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In this multi-parameter study, the effect of diverse factors related to adhesive application on the activation of host-derived gelatinases was investigated by gelatin zymography, in-situ zymography, fluorogenic DQ-gelatin assay and micro-tensile bond-strength (μTBS) testing. Gelatin zymography disclosed the presence of gelatinases in phosphoric acid-etched dentin powder, while two gold-standard adhesives generated no measurable MMP activation. In-situ zymography revealed that the interfacial gelatinolytic activity from specimens treated with the two adhesives appeared similar as that of the EDTA negative control, indicating no detectable gelatinases were activated upon adhesive treatment. In solution, MMP-2/9 activity significantly decreased upon interaction with both adhesives (two-way linear mixed effects model [LMEM]: p < 0.05); gelatinases were almost completely deactivated upon 1-week incubation at 37 °C (general linear model: p < 0.05); light-curing adhesives increased temperature up to 55 °C, which appeared sufficient to dramatically decrease MMP-2/9 activity (two-way ANOVA: p < 0.05). Finally, challenging adhesive-dentin interfaces with highly concentrated MMP-9 (at a much higher concentration than present in saliva) for 1 m did not significantly affect μTBS (two-way LMEM: p > 0.05). Taken together, the two adhesives did not activate but rather inhibited the release and activation of dentinal gelatinases. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). Methods: Patients with LHI within 24 h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3 months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5 mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. Results: Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82 ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144–6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841–10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56 ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236–6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534–9.637, p = 0.004). Conclusions: Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies. [ABSTRACT FROM AUTHOR]

Objective This study aimed to investigate the levels of chitinase-3-like protein-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and monocyte chemoattractant protein-1 (MCP-1) in adenomyosis, as compared to normal myometrial tissue. These biomarkers may be useful for determining potential treatment targets. Methods This was a correlative, analytical, and observational study with a cross-sectional design. Participants with a diagnosis of moderate-to-severe adenomyosis, as determined through transvaginal ultrasonography and histological examination, and who underwent laparotomy or laparoscopic surgery for the treatment of adenomyosis, were enrolled in the study. Unlike other studies that recruited healthy women as controls, our study used adenomyotic and healthy nonadenomyotic myometria obtained from the same individual. The levels of CHI3L1, MMP-9, and MCP-1 in the biopsy samples were determined using enzyme-linked immunoassay kits, according to the manufacturer’s protocol. Results A highly significant increase in the levels of CHI3L1, MMP-9, and MCP-1 was found in adenomyotic tissues compared to non-adenomyotic tissues (P

Background: The aim of this study was to further explore the role of caveolin-1 (Cav-1) related Akt/mTOR signaling pathway in blood brain barrier (BBB) dysfunction caused by NMDAR activation. Methods: The cell localization of NMDAR GluN1 subunit and Cav-1 was observed on human brain microvascular HBEC-5i cells after immunofluorescence double staining. The transendothelial resistance (TEER) of BBB in vitro was measured by Millicell-ERS cell resistance meter. Sodium fluorescein (SF) was used to measure the permeability of BBB in vitro. A stable Cav-1-silenced HBEC-5i cell line was established by infecting the cells with a lentivirus encoding Cav-1 shRNA. The changes of the protein and mRNA of MMP9 and Occludin induced by NMDA were detected by Western blot (WB) and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. The phosphorylated proteins of Cav-1, Akt, and mTOR were detected by WB. Results: NMDAR GluN1 was expressed in the cytoplasm and part of the cell membrane of the HBEC-5i cell line. NMDAR activation decreased TEER and increased the SF of BBB in vitro. HBEC-5i cells incubated with NMDA enhanced the phosphorylation of Cav-1, Akt, and mTOR, also promoting the expression of MMP9 along with the degradation of Occludin. These effects could be reversed by pretreatment with NMDAR antagonist (MK801) or Cav-1 antagonist (Daidzein), or Akt antagonist (LY294002), respectively. Further silencing Cav-1 with LV-Cav-1-RNAi also played a similar protective effect. Conclusion: Caveolin-1 (Cav-1) related Akt/mTOR signaling probably contributes to BBB dysfunction by activating NMDAR on human brain microvascular cells. [ABSTRACT FROM AUTHOR]

Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.

Tissue-resident macrophages are heterogeneous and perform location-dependent functions. Skin resident macrophages play intriguing roles in long-distance intercellular signaling by mediating cellular protrusions called airinemes in zebrafish. These macrophages relay signaling molecules containing airineme vesicles between pigment cells, and their absence disrupts airineme-mediated signaling and pigment pattern formation. It is unknown if the same macrophages control both these signaling and typical immune functions or if a separate subpopulation functions in intercellular communication. With high-resolution imaging and genetic ablation approaches, we identify a macrophage subpopulation responsible for airineme-mediated signaling. These seem to be distinct from conventional skin-resident macrophages by their ameboid morphology and faster or expansive migratory behaviors. They resemble ectoderm-derived macrophages termed metaphocytes. Metaphocyte ablation markedly decreases airineme extension and signaling. In addition, these ameboid/metaphocytes require matrix metalloproteinase-9 for their migration and airineme-mediated signaling. These results reveal a macrophage subpopulation with specialized functions in airineme-mediated signaling, which may play roles in other aspects of intercellular communication.

