المؤلفون: Bouras, Emmanouil, Kim, Andre, Lin, Yi, Morrison, John, Du, Mengmeng, Albanes, Demetrius, Barry, Elizabeth, Baurley, James, Berndt, Sonja, Bien, Stephanie, Bishop, Timothy, Brenner, Hermann, Budiarto, Arif, Burnett-Hartman, Andrea, Campbell, Peter, Carreras-Torres, Robert, Casey, Graham, Cenggoro, Tjeng, Chan, Andrew, Chang-Claude, Jenny, Conti, David, Cotterchio, Michelle, Devall, Matthew, Diez-Obrero, Virginia, Dimou, Niki, Drew, David, Figueiredo, Jane, Giles, Graham, Gruber, Stephen, Gunter, Marc, Harrison, Tabitha, Hidaka, Akihisa, Hoffmeister, Michael, Huyghe, Jeroen, Joshi, Amit, Kawaguchi, Eric, Keku, Temitope, Kundaje, Anshul, Le Marchand, Loic, Lewinger, Juan, Li, Li, Lynch, Brigid, Mahesworo, Bharuno, Männistö, Satu, Moreno, Victor, Murphy, Neil, Newcomb, Polly, Obón-Santacana, Mireia, Ose, Jennifer, Palmer, Julie, Papadimitriou, Nikos, Pardamean, Bens, Pellatt, Andrew, Peoples, Anita, Platz, Elizabeth, Potter, John, Qu, Conghui, Rennert, Gad, Ruiz-Narvaez, Edward, Sakoda, Lori, Schmit, Stephanie, Shcherbina, Anna, Stern, Mariana, Su, Yu-Ru, Tangen, Catherine, Thomas, Duncan, Tian, Yu, Um, Caroline, van Duijnhoven, Franzel, Van Guelpen, Bethany, Visvanathan, Kala, Wang, Jun, White, Emily, Wolk, Alicja, Woods, Michael, Ulrich, Cornelia, Hsu, Li, Gauderman, W, Peters, Ulrike, Tsilidis, Konstantinos, Qi, Lihong

المصدر: American Journal of Clinical Nutrition. 118(5)

مصطلحات موضوعية: CRC, European, GWIS, SYN2, TIMP4, colorectal cancer, folate, folic acid, genome-wide, interaction, synapsin, tissue inhibitor of metalloproteinase 4, Humans, Folic Acid, Risk Factors, Colorectal Neoplasms, Case-Control Studies, Dietary Supplements

الوصف: BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folates role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/04x3z65rTest

المؤلفون: Tooran Akbari, Toktam Kazemi Fard, Reza Fadaei, Rahim Rostami, Nariman Moradi, Monireh Movahedi, Soudabeh Fallah

المصدر: Journal of Cardiovascular and Thoracic Research, Vol 15, Iss 4, Pp 223-230 (2023)

مصطلحات موضوعية: coronary artery disease (cad), cytokines, inflammation, matrix metallopeptidase 9 (mmp-9), tissue inhibitor of metalloproteinase (timp-1), Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Introduction: Coronary artery disease (CAD) is the main cause of death and is characterized by atherosclerosis in coronary arteries. Inflammation plays a crucial role in the progression and development of atherosclerosis. Methods: The present study consisted of 132 Iranian individuals who underwent coronary angiography, 65 patients with CAD, and 67 controls. The matrix metalloproteinase-9 (MMP-9), TNF-α, IL-6, and vitamin D serum levels were measured by the ELISA technique. The gene expression of MMP-9 and tissue inhibitors of metalloproteinase (TIMP-1) was estimated by real-time PCR assay. Results: A considerable increase in levels and PBMC gene expression of MMP-9 and serum levels of IL-6 and TNF-α were found in CAD patients compared with controls. A significant decrease was detected in vitamin D levels of CAD patients in comparison with controls. A considerable direct correlation was found between MMP-9 levels and MMP-9 and TIMP1 gene expression in CAD patients. MMP-9 levels positively correlated with LDL-C in CAD patients. The correlation between TIMP1 gene expression and IL-6 levels was also negatively significant. There were positive correlations between MMP-9 levels with IL-6 and TNF-α serum levels in CAD patients. Conclusion: This study showed that the interaction between MMPs, TIMP1, and cytokines could play a role in the pathogenesis of atherosclerosis. The present study suggested that high levels of TNF-α and IL-6 and vitamin D deficiency in our studied patients could disturb the MMP-9/TIMP-1 balance and lipid metabolism, leading to plaque formation/ rupture in predisposed CAD patients.

