins that inhibit MMPs and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties of a drug candidate, such as complete MMP inhibition, low toxicity and immunogenicity, high tissue permeability and others. A major challenge with TIMPs, however, is their formulation and delivery, as these proteins are quickly cleared from the bloodstream due to their small size. In this study, we explore a new method for plasma half-life extension for the N-terminal domain of TIMP2 (N-TIMP2) through appending it with a long intrinsically unfolded tail containing a random combination of Pro, Ala, and Thr (PATylation). We design, produce and explore two PATylated N-TIMP2 constructs with a tail length of 100- and 200-amino acids (N-TIMP2-PAT100 and N-TIMP2-PAT200, respectively). We demonstrate that both PATylated N-TIMP2 constructs possess apparent higher molecular weights compared to the wild-type protein and retain high inhibitory activity against MMP-9. Furthermore, when injected into mice, N-TIMP2-PAT200 exhibited a significant increase in plasma half-life compared to the non-PATylated variant, enhancing the therapeutic potential of the protein. Thus, we establish that PATylation could be successfully applied to TIMP-based therapeutics and offers distinct advantages as an approach for half-life extension, such as fully genetic encoding of the gene construct, mono-dispersion, and biodegradability. Furthermore, PATylation could be easily applied to N-TIMP2 variants engineered to possess high affinity and selectivity toward individual MMP family members, thus creating attractive candidates for drug development against MMP-related diseases.

Expression of hsa-miRNA-15b, -99b, -181a and Their Relationship to Angiogenesis in Renal Cell Carcinoma.

MicroRNAs (miRNAs) play a regulatory role in various human cancers. The roles of hsa-miR-15a-5p, hsa-miR-99b-5p, and hsa-miR-181a-5p have not been fully explored in the angiogenesis of renal cell carcinoma (RCC). The present study aimed to evaluate the expression of these miRNAs in tumorous and adjacent healthy tissues of RCC. Paired tumorous and adjacent normal kidney tissues from 20 patients were studied. The expression levels of hsa-miR-15b-5p, hsa-miR-99b-5p, and hsa-miR-181a-5p were quantified by TaqMan miRNA Assays. Putative targets were analyzed by qRT-PCR. Significant downregulation of all three miRNAs investigated was observed in tumorous samples compared to adjacent normal kidney tissues. Spearman analysis showed a negative correlation between the expression levels of miRNAs and the pathological grades of the patients. Increased expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α), a tissue inhibitor of metalloproteinases-1 (TIMP-1), was observed in tumorous samples compared to adjacent normal tissues. Depletion of tissue inhibitors of metalloproteinase-2 (TIMP-2) and metalloproteinase-2 (MMP-2) was detected compared to normal adjacent tissues. The examined miRNAs might function as contributing factors to renal carcinogenesis. However, more prospective studies are warranted to evaluate the potential role of miRNAs in RCC angiogenesis.

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.

Coordinated molecular and ecological adaptations underlie a highly successful parasitoid.

The success of an organism depends on the molecular and ecological adaptations that promote its beneficial fitness. Parasitoids are valuable biocontrol agents for successfully managing agricultural pests, and they have evolved diversified strategies to adapt to both the physiological condition of hosts and the competition of other parasitoids. Here, we deconstructed the parasitic strategies in a highly successful parasitoid, Trichopria drosophilae, which parasitizes a broad range of Drosophila hosts, including the globally invasive species D. suzukii. We found that T. drosophilae had developed specialized venom proteins that arrest host development to obtain more nutrients via secreting tissue inhibitors of metalloproteinases (TIMPs), as well as a unique type of cell-teratocytes-that digest host tissues for feeding by releasing trypsin proteins. In addition to the molecular adaptations that optimize nutritional uptake, this pupal parasitoid has evolved ecologically adaptive strategies including the conditional tolerance of intraspecific competition to enhance parasitic success in older hosts and the obligate avoidance of interspecific competition with larval parasitoids. Our study not only demystifies how parasitoids weaponize themselves to colonize formidable hosts but also provided empirical evidence of the intricate coordination between the molecular and ecological adaptations that drive evolutionary success.