AimThis study systematically evaluated the potential efficacy of serum matrix metalloproteinase-9 (MMP-9) concentration as a diagnostic marker for endometriosis through meta-analysis. Early and accurate diagnosis of endometriosis, a common gynecological disease, is crucial for improving patient prognosis. Hence, this study aimed to comprehensively analyze the data from multiple studies to assess the diagnostic value of serum MMP-9 concentration for endometriosis.MethodsArticles investigating the association between MMP-9 and endometriosis, published from the inception of the databases until February 2024, were systematically retrieved from multiple databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and CNKI. Download and analyze the GSE7305, GSE23339, and GSE51981 datasets. Statistical analyses of all eligible studies were conducted using RevMan 5.4, Stata 11.0, and R software version 4.3.3.ResultsFifteen studies fully met the inclusion criteria for the meta-analysis. The concentration of MMP-9 in the blood of patients with endometriosis was significantly higher compared to that of the control group (p < 0.0001). Subgroup analysis based on different stages of endometriosis revealed a trend towards significantly higher serum MMP-9 concentrations in patients, whether in stages I-II or III-IV. Bioinformatics analysis revealed differences in the expression of MMP-9 in endometrial tissue between EMT patients and healthy controls in the GSE7305 and GSE23339 datasets. Additionally, in the GSE51981 dataset, we found significant differences between the normal group and both mild and severe cases of endometriosis.ConclusionBoth the current meta-analysis and bioinformatics analysis indicate differences in MMP-9 concentration levels between endometriosis patients and healthy individuals, with potentially elevated MMP-9 concentrations in serum samples from patients with endometriosis.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42024525864.

Abstract Background Stroke is one of the most frequent causes of mortality and disability, blood protein biomarkers are used to determine patients at high risk for a severe illness and to estimate the outcome. This study aimed to detect the relation between serum levels of C-reactive protein, matrix metalloproteinase 9, S100 calcium-binding protein B, brain natriuretic peptide, D-dimer and stroke severity and outcome in acute ischemic stroke patients. Results One hundred eighty-six patients with acute ischemic stroke participated and were subjected to complete general, neurological examination, assessment of stroke severity clinically and radiologically using National Institute of Health Stroke Scale (NIHSS), and Alberta Stroke Program Early CT (ASPECT) score and assessment of functional outcome using (modified Rankin Scale). C-reactive protein, matrix metalloproteinase 9, S100 calcium-binding protein B, brain natriuretic peptide and D-dimer were assessed. Higher C-reactive protein was found in patients with ASPECT score ≤ 7 and in patients with cerebral edema, seizures and was positively correlated with stroke severity according to NIHSS and modified Rankin Scale. C-reactive protein serum level at onset was negatively correlated with NIHSS at onset and is a significant predictor for mortality. D-dimer was negatively correlated with NIHSS. S100 calcium-binding protein B was significantly elevated in patients who developed hemorrhagic transformation. Conclusions Serum C-reactive protein level can be used as a predictor for mortality and higher S100 calcium-binding protein B was detected in patients with hemorrhagic transformation.

Lingfang Tan,1 Xuefeng Yang,2 Jianxin Zhang,3 Kebing Zhou1,2 1The Nanhua Affiliated Hospital, Department of Respiratory Physicians, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 2The Nanhua Affiliated Hospital, Department of General Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 3The Nanhua Affiliated Hospital, Department of Cardiothoracic Surgeon, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of ChinaCorrespondence: Kebing Zhou, Tel +86-17397392536, Email zhoukebing9999@163.comBackground: Airway remodeling is a significant pathological characteristic of chronic obstructive pulmonary disease (COPD). In recent years, hypoxia-inducible factor 1-α (HIF-1α), a member of the hypoxia-inducible factor protein family, has gained attention. However, the potential correlation between HIF-1α and COPD airway remodeling remains unclear.Objective: This study explored the expression patterns of HIF-1α in patients with COPD and its association with airway remodelling. This investigation aims to furnish novel insights for the clinical identification of prospective therapeutic targets for ameliorating COPD-related airway remodelling.Patients and Methods: A total of 88 subjects were included, consisting of 28 controls and 60 COPD patients. Various staining methods were employed to observe the pathological changes in airway tissues. Immunohistochemistry was utilized to detect the expression of HIF-1α and MMP9 (matrix metalloproteinase 9) in airway tissues. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration in serum of HIF-1α and MMP9. Computed tomography (CT) airway parameters were measured in all participants to assess airway remodeling. The relationship between serum HIF-1α and MMP9 concentrations and airway parameters was analyzed.Results: Staining of airway structures in COPD patients revealed significant pathological changes associated with airway remodelling, including mixed cilia and subepithelial fibrosis. The expression of HIF-1α and MMP9 was significantly higher in both human airway tissue and serum compared to controls. Chest CT scans exhibited typical imaging features of airway remodeling and increased airway parameters.Conclusion: The findings suggest a correlation between increased HIF-1α expression and COPD airway remodelling. This study provides novel evidence that HIF-1α may be a potential biomarker for airway remodelling in COPD patients.Keywords: hypoxia-inducible factor 1-α, chronic obstructive pulmonary disease, matrix metalloproteinase 9, airway remodelling

Type 2 Diabetes (T2D) is associated with impaired vascularization of adipose tissue (AT) . IL8, GROα and IL15 are pro-angiogenic myokines, secreted at elevated levels by T2D myotubes. We explored the direct impact of these myokines on AT vascularization. AT explants from subjects with T2D and without diabetes (non-diabetic, ND) were treated with rIL8, rGROα and rIL15 in concentrations equal to those in conditioned media (CM) from T2D and ND myotubes, and sprout formation evaluated. Endothelial cells (EC) were isolated from T2D and ND-AT, treated with rGROα and tube formation evaluated. Finally, we investigated the involvement of MMP-2 and -9 in vascularization. ND and T2D concentrations of IL8 or IL15   caused similar stimulation of sprout formation in ND- and T2D-AT. GROα exerted a similar effect in ND-AT. When T2D-AT explants were exposed to GROα, sprout formation in response to T2D concentrations was reduced compared to ND. Exposure of EC from T2D-AT to GROα at T2D concentrations resulted in reduced tube formation. Reduced responses to GROα in T2D-AT and EC were also seen for secretion of MMP-2 and -9. The data indicate that skeletal muscle can potentially regulate AT vascularization, with T2D-AT having impairments in sensitivity to GROα, while responding normally to IL8 and IL15.

Objective To study changes and correlation of peripheral bold endothelial progenitor cells (EPCs) and serum bFGF, VEGF and MMP-9 in rats with peripheral nerve injury (PNI). Methods Forty-two SD rats were divided into the control group, the PNI 1 d group, the PNI 3 d group, the PNI 5 d group, the PNI 7 d group and the PNI 14 d group according to random number table method, with 7 rats in each group. The sciatic nerve injury model was established in all groups except the control group. In each group, blood samples were collected by living heart puncture at a predetermined time point. Mononuclear cells were extracted by Ficoll density gradient centrifugation. CD34 and CD133 double positive cells were labeled with EPCs, and the number of EPCs in each group was detected by flow cytometry. The contents of bFGF, VEGF and MMP-9 in peripheral blood of each group were detected by enzyme-linked immunosorbent assay, and the correlation between the number of EPCs and bFGF, VEGF and MMP-9 was analyzed. Results Compared with the control group, EPCs in peripheral blood were increased in the PNI 3 d group, the PNI 5 d group and PNI 7 d group. bFGF contents in peripheral blood were increased in the PNI 3 d group, the PNI 5 d group, the PNI 7 d group and the PNI 14 d group, and VEGF contents in peripheral blood were increased in the other groups. The content of MMP-9 in peripheral blood was increased in the PNI 5 d group, the PNI 7 d group and the PNI 14 d group (P＜0.05). The number of EPCs in peripheral blood in the PNI 5 d group and the PNI 7 d group was positively correlated with serum bFGF level (r=0.784 and 0.788, P＜ 0.05) and serum VEGF level (r=0.889 and 0.852, P＜0.05). The number of EPCs in peripheral blood of the PNI 5 d group, the PNI 7 d group and the PNI 14 d group was positively correlated with serum MMP-9 level (r=0.788, 0.852 and 0.873, P＜ 0.05), and it was positively correlated with serum VEGF level (r=0.889 and 0.852, P＜0.05). The number of EPCs in peripheral blood was positively correlated with serum MMP-9 level in the PNI 5 d group, the PNI 7 d group and the PNI 14 d group (r=0.788, 0.852 and 0.873, P＜0.05). Conclusion EPCs, bFGF, VEGF and MMP-9 are involved in the pathophysiological process of blood supply repair after PNI. [ABSTRACT FROM AUTHOR]

Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 g/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 g/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways. [ABSTRACT FROM AUTHOR]

Background: Stroke is one of the most frequent causes of mortality and disability, blood protein biomarkers are used to determine patients at high risk for a severe illness and to estimate the outcome. This study aimed to detect the relation between serum levels of C-reactive protein, matrix metalloproteinase 9, S100 calcium-binding protein B, brain natriuretic peptide, D-dimer and stroke severity and outcome in acute ischemic stroke patients. Results: One hundred eighty-six patients with acute ischemic stroke participated and were subjected to complete general, neurological examination, assessment of stroke severity clinically and radiologically using National Institute of Health Stroke Scale (NIHSS), and Alberta Stroke Program Early CT (ASPECT) score and assessment of functional outcome using (modified Rankin Scale). C-reactive protein, matrix metalloproteinase 9, S100 calcium-binding protein B, brain natriuretic peptide and D-dimer were assessed. Higher C-reactive protein was found in patients with ASPECT score ≤ 7 and in patients with cerebral edema, seizures and was positively correlated with stroke severity according to NIHSS and modified Rankin Scale. C-reactive protein serum level at onset was negatively correlated with NIHSS at onset and is a significant predictor for mortality. D-dimer was negatively correlated with NIHSS. S100 calcium-binding protein B was significantly elevated in patients who developed hemorrhagic transformation. Conclusions: Serum C-reactive protein level can be used as a predictor for mortality and higher S100 calcium-binding protein B was detected in patients with hemorrhagic transformation. [ABSTRACT FROM AUTHOR]

Objective: Quinazolines and condensed quinazolines got a significant role to be treated as the pharmacophore nucleus for various diseases by acting on selected targets, cancer therapeutics is one of such ailments. By considering the importance of this privileged scaffold, some novel tetrazolo [5,1-b]quinazolines (Va–Vh) and (VIa–VIh) were designed and screened computationally for drug likeness properties. Methods: The selected compounds were synthesized and later were evaluated for in vitro anticancer activity on the human cervical carcinoma cell lines by MTT assay. Later the compounds were subjected for the molecular docking analysis on the matrix metalloproteinase 9 (PDB ID: 1GKC) and dihydroorotase (PDB ID: 2EG7). Results and Discussion: The compounds were found to possess good anticancer properties with IC50 value of 1.21 ± 0.10 to 6.32 ± 0.32 µM, some of the compounds were found to be more active than the standard drug, methotrexate. Conclusions: The same pattern has been observed in the docking study too, where the compounds were binding effectively to the two proteins studied. [ABSTRACT FROM AUTHOR]

Sodium, although essential for life, is a key factor in changes in vascular function and cardiovascular disease when consumed in excess. Sarcocornia spp., a halophyte plant with many nutritional benefits, presents itself as a promising substitute for the consumption of purified salt. Matrix metalloproteinases (MMPs) 2 and 9 are widely studied due to their action in physiological processes and as biomarkers at the diagnostic level due to their increased expression in inflammatory processes. This study aimed to evaluate whether replacing salt with Sarcocornia perennis (S. perennis) powder in healthy young people leads to an improvement in biochemical profiles and the attenuation of MMP-2 and MMP-9 activity. In the present study, 30 participants were randomized into a control group that consumed salt and an intervention group that replaced salt with powdered S. perennis. The evaluation of the biochemical parameters was carried out by the spectrophotometry method, and the evaluation of MMP activity was carried out by zymography. A significant decrease was observed in the intervention group in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and creatinine (p-value ≤ 0.05), along with lower but not significantly different mean values of triglycerides. Regarding MMP activity after the intervention, a lower mean value was observed for MMP-9 activity, with there being higher mean values for MMP-2 activity, both with p-values ≥ 0.05. The results confirmed that the consumption of S. perennis is a beneficial choice for health regarding the lipid profile. The evaluation of MMP activity indicated the potential of S. perennis in the regulation of MMP-9 activity in healthy individuals, along with the need for the further study of these proteases in individuals with pathologies. [ABSTRACT FROM AUTHOR]

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Copyright of Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas is the property of Universidad de Santiago de Chile and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ObjectiveEarly life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association.MethodsWe used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations.ResultsOf 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized β [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05).ConclusionsOur pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally.

Purpose: Cytokeratin 19-positive cancer stem cells (CK19 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Experimental design: Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), TCGA external cohort, and in vitro and in vivo experiments were used to validate the results. Results: A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. Conclusions: This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients. Lay summary: Cytokeratin 19-positive hepatocellular carcinoma is a highly aggressive malignancy with poor therapeutic progress. Understanding the characteristics of CK19 + CSCs and their immune microenvironment better might facilitate the development of effective targeted and immunotherapy. This study identified the heterogeneity and characteristics of CK19 + CSCs and explored their unique immunosuppressive SPP1+TAM niche. The results suggested that the VEGFA signal activates TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. The study might have an important therapeutic value. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED), primarily classified as multifactorial ocular surface disorder, afflicts tens of millions of individuals worldwide, adversely impacting their quality of life. Extensive research has been conducted on tear film analysis over the past decades, offering a range of tests to evaluate its volume, health, and integrity. Yet, early diagnosis and effective treatment for DED continue to pose significant challenges in clinical settings. Nevertheless, by recognizing key phenomena in DED such as ocular surface inflammation, hyperosmolarity, and tear film instability, this article provides a comprehensive overview of both traditional and recently developed methods for diagnosing and monitoring DED. The information serves as a valuable resource not only for clinical diagnosis but also for further research into DED.

Abstract Background Gonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling. Methods We used clonal murine pituitary αT3-1 and LβT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LβT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHβ. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LβT2 migration responses to GnRH and AXL. Results We observed AXL, along with the GnRH receptor, expression in αT3-1 and LβT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LβT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LβT2 cells, Gas6/AXL signaling stimulated LHβ production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration. Conclusions Altogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling. Video Abstract

Background. Impaired homeostasis of the retinal tissue in diabetes primarily involves microglia, which triggers a cascade of inflammatory reactions, one of the main mechanisms of diabetic retinopathy (DR). The purpose of the study was to determine the state of microglia in experimental DR and the effect of the tyrosine protein kinase blocker imatinib. Materials and methods. In 45 three-month-old male Wistar rats, diabetes was simulated by a single injection of streptozotocin (50 mg/kg; Sigma-Aldrich). The rats were divided into 3 groups: controls; short-acting insulin; insulin and imatinib (Grindex, Latvia). Immunohistochemically, CD68-positive cells were detected in the retina, and the levels of ionized calcium-binding adapter molecule 1 (Iba-1) and matrix metalloproteinase 9 (MMP-9) was evaluated by immunoblotting. Results. The retinal content of Iba-1 progressively increased and exceeded the initial level by 2.0 times after 7 days, and by 3.55 times after 28 days (p 0.05). CD68-positive cells in the retina were noted in the vessels of the choroid plexus throughout the observation, from the 14th day — in the dilated venules of the outer plexiform layer (monocytic pool), and from day 28 — diffusely in the parenchyma of the inner layers (microglial pool). The latter had either a rounded or a ramified shape, which corresponded to the morphology of amoeboid (phagocytic) or activated microglia. Tyrosine protein kinase blockade prevented the microglial activation in the retina. Signs of inflammation in the form of retinal MMP-9 increase and fibrotic retinal proliferations were absent on the 28th day when using insulin and imatinib. Conclusions. The blockade of retinal inflammation and microglial activation by imatinib indicated the prospects of tyrosine protein kinases inhibition in DR and substantiated the prospect of further research with the clarification of such an effect on other mechanisms of DR development.

Introduction: Wounds have a significant influence on socioeconomic and the quality of life. Many attempts have been taken to produce advanced wound dressing to fulfill demands. The incorporation of natural therapeutics like medicinal plants in wound dressings is currently popular. However, several medications have failed to enter the market due to inadequate pharmacokinetics data. Computer-aided tools are now available as advanced drug discovery methods, which can be used to screen pharmaceuticals from phytochemicals found in various medicinal plants. This study aims to evaluate the phytoconstituents of Chromolaena odorata extract and its pharmacological potential as a wound-healing agent. Methods: Phytoconstituents from C. odorata were identified using qualitative screening methods and gas chromatography-mass spectrometry (GC-MS), and their mechanistic properties were assessed using molecular docking and SwissADME tools. Results: Current works revealed that the topmost phytoconstituents in C. odorata were phytol (49.83%), hexadecanoic acid ethyl ester (9.40%), linolenic acid (8.07%), and squalene (3.53%). Through SwissADME analysis, all four topmost compounds obeyed Lipinski’s Rule of 5. In silico molecular docking study of these top phytoconstituents against several protein targets involved in wound healing revealed that squalene had the highest binding affinity to GSK3-β (-6.8 kJ/ mol), MMP-9 (-7.4 kJ/mol), and COX-2 (-8.6 kJ/mol) as compared to other ligands (phytol, linolenic acid, and hexadecenoic acid ethyl ester). Conclusion: These findings suggest that the most prominent compound that contributes to C. odorata’s wound healing capacity is squalene and the incorporation of C. odorata in potential wound dressing formulation is justified.

Intracranial inoculation of the neuroadapted JHM strain of mouse hepatitis virus (JHMV) into susceptible strains of mice results in acute encephalomyelitis followed by a cimmune-mediated demyelination similar to the human demyelinating disease multiple sclerosis (MS). JHMV infection of transgenic mice in which expression of the neutrophil chemoattractant chemokine CXCL1 is under the control of a tetracycline-inducible promoter active within GFAP-positive cells results in sustained neutrophil infiltration in the central nervous system (CNS) that correlates with an increase in spinal cord demyelination. We used single cell RNA sequencing (scRNAseq) and flow cytometry to characterize molecular and cellular changes within the CNS associated with increased demyelination in transgenic mice compared to control animals. These approaches revealed the presence of activated neutrophils as determined by expression of mRNA transcripts associated with neutrophil effector functions, including CD63, MMP9, S100a8, S100a9, and ASPRV1, as well as altered neutrophil morphology and protein expression. Collectively, these findings reveal insight into changes in the profile of neutrophils associated with increased white matter damage in mice persistently infected with a neurotropic coronavirus.

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = -2.10 [-3.97 to -0.27], p = 0.027 and β = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

Our goal was to evaluate the effects of EC refill fluids and EC exhaled aerosol residue (ECEAR) on cultured human keratinocytes and MatTek EpiDerm™, a 3D air liquid interface human skin model. Quantification of flavor chemicals and nicotine in Dewberry Cream and Churrios refill fluids was done using GC-MS. The dominant flavor chemicals were maltol, ethyl maltol, vanillin, ethyl vanillin, benzyl alcohol, and furaneol. Cytotoxicity was determined with the MTT and LDH assays, and inflammatory markers were quantified with ELISAs. Churrios was cytotoxic to keratinocytes in the MTT assay, and both fluids induced ROS production in the medium (ROS-Glo™) and in cells (CellROX). Exposure of EpiDerm™ to relevant concentrations of Dewberry Cream and Churrios for 4 or 24 h caused secretion of inflammatory markers (IL-1α, IL-6, and MMP-9), without altering EpiDerm™ histology. Lab made fluids with propylene glycol (PG) or PG plus a flavor chemical did not produce cytotoxic effects, but increased secretion of IL-1α and MMP-9, which was attributed to PG. ECEAR derived from Dewberry Cream and Churrios did not produce cytotoxicity with Epiderm™, but Churrios ECEAR induced IL-1α secretion. These data support the conclusion that EC chemicals can cause oxidative damage and inflammation to human skin.

Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor-driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, in vitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation in vitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.

Background. Coronary artery disease (CAD) persistently remains the leading cause of mortality globally. Given the severity and impact of this condition, researchers have been meticulously studying the pathogenesis of athe-rosclerosis, a principal cause behind CAD. The pathogenesis stages are complex and multifaceted, including factors such as lipid accumulation, inflammation, and plaque formation. A particular area of active exploration pertains to the influence and role of different biomarkers, including matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO), on these processes. These biomarkers have been associated with the progression and destabilization of athe-rosclerotic plaques, which are central to CAD. However, the use of these biomarkers in the context of comorbidities, such as chronic kidney disease, remains an open area of research, especially in patients after myocardial infarction. Materials and methods. In our study, 96 patients who had acute coronary syndrome and subsequently undergone percutaneous coronary intervention were enrolled. They were stratified into groups (A and B) based on respective glomerular filtration rates. The primary endpoint of the study was all-cause mortality and major adverse cardiovascular and cerebrovascular events. Results. Our analysis revealed that serum levels of MPO in group B were insignificantly higher than those in group A. Conversely, the area under the receiver operating characteristic (ROC) curve for MMP-9 in group A exhibited a significant difference, standing at 0.8 (95% confidence interval 0.609–0.991; p = 0.039). However, the ROC curve for MPO did not yield a significant result in any group. A combined ROC curve was also generated, with the area under this curve showing a significantly higher value of 0.890 (95% confidence interval 0.805–0.975; p < 0.001). Conclusions. We found that plasma levels of the above-mentioned biomarkers do not seem to influence a decrease in glomerular filtration rate. Nonetheless, MMP-9 levels offered significant prognostic information regarding predicted outcomes.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka (Leptospermum scoparium) nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation. Using gelatin zymography, 40 μg/mL LepteridineTM inhibited the gelatinase activities of both pro- (22%, p < 0.0001) and activated (59%, p < 0.01) MMP-9 forms. By comparison, LepteridineTM exerted modest (~10%) inhibition against a chromogenic peptide substrate and no effect against a fluorogenic peptide substrate. These findings suggest that LepteridineTM may not interact within the catalytic domain of MMP-9 and exerts a negligible effect on the active site hydrolysis of small soluble peptide substrates. Instead, the findings implicate fibronectin II domain interactions by LepteridineTM which impair gelatinase activity, possibly through perturbed tethering of MMP-9 to the gelatin matrix. Molecular modelling analyses were equivocal over interactions at the S1′ pocket versus the fibronectin II domain, while molecular dynamic calculations indicated rapid exchange kinetics. No significant degradation of synthetic or natural LepteridineTM in Mānuka honey occurred during simulated gastrointestinal digestion. MMP-9 regulates skin and gastrointestinal inflammatory responses and extracellular matrix remodelling. These results potentially implicate LepteridineTM bioactivity in Mānuka honey's reported beneficial effects on wound healing via topical application and anti-inflammatory actions in gastrointestinal disorder models via oral consumption. [ABSTRACT FROM AUTHOR]

Background: Stroke is a heterogeneous and multi-factorial disease that affects people globally. Matrix Metalloproteinase-9 is involved in blood- brain barrier breakdown, edema development, pro-inflammatory cytokine activation and destruction of myelin proteins are all connected to the pathogenic events that take place during an ischemic stroke., matrix metalloproteinase- 9 concentration is greatly related to infarct extension, neurologic impairments, and hemorrhagic transformation in individuals with ischemic stroke. Objective: We focused our research on improving individuals' outcomes after having an acute ischemic stroke by assessing the level of serum matrix metalloproteinase-9 24 hours after the stroke begins and the relation between Serum levels of matrix metalloproteinase-9, clinical severity, and ischemic stroke prognosis. Methods: This follow up prospective cohort research was conducted at Zagazig University Hospitals' Intensive Care Unit and Stroke Unit at the Neurology Department and Emergency Room. The study included 54 people experiencing their first acute ischemic stroke. Stroke severity and serum MMP-9 level were assessed on admission and following a 15-day follow-up. Results: Level of Serum MMP-9 was 1085.93 ng/ml with a range from 485 to 1544 ng/ml. Statistically significant positive correlation was found between serum MMP-9 and neurological severity as measured by NIHSS at admission and after 15 days. Also, there was a highly significant positive correlation between MMP-9 and functional outcome as assessed by mRS after 15 da ys follow up. The best cutoff of MMP-9 in prediction of large size infarction, that was ≥ 1042 Also, the best cutoff of MMP-9 in prediction of severe stroke was ≥ 1091 ng/ml. The best cutoff of MMP-9 in prediction of severe stroke after 15 days is ≥972.5 ng/ml. Among factors significantly correlated with baseline NIHSS, MMP-9, size of infarct, BI and mRS were significantly independently associated with baseline NIHSS among studied patients.Conclusion: Serum MMP-9 may act as potential prognostic factor predicting neurological severity and short term outcome in individuals with ischemic stroke. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood–brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives. [ABSTRACT FROM AUTHOR]

Background: Gonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling. Methods: We used clonal murine pituitary αT3-1 and LβT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LβT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHβ. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LβT2 migration responses to GnRH and AXL. Results: We observed AXL, along with the GnRH receptor, expression in αT3-1 and LβT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LβT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LβT2 cells, Gas6/AXL signaling stimulated LHβ production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration. Conclusions: Altogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling. 5LYCavpivq5eiBQqEyV1Bj Video Abstract [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological studies have found that female workers who are exposed to waste sevoflurane for a long time have reduced fertility and increased incidence of abortion and fetal deformity. OBJECTIVE: To imitate the working environment of long-term exposure to waste sevoflurane and investigate the mechanism of embryo implantation disorder induced by low-concentration sevoflurane exposure by observing the expression of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 in endometrium of pregnant mice exposed to low concentrations of sevoflurane, attempting to provide a basis for clinical safe drug use and occupational protection and to lay a foundation for further research on the mechanism of inhalation anesthetics on embryo implantation at gene and molecular levels. METHODS: Forty female Kunming mice and sixteen male Kunming mice, aged 6 weeks, weighting (20±2) g, were caged separately. Forty female mice were randomly divided into experimental group and control group. Mice in the experimental group were exposed to 0.1% sevoflurane, 6 hours per day, while those in the control group were exposed to the air. Thirty days later, the female mice in estrus were caged with mature male mice at a rate of 2:1. Whether the female mice were pregnant was observed at 7:00 am on the second day after mating. The pregnant mice were kept independently in the original condition (n ≥ 8 pregnant mice in each group). Mouse uterus on day 4.5 of gestation was removed and sliced for histological observation. The expression of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 in endometrial tissue was detected by immunohistochemistry and statistically analyzed. The average integrated absorbance value of positive reactants was calculated. RESULTS AND CONCLUSION: In the experimental and control groups, 17 and 15 female mice were respectively found in estrus; 12 and 10 female mice respectively were found vaginal plugs after mating. Five and two female mice were found pseudopregnant on day 4.5 of gestation in the experimental and control groups, respectively. Therefore, there were 7 and 8 pregnant mice in the experimental and control groups, respectively, and the vacant value in the experimental group was replaced by the average value obtained in the same group, which would be subsequently used in the controlled trial. Immunohistochemical results showed that the endometrium (glandular epithelial cells, luminal epithelial cells and stromal cells) of all pregnant mice were positively stained brownish yellow, but the expressions of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9 (0.019±0.007, 0.017±0.007, 0.015±0.005, 0.012±0.005) in the experimental group were significantly lower than those in the control group (0.032±0.014, 0.025±0.008, 0.021±0.007, 0.023±0.005) (P < 0.05). All these findings indicate that long-term exposure to 0.1% sevoflurane may affect the adhesion of mouse embryos to endometrium and the embryo implantation, which may be related to the inhibitory effects of sevoflurane on the expressions of intercellular adhesion molecule 1, integrin β1, P-selectin, and matrix metalloproteinase 9, causing the imbalance in endometrial immunoregulation, the invasion of trophoblast cells into the endometrium and the inhibition of endometrial decidualization, and miscarriage and bleeding due to damaged vascular endothelium. [ABSTRACT FROM AUTHOR]

Background and aims In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC–ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets. Methods and results Thirty-two patients with IFC–ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC–ACS) from the OPTICO–ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)–embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC–ACS than RFC–ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC–ACS–derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC–ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid. Conclusion The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC–ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss–triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC–ACS. [ABSTRACT FROM AUTHOR]

An electrochemiluminescence (ECL) bioassay with high sensitivity and anti-fouling ability was developed for determination of matrix metalloproteinase 9 (MMP-9) secreted from living cells under external stimulation. A peptide with sequence of CLGRMGLPGK and a new cyclometalated iridium(III) complex bearing carboxyl group, (pq)2Ir(dcbpy) (pq = 2-phenylquinoline, dcbpy = 2,2′-bipyridyl-4,4′-dicarboxyli acid, abbreviated as Ir) were employed as molecular recognition substrate and ECL emitter, respectively. The peptide was labelled with the Ir to form Ir-peptide as ECL probe. Ir-peptide was self-assembled onto Nafion and gold nanoparticles (AuNPs) modified glassy carbon electrode (AuNPs/Nafion/GCE) and then both of 6-mercapto-1-hexanol (MCH) and zwitterionic peptide as blocking reagents were co-assembled on Ir-peptide/AuNPs/Nafion/GCE to form an anti-fouling ECL peptide-based biosensor. MMP-9 can be quantified in the range 1.0–50 ng·mL−1 with a detection limit of 0.50 ng·mL−1 based on the decreased ECL intensity. Relative standard derivation was 2.3% for six fabricated anti-fouling ECL peptide-based biosensors after reaction with 50 ng·mL−1 MMP-9. The anti-fouling ECL peptide-based biosensor can be used to monitor MMP-9 secreted from living cells under external stimulation. 96.0%–108.0% of recoveries were obtained in 60-diluted cell culture media. This study demonstrates that the ECL biosensor by the combination of iridium(III) complex-based sensitive ECL method and the anti-fouling interface provides a promising way for the determination of MMP-9 in biological sample, which is viable in clinical diagnosis and point-of-care test of protease. [ABSTRACT FROM AUTHOR]

Preeclampsia is one of the major causes of maternal and foetal morbidity and mortality worldwide. Its complications include but are not limited to eclampsia, intracerebral haemorrhage and cardiovascular diseases in the later stages of life. The combination of clinical and risk variables and a panel of multiple biomarkers will help clinicians in risk stratification and prognostication of clinical outcomes among preeclamptic women. We evaluated MMP-9 (matrix metalloproteinase - 9) and ST2 (suppression of tumorigenicity 2) for utility as biomarkers and for predicting maternal and foetal outcomes in women with preeclampsia. This prospective cohort study involved 49 preeclamptic women and 80 healthy controls. Biomarkers were measured in plasma using ELISA. The patients were followed up to assess maternal and foetal outcomes. The mean value of MMP-9 was 2.42 ng/mL in the preeclamptic group and 2.67 ng/mL in controls. The mean value of ST2 (1937.4 ± 747.81) in the preeclamptic group was high compared to the control group (1005.7 ± 683.6) and the difference was significant (P = 0.0001). The study population was divided into those with high and low MMP-9 and those with high and low ST2. Lower levels of MMP-9 seemed to be related to both early and late onset preeclampsia. The ROC (Receiver Operating Characteristic) curve did not show the ability to predict maternal and foetal outcomes. Our study demonstrated that women with preeclampsia had low MMP-9 and high ST2 compared to healthy pregnant women. But neither of the biomarkers could predict complications of preeclampsia. • Circulatory biomarkers ST2 and MMP-9 in preeclampsia. • Risk stratification in preeclampsia. • Utility of biomarkers in predicting maternal and foetal outcomes in preeclampsia. [ABSTRACT FROM AUTHOR]

The aim. To assess the dynamics of cytokine content in tear fluid of primary openangle glaucoma (POAG) patients at various terms after non-penetrating deep sclerectomy (NPDS) in relation to the functional state of the outflow tracts.Material and methods. We carried out prospective examination of 65 patients with advanced stage of primary open-angle glaucoma after NPDS. Depending on the course of the postoperative period and the conditions for achieving the hypotensive effect of NPDS, all patients were divided into three groups: group 1 – with the optimal hypotensive effect; group 2 – with the conditional hypotensive effect; group 3 – with no hypotensive effect after NPDS. The intraocular pressure and the concentration of TGF-β, MMP-9, IL-6, IL-8, VEGF-A (121 and 165) in the tear fluid were studied using ELISA method in pre- and postoperative period. We studied the outflow tracts using optical coherence tomography and carried out ultrastructural analysis of filtering blebs tissue.Results. In group 1, the minimum initial concentrations of IL-6, IL-8 and TGF-β in the tear fluid and their moderate increase in the postoperative period; high concentrations of MMP-9 at all stages and an increase in VEGF-A by 2 months after NPDS were registered. In group 2, there was a high level of VEGF-A in the tear fluid before and 2 months after NPDS, an increase in TGF-β, IL-6 and IL-8 in the tear fluid in the early period with their suppression in the late period, as well as an increase in MMP-9 in the early postoperative period. Group 3 had maximum concentrations of TGF-β and IL-8 in the tear fluid initially and in the early postoperative period, suppression of MMP-9 in the tear fluid 2 weeks after and of VEGF-A 2 months after NPDS.Conclusion. Initially high concentrations of IL-6, IL-8, and TGF-β in the tear fluid and the suppression of MMP-9 and VEGF-A in the postoperative period contribute to the surgical failure of the NPDS.

Background: Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease. