Levels Of Matrix Metallopeptidase Research Articles

Synthesis of 1,3,5-triphenyl-1,2,4-triazole derivatives and their neuroprotection by anti-oxidative stress and anti-inflammation and protecting BBB

Acute ischemic stroke (AIS) is a serious cardiovascular and cerebrovascular disease; Oxidative stress and neuroinflammation are important factors which destroy blood-brain barrier (BBB) in AIS. In the study, a series of 1,3,5-triphenyl-1,2,4-triazole derivatives were designed and synthesized; the optimal compound 9 was obtained by screening their anti-oxidant and anti-inflammatory effects; the neuroprotection effect of compound 9 was evaluated with a rat middle cerebral artery occlusion (MCAO) model. Subsequently, the mechanism of neuroprotection were explored via Western blot. The results prompt compound 9 maybe exert anti-AIS neuroprotection by inhibiting oxidative stress and neuroinflammation inhibition by inhibiting Keap1, COX-2 and iNOS. At the same time, it can protect BBB by reducing glycocalyx degradation and matrix metallopeptidase-9 levels. Its LD50 > 1000 mg/kg on mice and hERG channel inhibition IC50 > 30 μM, which lower acute toxicity and hERG channel inhibition would make compound 9 a promising stroke treatment candidate.

The role of neutrophils in corneal nerve regeneration

BackgroundTo investigate the role of neutrophils in corneal nerve regeneration.MethodsA mouse model simulating corneal nerve injury was established and samples from corneal scraping with and without neutrophil closure were collected. These samples were used for corneal nerve staining, ribonucleic acid sequencing, and bioinformatics. Differential expression analysis was used to perform enrichment analysis to identify any significant differences between these two groups. The differential genes were then intersected with neutrophil-associated genes and a protein-protein interaction network was constructed using the intersected genes. The immune infiltration between the two groups was examined along with the immune cell variation between the high and low gene expression groups.ResultsNeutrophil removal delays corneal epithelial and nerve regeneration. A total of 546 differential genes and 980 neutrophil-associated genes, with 27 genes common to both sets were obtained. Molecular Complex Detection analysis yielded five key genes, namely integrin subunit beta 2 (ITGB2), matrix metallopeptidase 9 (MMP9), epidermal growth factor (EGF), serpin family E member 1 (SERPINE1), and plasminogen activator urokinase receptor (PLAUR). Among these genes, ITGB2, SERPINE1, and PLAUR exhibited increased expression in the neutrophil-confined group, while MMP9 and EGF showed decreased expression, with MMP9 and EGF displaying a more significant difference. Immune infiltration was also observed between the two groups, revealing significant differences in the infiltration of M0 macrophages, activated mast cells, and neutrophils. Moreover, the neutrophil levels were lower in the groups with low MMP9 and EGF expressions and higher in the high-expression group.ConclusionNeutrophil confinement might significantly affect the MMP9 and EGF expression levels. Strategies to inhibit MMP9 could potentially yield therapeutic benefits.

Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation

BackgroundIncreasing evidence suggests a vital role of the pre-metastatic niche in the formation of distant metastasis of many cancers. However, how the pre-metastatic niche is formed and promotes pulmonary metastasis of hepatocellular carcinoma (HCC) remains unknown.MethodsOrthotopic liver tumor models and RNA-Seq were used to identify dysregulated genes in the pre-metastatic lung. Il1b knockout (Il1b−/−) mice and lentivirus-mediated gene knockdown/overexpression were utilized to demonstrate the role of interleukin 1 beta (IL-1β)/serum amyloid A3 (SAA3) in the pre-metastatic niche formation and pulmonary metastasis. The potential molecular mechanisms were investigated by RNA-Seq, real-time quantitative PCR (qPCR), western blotting, immunohistochemistry (IHC), flow cytometry, luciferase reporter assay, double immunofluorescent staining and H&E staining.ResultsAccumulation of myeloid cells and upregulation of IL-1β were observed in the pre-metastatic lung of orthotopic liver tumor models. Myeloid cells accumulation and pulmonary metastasis were suppressed in Il1b−/− mice and Il1r1-silencing mice. Mechanistically, SAA3 and matrix metallopeptidase 9 (MMP9) were identified as potential downstream targets of IL-1β. Overexpression of SAA3 in the lungs of Il1b−/− mice restored myeloid cells accumulation and pulmonary metastasis of the orthotopic HCC xenografts. Moreover, alveolar macrophages-derived IL-1β dramatically enhanced SAA3 expression in alveolar epithelial cells in an NF-κB dependent manner and increased MMP9 levels in an autocrine manner. Furthermore, SAA3 recruited myeloid cells to the lung without affecting the expression of MMP9 in myeloid cells.ConclusionsOur study suggests a key role of pulmonary IL-1β and SAA3 in creating a permissive lung pre-metastatic niche by enhancing MMP9 expression and recruiting myeloid cells, respectively, thus promoting pulmonary metastasis of HCC.

Salvianolic acid B promotes the invasion and migration of HO-induced HTR-8/Svneo trophoblast cells by upregulating matrix metalloproteinase-9 the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B pathway.

To elucidate the regulatory effects of salvianolic acid B (SalB) on trophoblast cells in preeclampsia (PE). 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenylte-trazolium bromide (MTT) assays were used to detect the viability of human extravillous trophoblast HTR-8/Svneo cells induced by HO following treatment with different concentrations of SalB. The levels of oxidative stress-related molecules, including superoxide dismutase, glutathione-Px and malondialdehyde were detected using corresponding kits. Cell apoptosis was detected using a Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay, and the expression of apoptosis-related proteins was detected using western blot analysis. In the present study, wound healing and Transwell assays were performed to measure the levels of cell invasion and migration. Western blot analysis was also used to detect the expression levels of epithelial-mesenchymal transition-related proteins. The mechanisms underlying SalB were further investigated using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis, to determine the expression levels of matrix metallopeptidase 9 (MMP-9) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt). SalB increased the activity of HTR-8/Svneo cells, inhibited oxidative damage and promoted the invasion and migration of trophoblast cells induced by HO. Furthermore, the expression levels of MMP-9 and members of the PI3K/Akt signaling pathway were significantly decreased. The pathway agonist, LY294002, and MMP-9 inhibitor, GM6001, reversed the effects of SalB on HO-induced cells. SalB promoted the invasion and migration of HO-induced HTR-8/Svneo trophoblast cells by upregulating MMP-9 the PI3K/Akt signaling pathway.

Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia.

Increased local angiogenesis is important for the growth and dissemination of cancer. The myeloproliferative neoplasm essential thrombocythemia (ET) is known to involve increased bone marrow angiogenesis. Blood levels of several angiogenesis-related proteins are increased in different types of cancer. The aim of this study was to investigate whether a subset of such proteins was elevated in treatment-naïve ET patients. Blood plasma from 41 ET patients and 43 healthy aged-matched controls was analyzed for eight different angiogenesis-related proteins. The ET cohort displayed a more homogenous expression pattern of these proteins compared with controls. Five of the eight proteins were significantly increased in ET patients. Increased plasma levels of matrix metallopeptidase 9 (MMP9) and endostatin have not previously been reported in ET. In our patients, MMP9 levels correlated positively with Janus kinase 2 (JAK2) V617F allele burden and leukocyte count.

The Potential Inhibitory Role of Acetyl-L-Carnitine on Proliferation, Migration, and Gene Expression in HepG2 and HT29 Human Adenocarcinoma Cell Lines.

Malignancies of the liver and colon are the most prevalent forms of digestive system cancer globally. Chemotherapy, one of the most significant treatments, has severe side effects. Chemoprevention using natural or synthetic medications can potentially reduce cancer severity. Acetyl-L-carnitine (ALC) is an acetylated derivative of carnitine essential for intermediate metabolism in most tissues. This study aimed to investigate the effects of ALC on the proliferation, migration, and gene expression of human liver (HepG2) and colorectal (HT29) adenocarcinoma cell lines. The cell viability and half maximal inhibitory concentration of both cancer cell lines were determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Wound healing after treatment was assessed using a migration assay. Morphological changes were imaged using brightfield and fluorescence microscopy. Post treatment, apoptotic DNA was detected using a DNA fragmentation assay. The relative mRNA expressions of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor (VEGF) were evaluated using RT-PCR. The results showed that ALC treatment affects the wound-healing ability of HepG2 and HT29 cell lines. Changes in nuclear morphology were detected under fluorescent microscopy. ALC also downregulates the expression levels of MMP9 and VEGF in HepG2 and HT29 cell lines. Our results indicate that the anticancer action of ALC is likely mediated by a decrease in adhesion, migration, and invasion.

Assessment of Tuberculosis Biomarkers in Paratuberculosis-infected Cattle.

Mycobacterium bovis and Mycobacterium avium subsp. paratuberculosis, respectively the causative agents of bovine tuberculosis (bTB) and bovine paratuberculosis (PTB), share a high number of antigenic proteins. This characteristics makes the differential diagnosis of the diseases difficult. The interferon gamma (IFN-γ), C-X-C motif chemokine ligand 10 (CXCL10), matrix metallopeptidase 9 (MMP9), interleukin 22 (IL-22) and thrombospondin 1 (THBS1) bovine genes have already been shown to be accurate transcriptional biomarkers of bTB. In order to improve the diagnosis of bTB and PTB, in the present study we evaluated the risk of false positivity of these bTB biomarkers in cattle with PTB. The transcription of these genes was studied in 13 PTB-infected cattle, using Mycobacterium avium subsp. paratuberculosis (MAP)-stimulated peripheral blood mononuclear cells (PBMC). Overall, the levels of IFN-γ, CXCL10, MMP9 and IL-22 transcripts in MAP-stimulated PBMC failed to differentiate animals with PTB from healthy animals. However, as bTB-afflicted cattle do, the MAP-infected group also displayed a lower level of THBS1 transcription than the non-infected animals. The results of this study add new specificity attributes to the levels of transcription of IFN-γ, CXCL10, MMP9 and IL-22 as biomarkers for bTB.

Effect of Diammonium Glycyrrhizinate in Improving Focal Cerebral Ischemia-Reperfusion Injury in Rats Through Multiple Mechanisms.

Acute ischemic stroke is a current major disabling and killer disease worldwide. We aimed to investigate the protective effect and mechanism of diammonium glycyrrhizinate in alleviating acute ischemic stroke. Ninety male Sprague Dawley (SD) rats (weighing 250-300g) were randomly allocated into three groups: sham operation group (sham group), diammonium glycyrrhizinate group (DG group) and model group (model group) each with 30 individuals. A rat model of focal CIR injury was established by reversible middle cerebral artery occlusion. Zea-Longa scores for the rats in the DG group and model group were 7-fold and 8-fold higher than those of the sham group 2 h post-surgery (2.90 ± 0.99 vs. 0.30 ± 0.53, P < .05; 2.80 ± 0.61 vs. 0.30 ± 0.53, P < .05, respectively). Three days after model establishment, the scores of DG group were 26.92% lower compared with those of the model group (1.90 ± 0.76 vs. 2.60 ± 0.62, P < .05). In addition, compared with the sham group, the number of Nissl bodies and Akt-positive cells in were 27.35% and 30.42% lower in the hippocampus of the DG group (Nissl bodies: 83.40 ± 7.01 vs. 115.60 ± 11.97, p < 0.05; Akt-positive cells: 94.70 ± 8.23 vs. 136.10 ± 10.37, P < .05) and 58.65% and 57.31% lower in the model group (Nissl bodies: 47.80 ± 4.91 vs. 115.60 ± 11.97, P < .05; Akt-positive cells: 58.10 ± 4.98 vs. 136.10 ± 10.37, P < 0.05), respectively. However, the number of Nissl bodies and Akt-positive cells in the hippocampus of DG group were 74.48% and 62.9% higher compared with the model group, respectively (Nissl bodies: 83.40 ± 7.01 vs. 47.80 ± 4, P < 0.05; Akt-positive cells: 94.70 ± 8.23 vs. 58.10 ± 4.98, P < .05). In addition, compared with the sham group, the number of caspase-3-positive cells, the expression level of p38 mitogen-activated protein kinase (MAPK) and the expression of matrix metallopeptidase 9 (MMP-9) were 2-fold, 34.38%, 64.78% higher in the DG group (caspase-3-positive cells: 78.70 ± 6.52 vs. 27.10 ±3.00, P < .05; p-38MAPK: 0.43 ± 0.15 vs. 0.32 ± 0.10, P < .05; MMP-9: 14.83 ± 1.18 vs. 9.00 ± 2.05, P < .05, respectively), and more than 3-fold, 1-fold and 1-fold higher in model group (caspase-3-positive cells: 121.10 ± 11.04 vs. 27.10 ± 3.00, P < .05; p-38MAPK: 0.70 ± 0.12 vs. 0.32 ± 0.10, P < .05; MMP-9: 19.00 ± 1.90 vs. 9.00 ± 2.05, P < .05), respectively. However, the number of caspase-3-positive cells and the expression levels of p-38MAPK and MMP-9 were 35.01%, 38.57% and 28.12% lower in DG group compared with the model group (caspase-3-positive cells: 78.70 ± 6.52 vs. 121.10 ± 11.04, P < .05; p-38MAPK: 0.43 ± 0.15 vs. 0.70 ± 0.12, P < .05; MMP-9: 14.83 ± 1.18 vs. 19.00 ± 1.90, P < .05). Our study showed that diammonium glycyrrhizinate at 20mg/kg/day had a protective effect on cerebral ischemia-reperfusion injury in rats by promoting formation of Nissl bodies and increasing protein expression of Akt while decreasing that of caspase-3, p38 MAPK and MMP-9, either directly or indirectly, by inhibiting apoptosis and reducing neuroinflammation. All these mechanisms resulted in improved overall neurological function.

Bioinformatic analysis of the LCN2-SLC22A17-MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment.

Several features of cancer cells such as proliferation, invasion, metastatic spreading, and drug resistance are affected by their interaction with several tumor microenvironment (TME) components, including neutrophil gelatinase-associated lipocalin (NGAL), solute carrier family 22 member 17 (SLC22A17), and matrix metallopeptidase 9 (MMP9). These molecules play a key role in tumor growth, invasion, and iron-dependent metabolism of cancer cells. However, the precise epigenetic mechanisms underlying the gene regulation of Lipocalin 2 (LCN2), SLC22A17, and MMP9 in cancer still remain unclear. To this purpose, computational analysis was performed on TCGA and GTEx datasets to evaluate the expression and DNA methylation status of LCN2, SLC22A17, and MMP9 genes in different tumor types. Correlation analysis between gene/isoforms expression and DNA methylation levels of LCN2, SLC22A17, and MMP9 was performed to investigate the role of DNA methylation in the modulation of these genes. Protein network analysis was carried out using reverse phase protein arrays (RPPA) data to identify protein–protein interactions of the LCN2–SLC22A17–MMP9 network. Furthermore, survival analysis was performed according to gene expression and DNA methylation levels. Our results demonstrated that LCN2 and MMP9 were mainly upregulated in most tumor types, whereas SLC22A17 was largely downregulated, representing a specific hallmark signature for all gastrointestinal tumors. Notably, the expression of LCN2, SLC22A17, and MMP9 genes was negatively affected by promoter methylation. Conversely, intragenic hypermethylation was associated with the overexpression of SLC22A17 and MMP9 genes. Protein network analysis highlighted the role of the LCN2–SLC22A17–MMP9 network in TME by the interaction with fibronectin 1 and claudin 7, especially in rectal tumors. Moreover, the impact of expression and methylation status of LCN2, SLC22A17, and MMP9 on overall survival and progression free interval was tumor type–dependent. Overall, our analyses provide a detailed overview of the expression and methylation status of LCN2, SLC22A17, and MMP9 in all TCGA tumors, indicating that the LCN2–SLC22A17–MMP9 network was strictly regulated by DNA methylation within TME. Our findings pave the way for the identification of novel DNA methylation hotspots with diagnostic and prognostic values and suitable for epi-drug targeting.

Babao Dan inhibits lymphangiogenesis of gastric cancer in vitro and in vivo via lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis

Gastric cancer (GC) is one of the most common gastrointestinal malignancies in the world. Growing evidence emphasizes the critical role of long non-coding RNA (lncRNA) in GC tumorigenesis. The aim of the research was to elucidate the effect and mechanism of Babao Dan (BBD) on lymphangiogenesis of GC in vitro and in vivo via lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis. The present study investigated BBD significantly decreased the expression of lncRNA-ANRIL and VEGF-C in GC cells (AGS, BGC823, and MGC80–3) by using real-time quantitative polymerasechain reaction (RT-qPCR) and the secretion and expression of VEGF-C by (enzyme linked immunosorbent assay) ELISA and western blot (WB). BBD significantly inhibited the tumor xenograft of GC growth and the expression of lncRNA-ANRIL, VEGF-C, VEGFR-3 and LYVE-1 in vivo. BBD reduced serum VEGF-C level. In vitro, BBD inhibited the tube formation and decreased the cell viability, proliferation and migration of HLECs by using tube formation, MTT, Hoechst and Transwell assays. In addition, WB assay found that BBD decreased the expression levels of VEGF-C, VEGFR-3, matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9), and RT-qPCR assay found that the mRNA expression levels of lncRNA-ANRIL, VEGF-C, VEGFR-3, MMP-2, MMP-9, CDK4, Cyclin D1, and Bcl-2 were down-regulated, and the expression of p21 and Bax were increased. Taken together, these results demonstrated that BBD inhibited lymphangiogenesis of GC in vitro and in vivo via the lncRNA-ANRIL/VEGF-C/VEGFR-3 signaling axis.

Increase in Serum MMP-9 and TIMP-1 Concentrations during Alcohol Intoxication in Adolescents-A Preliminary Study.

Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still unclear. This study is a follow-up to work on liver damage from alcohol intoxication. The aim of our study was to explore the early effects of alcohol intoxication on liver fibrosis in adolescents. Methods: The prospective study included 57 adolescents aged 14–17 years admitted to the emergency department (ED) from February 2017 to June 2018 due to acute alcohol intoxication. Serum levels of amino terminal propeptide of type III procollagen (PIIINP), type IV collagen, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were determined by enzyme-linked immunosorbent assays. Results: There were significant differences in MMP-9 (p = 0.02) and TIMP-1 (p = 0.007) levels between the study and control groups. Liver parameters and selected markers of fibrosis were similar in groups in terms of blood alcohol concentrations (BAC). MMP-9 was positively correlated with alanine aminotransferase (ALT) (r = 0.38; p = 0.004) and total bilirubin (r = 0.39; p = 0.004). Positive significant correlations were also found between TIMP-1 and ALT (r = 0.47; p < 0.001), AST (r = 0.29; p = 0.03) and total bilirubin (r = 0.32; p = 0.02). In receiver operating characteristic (ROC) analysis, MMP-9 (AUC = 0.67, p = 0.02) and TIMP-1 (AUC = 0.69, p = 0.003) allowed for the differentiation of patients with and without alcohol intoxication. Conclusion: Our results show that even a single episode of alcohol intoxication in adolescents can lead to imbalance in markers of fibrosis.

Exosomes Derived from Senescent Endothelial Cells Contain Distinct Pro-angiogenic miRNAs and Proteins.

Exosomes from senescence cells play pivotal roles in endothelium dysfunction. We investigated the exosomal angiogenic cargo of endothelial cells (ECs) in a model of senescence in vitro. After inducing aging by H2O2, the expression of P53, P21, and P16 was investigated by western blotting, while the expression of FMR1, miR-21, and miR-126 were measured by real-time PCR (q-PCR). Oil Red O dye was used to stain cells. Acetylcholinesterase (AChE) assay, transmission electron microscopy (TEM), and western blotting characterized Exosomes. Exosomal miR-21, miR-126, matrix metallopeptidase-9 (MMP-9), and tumor necrosis factor- ɑ (TNF-ɑ) proteins were measured by Q-PCR and western blotting. A wound-healing assay was used to explore the effect of exosomes on ECs migration rate. The results showed that the expression of P53, P21, P16, FMR1, and miR-21 was increased in treated cells as compared with control cells (P < 0.05). In addition, the expression of miR-126 was decreased in treated cells (P < 0.05). The number of Oil Red O-positive-treated cells increased (P < 0.05). The AChE activity of exosomes from treated cells was increased (P < 0.05). In comparison with control cells, an increase in the expression levels of exosomal miR-21 and TNF-ɑ of treated cells coincided with a decrease in the expression levels of miR-126 and MMP-9 levels (P < 0.05). We found that the migration rate of ECs co-cultured with exosomes from treated cells was decreased (P < 0.05). The data indicate ECs under H2O2 condition produce exosomes with distinct cargo that may be useful as a biomarker of age-related vascular disease.

Low Level of PALMD Contributes to the Metastasis of Uveal Melanoma.

Uveal melanoma (UM) is a highly aggressive disease. There is an urgent need to develop the metastasis prediction markers of UM. This study aims to detect the key role of PALMD in UM metastasis. Transcriptome sequencing results of 2 sets of UM metastatic samples (GSE22138 and GSE156877) were downloaded from the Gene Expression Omnibus (GEO), and 18 overlapping differentially expressed genes were screened out, including PALMD. PALMD was significantly underexpressed in metastatic UM tissue. Low expression of PALMD was associated with poor prognosis in UM patients. The decreased expression of PALMD promoted the invasion and migration of 92-1 and Mel270 cells, while the high expression of PALMD inhibited the invasion and migration of UM cells. Furthermore, the levels of matrix metallopeptidase (MMP) 2 and MMP9 increased after transfection of siRNAs specifically targeting PALMD, whereas the levels of MMP2 and MMP9 were decreased after PALMD overexpression. However, PALMD did not affect the proliferation of UM cells. In addition, ZNF263 promoted the transcription of PALMD through the putative binding sequence using the JASPAR database, luciferase reporter gene analysis and chromatin immunoprecipitation assay. In summary, the expression of PALMD regulated by ZNF263 plays an important role in UM metastasis.

Left Atrial Phasic Function in Older Adults Is Associated with Fibrotic and Low-Grade Inflammatory Pathways

Introduction: Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. Methods: Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (εs), conduit strain (εe), and booster strain (εa) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. Results: We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, εe and SRe were reduced in gradation with increasing risk factors (all p values <0.0001). Corresponding levels of sUPAR (ng/mL) were quantitatively higher in older adults with <2 risk factors (2.5 ± 1.6 vs. 1.7 ± 1.3, p = 0.0005), in those with ≥2 risk factors (3.3 ± 2.4 vs. 1.7 ± 1.3, p < 0.0001), compared to young adults; including between older adults with ≥2 risk factors and older adults with <2 risk factors (3.3 ± 2.4 vs. 2.5 ± 1.6, p = 0.017). Based on multivariate analysis, sUPAR was significantly associated with both εe (OR 1.52, p = 0.006) and SRe decline (OR 1.5, p = 0.019). The associations between Gal-3 and εe reduction (OR 1.2, p = 0.022) and between BNP and SRe decline were generally weaker (OR 1.03, p = 0.027). The addition of sUPAR to a model consisting of age, risk factors, Gal-3, and BNPs increased the area under the curve of εe from 0.72 to 0.77 (p = 0.015). Conclusion: By advanced CMR imaging, a panel of circulating biomarkers comprising galectin, MMP-9 and sUPAR were associated with left atrial dysfunction in older adults. Higher levels of Gal-3 and MMP-9 may be suggestive of fibrotic mechanisms in left atrial aging while impairments in left atrial strain seen in association with circulating sUPAR may be related to immune activation in the left atrium in response to left atrial remodeling and fibrotic processes.

Hypoxia Inducible Factor 1 Alpha and Matrix Metalloproteinase-9 in Dysfunctional Uterine Bleeding

Introduction: Dysfunctional Uterine Bleeding (DUB) is prevalent in 10-15% of gynaecological patients. Matrix metallopeptidase-9 (MMP-9) expression is stimulated by reduced oxygen levels in a highly aggressive, metastatic breast cancer cell line, although MMP-2 expression is unaffected. Under hypoxic conditions, Hypoxia Inducible Factor 1 Alpha (HIF-1α) rapidly accumulates and transactivates hundreds of genes, including angiogenic growth factors as well as receptors. Aim: To compare and estimate the serum HIF-1alpha, serum MMP-9 in ultrasonographically proven DUB patients and in controls with normal menstruation. Materials and Methods: This case-control study was conducted in Department of Biochemistry at Heritage Institute of Medical Sciences, Varanasi, Uttar Pradesh, India, from July 2020 to November 2021. A random venous blood sample (4 mL) was drawn from the DUB cases and controls into a sterile red topped vacutainer which was allowed to clot for 30 minutes. The sample was centrifuged and the serum was separated and analysed for desired parameters. Serum HIF-1α and MMP-9 was estimated by using sandwich Enzyme Linked Immunosorbent Assay (ELISA) method. Student’s t test was used for comparison between the variables and pearson’s correlation test was used to assess the correlation between the parameters. Results: The mean age of controls was 33.9±7.10 years (N=40) compared to cases where it was 38.8±5.32 years (N=40). Serum HIF-1α showed significantly elevated levels of median in DUB cases (1.16 ng/mL) compared to normal control group (0.28 ng/ mL, p-value=0.04). Mean serum levels of MMP-9 significantly decreased in DUB cases as compared to normal control group (34,142±19,043, 61,500±16,169 respectively, p-value=0.003). Presence of hypoxia leading to HIF-1α and MMP-9 formation plays a role in endometrial thickness and angiogenesis leading to various signs and symptoms of DUB. The present study did not find any correlation between MMP-9 and endometrial thickness as well as HIF-1α and endometrial thickness in DUB cases and controls. There was significant low positive correlation between serum MMP-9 and HIF-1α in DUB cases (r-value=0.423, p-value &lt;0.05). Conclusion: Elevated levels of HIF-1α and decreased levels of MMP-9 was observed in DUB cases. No correlation was found between MMP-9 and endometrial thickness as well as HIF-1α and endometrial thickness in DUB cases and controls. Hence, whether this can be used for diagnostic and therapeutic prospects needs to be further studied.

Characteristics and Significance of Gene Expression Changes in Peripheral Blood of Lumbar Disc Extrusion Patients before and after Nonoperative Treatment

To define the gene expression characteristics in the peripheral blood of patients with lumbar disc extrusion (LDE) and the effect of nonoperative treatment on the gene expression. DNA microarray was used to identify semi-quantitatively the differentially expressed genes (DEGs) in the peripheral blood of patients with LDE and that of the healthy controls and the variation trend of these DEGs after nonoperative treatment. Enrichment analysis was done to reveal the functional characteristics of these DEGs, and network analysis was done to identify key genes that contribute to gene dysregulation. The levels of these key genes were measured by qRT-PCR to examine their expression in LDE patients and the controls, and the effect of nonoperative treatment on the expression level. We identified 153 DEGs in the peripheral blood of LDE patients and healthy controls, including 131 upregulated genes and 22 downregulated genes. Enrichment analysis revealed that most of the DEGs were related to immunity and the inflammatory response. Network analysis revealed that toll-like receptor 4 ( TLR4 ), matrix metallopeptidase 9 ( MMP9) and myeloperoxidase ( MPO), cathelicidin antimicrobial peptide ( CAMP), resistin ( RETN), toll-like receptor 5 ( TLR5) were the key genes in the protein-protein interaction network. These key genes were all enriched into the terms releated to immunity and the inflammatory response. The patients experienced pain relief after nonoperative treatment. Among the 153 DEGs, TLR5 , interleukin 1 receptor antagonist ( IL1 RN) and solute carrier family 8 member A1 ( SLC8 A1) were downregulated after nonoperative treatment. qRT-PCR revealed that the levels of TLR4, MMP9 , MPO, CAMP, RETN, TLR5, IL1 RN and SLC8 A1 in the peripheral blood of the LDE patients were higher than those of the healthy control group ( P<0.05). In addition, TLR5 , IL1 RN and SLC8 A1 expression levels decreased after treatmentin in comparison with the levels before treatment ( P<0.05). Gene expression in the peripheral blood of LDE patients was characterized by the dysregulation of immune and inflammatory response-related genes, among which, TLR4, MMP9, MPO, CAMP, RETN and TLR5, the genes relevant to immune and inflammatory response, played a key role in the dysregulation of gene expression in the peripheral blood of LDE patients. The outcome of non-operative treatment may be related to the downregulation of the overexpressed TLR5, IL1 RN and SLC8 A1 in the peripheral blood of patients.

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

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

Neuroprotective Effect of Trans-Resveratrol in Mild to Moderate Alzheimer Disease: A Randomized, Double-Blind Trial.

IntroductionAmyloid-beta (Aβ) protein is a major component of the extracellular plaque found in the brains of individuals with Alzheimer's disease (AD). In this study, we investigated the effect of trans-resveratrol as an antagonist treatment for moderate to mild AD, as well as its safety and tolerability.MethodsThis was a case–control study that enrolled 30 selected patients who had been clinically diagnosed with moderate to mild AD. These patients were randomly divided into two groups, namely, a placebo group (n = 15) and a trans-resveratrol group (n = 15) who received 500 mg trans-resveratrol orally once daily for 52 weeks. Brain magnetic resonance imaging (MRI) examinations were performed on and cerebrospinal fluid (CSF) samples were obtained from all participants before (baseline) and after the study (52 weeks). Enzyme-linked immunosorbent assays were used to determine the levels of plasma Aβ40 and Aβ42 and CSF Aβ40 and Aβ42.ResultsThe results showed that the changes over the study period in the levels of Aβ40 in the blood and CSF of the patients treated with trans-resveratrol were not statistically significant (P > 0.05). In contrast, patients who received placebo showed a significant decrease in Aβ40 levels compared with that at the beginning of the study (CSF Aβ40: P = 0.024, plasma Aβ40: P = 0.036). Analysis of the images on the brain MRI scans revealed that the brain volume of the patients treated with trans-resveratrol was significantly reduced at 52 weeks (P = 0.011) compared with that of patients in the placebo treatment group, Further analysis indicated that the level of matrix metallopeptidase 9 in the CSF of the patients treated with trans-resveratrol at 52 weeks decreased by 46% compared with that of patients in the placebo group (P = 0.033).ConclusionThese results indicate that trans-resveratrol has potential neuroprotective roles in the treatment of moderate to mild AD and that its mechanism may involve a reduction in the accumulation and toxicity of Aβ in the brain of patients, thereby reducing neuroinflammation.Trial RegistrationChinese clinical trial registry: CTR20151780X.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00271-2.

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

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

Effect of folic acid combined with pravastatin on arteriosclerosis in elderly hypertensive patients with lacunar infarction.

This study aimed to assess the effect of folic acid combined with pravastatin on atherosclerosis-related indexes in elderly patients with hypertension complicated with lacunar cerebral infarction.A total of 134 elderly hypertensive patients with lacunar cerebral infarction were randomly divided into 3 groups using the random number table method. Group A, the folic acid group, had 45 cases and received low-dose folic acid (0.8 mg/d) treatment on the basis of antihypertensive treatment. Group B, the pravastatin group, had 45 cases and received pravastatin (20 mg/d) treatment on the basis of antihypertensive treatment. Group C, the folic acid combined with the pravastatin group, had 44 cases. Members of this group received pravastatin (20 mg/d) and low-dose folic acid (0.8 mg/d) based on antihypertensive treatment. Levels of folic acid, homocysteine (Hcy), tumor necrosis factor alpha (TNF-a), matrix metallopeptidase 9 (MMP-9), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured by ELISA before treatment in all 3 groups. Carotid intima-media thickness (IMT) was measured using ultrasound, and systolic and diastolic blood pressure were measured with a mercury column. After 8 weeks of treatment, the levels of folic acid, Hcy, TNF-a, MMP-9, TC, LDL-C, and systolic and diastolic blood pressure were compared among the 3 groups. IMT levels were measured at 12 weeks of treatment.After 8 weeks of treatment, compared with group B, patients in groups A and C had folic acid levels significantly higher than baseline levels, with significantly lower Hcy levels (both P < .05). Patients in group C presented significantly decreased TNF-a, MMP-9, TC, and LDL-C levels and systolic and diastolic blood pressure after 8 weeks of treatment, compared with those in groups A and B (both P < .05). These patients also showed significantly decreased IMT levels compared with those in the other groups (P < .05).Low-dose folic acid combined with pravastatin in elderly patients with lacunar cerebral infarction can reduce the level of homocysteine, improve the degree of carotid atherosclerosis, protect vascular endothelium, and reduce blood lipids and blood pressure, presenting better benefits than pravastatin alone.