وصف الملف: electronic resource

العلاقة: https://jcvtr.tbzmed.ac.ir/PDF/jcvtr-15-223.pdfTest; https://doaj.org/toc/2008-5117Test; https://doaj.org/toc/2008-6830Test

الوصول الحر: https://doaj.org/article/249117eaaeeb4e18befd7e690a081a68Test

المؤلفون: Magdalena Kopańko, Magdalena Zabłudowska, Dariusz Pawlak, Beata Sieklucka, Anna Krupa, Katarzyna Sokołowska, Marta Ziemińska, Krystyna Pawlak

المصدر: Journal of Clinical Medicine, Vol 13, Iss 7, p 1847 (2024)

مصطلحات موضوعية: β-blockers, chronic kidney disease (CKD), metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase 2 (TIMP-2), inflammation, oxidative stress, Medicine

الوصف: Background: The purpose of the study was to determine whether the use of β-adrenoceptor antagonists (β-blockers) can affect metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in patients with chronic kidney disease (CKD) on conservative treatment. Methods: The circulating MMP-2/TIMP-2 system, proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the marker of oxidative stress—Cu/Zn superoxide dismutase (Cu/Zn SOD)—were measured in 23 CKD patients treated with β-blockers [β-blockers (+)] and in 27 CKD patients not receiving the above medication [β-blockers (−)]. Results: The levels of MMP-2, TIMP-2, and IL-6 were significantly lower in the β-blockers (+) than in the β-blockers (−) group, whereas Cu/Zn SOD concentrations were not affected by β-blocker use. There was a strong, independent association between MMP-2 and TIMP-2 in both analyzed patient groups. In the β-blockers (+) group, MMP-2 levels were indirectly related to the signs of inflammation, whereas in the β-blockers (−) group, the alterations in the MMP-2/TIMP-2 system were associated with the oxidative stress marker and CKD etiology. Conclusions: This study is the first to suggest that the use of β-blockers was associated with the reduction in IL-6 and the MMP-2/TIMP-2 system in CKD, providing a pharmacological rationale for the use of β-blockers to reduce inflammation and abnormal vascular remodeling in CKD.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2077-0383/13/7/1847Test; https://doaj.org/toc/2077-0383Test

الوصول الحر: https://doaj.org/article/3070d6e2819c4da8b94b7679aa2a5dc3Test

المؤلفون: 石原, 領

مصطلحات موضوعية: multiple myeloma, tissue inhibitor of metalloproteinase, tumour microenvironment, fibroblast

وصف الملف: application/pdf

الوصول الحر: https://ndlsearch.ndl.go.jp/books/R100000039-I13342454Test

Degree: 博士（保健学） -- 群馬大学

المؤلفون: Zi-Meng Xia, Meng-Yu Song, Yan-Ling Chen, Guozhen Cui, Dong Fan

المصدر: Frontiers in Cardiovascular Medicine, Vol 10 (2023)

مصطلحات موضوعية: tissue inhibitor of metalloproteinase 3, angiogenesis, heart rate, cardiovascular system, signal pathway, gene expression, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: BackgroundTissue inhibitor of metalloproteinase 3 (TIMP3) was recently demonstrated capable to regulate some gene expression in a myocardial infarction model. Here we aim to explore the gene expression profile in TIMP3-treated cardiomyocytes and related potential cardiovascular functions.MethodsTotal RNA extracted from cultured neonatal rat ventricular myocytes (NRVMs) were used for RNA sequencing analysis and real-time PCR. KEGG pathway enrichment assay and Ingenuity Pathway Analysis (IPA) were performed to study the signaling pathways and downstream effects. Western blot was used to detect phosphorylation of protein kinase B (Akt). A Cell Counting Kit-8 assay was employed to evaluate the proliferation of human umbilical vein endothelial cells (HUVECs). Contraction rate of NRVMs was measured with microscopy.ResultsRNA sequencing data showed that expression of 2,526 genes were significantly modulated by recombinant TIMP3 (rTIMP3, 100 ng/ml) in NRVMs. Some differentially expressed genes (DEGs) were validated with real-time PCR. Several KEGG pathways including the phosphoinositide-3-kinase (PI3K)-Akt pathway were significantly regulated by rTIMP3. Phosphorylation of Akt was increased by rTIMP3 and a PI3K inhibitor LY294002 suppressed rTIMP3-induced up-regulation of some genes. Some DEGs were predicted by IPA to increase vascularization, and some to decrease heart rate. RTIMP3 could reduce the contraction rate of NRVMs and its conditioned media increased the proliferation of HUVECs.ConclusionTIMP3 can regulate expression of multiple genes partly through PI3K. Some DEGs were associated with activation of vascularization and some with heart rate reduction. This study suggests that TIMP3 can potentially modulate cardiovascular functions via DEGs.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130388/fullTest; https://doaj.org/toc/2297-055XTest

الوصول الحر: https://doaj.org/article/fa05cccebeaa415ebc8752df14370088Test

المؤلفون: Raeeszadeh-Sarmazdeh, Maryam, Greene, Kerrie A, Sankaran, Banumathi, Downey, Gregory P, Radisky, Derek C, Radisky, Evette S

المصدر: Journal of Biological Chemistry. 294(24)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, 2.1 Biological and endogenous factors, Aetiology, Amino Acid Sequence, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Directed Molecular Evolution, Humans, Matrix Metalloproteinase 3, Matrix Metalloproteinase Inhibitors, Mutation, Protein Binding, Protein Conformation, Protein Domains, Tissue Inhibitor of Metalloproteinase-1, Two-Hybrid System Techniques, crystal structure, directed evolution, matrix metalloproteinase, metalloprotease, protease inhibitor, protein domain, protein engineering, protein structure, protein-protein interaction, tissue inhibitor of metalloproteinase, yeast surface display, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences

الوصف: Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs), enzymes that contribute to cancer and many inflammatory and degenerative diseases. The TIMP N-terminal domain binds and inhibits an MMP catalytic domain, but the role of the TIMP C-terminal domain in MMP inhibition is poorly understood. Here, we employed yeast surface display for directed evolution of full-length human TIMP-1 to develop MMP-3-targeting ultrabinders. By simultaneously incorporating diversity into both domains, we identified TIMP-1 variants that were up to 10-fold improved in binding MMP-3 compared with WT TIMP-1, with inhibition constants (Ki ) in the low picomolar range. Analysis of individual and paired mutations from the selected TIMP-1 variants revealed cooperative effects between distant residues located on the N- and C-terminal TIMP domains, positioned on opposite sides of the interaction interface with MMP-3. Crystal structures of MMP-3 complexes with TIMP-1 variants revealed conformational changes in TIMP-1 near the cooperative mutation sites. Affinity was strengthened by cinching of a reciprocal "tyrosine clasp" formed between the N-terminal domain of TIMP-1 and proximal MMP-3 interface and by changes in secondary structure within the TIMP-1 C-terminal domain that stabilize interdomain interactions and improve complementarity to MMP-3. Our protein engineering and structural studies provide critical insight into the cooperative function of TIMP domains and the significance of peripheral TIMP epitopes in MMP recognition. Our findings suggest new strategies to engineer TIMP proteins for therapeutic applications, and our directed evolution approach may also enable exploration of functional domain interactions in other protein systems.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0vs384t9Test

المؤلفون: Loomba, Rohit, Kayali, Zeid, Noureddin, Mazen, Ruane, Peter, Lawitz, Eric J, Bennett, Michael, Wang, Lulu, Harting, Eliza, Tarrant, Jacqueline M, McColgan, Bryan J, Chung, Chuhan, Ray, Adrian S, Subramanian, G Mani, Myers, Robert P, Middleton, Michael S, Lai, Michelle, Charlton, Michael, Harrison, Stephen A

المصدر: Gastroenterology. 155(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Hepatitis, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Liver Disease, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Acetyl-CoA Carboxylase, Biomarkers, Carnitine, Double-Blind Method, Elasticity Imaging Techniques, Fatty Liver, Female, Humans, Isobutyrates, Liver Cirrhosis, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Oxazoles, Pyrimidines, De Novo Lipogenesis, Magnetic Resonance Elastography, Tissue Inhibitor of Metalloproteinase 1, Effects, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics

الوصف: Background & aimsDe novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.MethodsWe analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy.ResultsA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/83g1c15zTest

المؤلفون: Bašić, Jelena, Milošević, Vuk, Đorđević, Branka, Stojiljković, Vladana, Živanović, Milica, Jevtović Stoimenov, Tatjana, Stojanović Ivana

المصدر: Biologia Serbica 45

مصطلحات موضوعية: apolipoprotein E, Alzheimer's disease, matrix metalloproteinase, tissue inhibitor of metalloproteinase

الوصف: Summary. Apolipoprotein E (APOE) is a glycoprotein primarily produced by astrocytes and microglia. It plays a crucial role in complexing with amyloid β (Aβ) to accelerate its clearance. APOE genotyping holds great importance in determining whether an individual carries the APOE ε2/ε3/ε4 allele and the corresponding APOE2/E3/E4 protein isoform. Carrying the APOE ε4 allele has been associated with an increased risk of Aβ accumulation, amyloid plaque formation, and late-onset Alzheimer's disease (LOAD). The identification of novel biomarkers that indicate the earliest pathophysiological processes involved in Alzheimer's disease (AD) and the analysis of their diagnostic value in patients, especially through less invasive and cost-effective procedures that can visualize AD in a minimally invasive manner, are the focuses of numerous researchers. Matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and activators play a significant role in extracellular matrix remodeling, disruption of blood-brain barrier integrity, prolonged neuroinflammation, and Aβ clearance. These biomarkers are showing promise as potential blood-based diagnostic markers for patients with AD. In this context, we will discuss the possible mechanisms underlying the interrelation between APOE ε4 carrier status, matrix remodeling enzymes, and neurodegeneration in AD. Additionally, we will explore the diagnostic accuracy of these biomarkers in AD dementia patients based on the results obtained by our research group.

العلاقة: https://zenodo.org/record/8361280Test; https://doi.org/10.5281/zenodo.8361280Test; oai:zenodo.org:8361280

الإتاحة: https://doi.org/10.5281/zenodo.8361280Test
https://doi.org/10.5281/zenodo.8361279Test
https://zenodo.org/record/8361280Test

المؤلفون: Rei Ishihara, Tsukasa Oda, Yuki Murakami, Ikuko Matsumura, Saki Watanabe, Yuta Asao, Yuta Masuda, Nanami Gotoh, Tetsuhiro Kasamatsu, Hisashi Takei, Nobuhiko Kobayashi, Nobuo Sasaki, Takayuki Saitoh, Hirokazu Murakami, Hiroshi Handa

المصدر: International Journal of Molecular Sciences; Volume 24; Issue 3; Pages: 2216

مصطلحات موضوعية: multiple myeloma, tissue inhibitor of metalloproteinase, tumour microenvironment, fibroblast

جغرافية الموضوع: agris

الوصف: Tissue inhibitors of metalloproteinases (TIMPs) are endogenous matrix metalloproteinase inhibitors. TIMP1 is produced by cancer cells and has pleiotropic activities. However, its role and source in multiple myeloma (MM) are unclear. Here, we evaluated TIMP1 protein and mRNA levels in bone marrow (BM) plasma cells and assessed the effects of TIMP1 expression on fibroblast invasive capacity using three-dimensional spheroid cell invasion assays. TIMP1 mRNA and protein levels were elevated when patients progressed from monoclonal gammopathy of undetermined significance or smouldering myeloma to MM. Furthermore, TIMP1 levels decreased at complete response and TIMP1 protein levels increased with higher international staging. TIMP1 mRNA levels were markedly higher in extramedullary plasmacytoma and MM with t(4;14). Overall survival and post-progression survival were significantly lower in MM patients with high TIMP1 protein. Recombinant TIMP1 did not directly affect MM cells but enhanced the invasive capacity of fibroblasts; this effect was suppressed by treatment with anti-TIMP1 antibodies. Fibroblasts supported myeloma cell invasion and expansion in extracellular matrix. Overall, these results suggested that MM-derived TIMP1 induces the invasive phenotype in fibroblasts and is involved in disease progression. Further studies are required to elucidate the specific roles of TIMP1 in MM and facilitate the development of novel therapies targeting the TIMP1 pathway.

وصف الملف: application/pdf

العلاقة: Molecular Oncology; https://dx.doi.org/10.3390/ijms24032216Test

الإتاحة: https://doi.org/10.3390/ijms24032216Test

المؤلفون: Ying-Chin Lin, Ya-Li Huang, Horng-Sheng Shiue, Sheng-Lun Hsu, Yu-Mei Hsueh

المصدر: International Journal of Environmental Research and Public Health; Volume 20; Issue 3; Pages: 1886

مصطلحات موضوعية: tissue inhibitor of metalloproteinase 3, polymorphisms, total urinary arsenic, blood lead, chronic kidney disease

جغرافية الموضوع: agris

الوصف: The tissue inhibitor of metalloproteinase 3 (TIMP3) is known to be an anti-fibrotic factor. Arsenic, lead, and cadmium exposure and selenium intake may affect TIMP3 expression. The downregulation of TIMP3 expression is related to kidney fibrosis. Genotypes of TIMP3 are related to hypertension and cardiovascular diseases. Therefore, this study explored whether TIMP3 polymorphism is associated with hypertension-related chronic kidney disease (CKD). In addition, the combined effects of TIMP3 polymorphism and total urinary arsenic, blood lead and cadmium, and plasma selenium concentrations on CKD, were investigated. This was a case-control study, with 213 CKD patients and 423 age- and sex-matched controls recruited. Polymerase chain reaction-restriction fragment length polymorphism was used to determine TIMP3 gene polymorphisms. The concentrations of urinary arsenic species, plasma selenium, and blood lead and cadmium were measured. The odds ratio (OR) of CKD in the TIMP3rs9609643 GA/AA genotype was higher than that of the GG genotype at high levels of total urinary arsenic and blood lead; the OR and 95% confidence interval (CI) were 0.57 (0.31–1.05) and 0.52 (0.30–0.93), respectively, after multivariate adjustment. High blood lead levels tended to interact with the TIMP3rs9609643 GG genotype to increase the OR of CKD, and gave the highest OR (95% CI) for CKD of 5.97 (2.60–13.67). Our study supports a possible role for the TIMP3rs9609643 risk genotype combined with high total urinary arsenic or with high blood lead concentration to increase the OR of CKD.

وصف الملف: application/pdf

العلاقة: Toxicology and Public Health; https://dx.doi.org/10.3390/ijerph20031886Test

الإتاحة: https://doi.org/10.3390/ijerph20031886Test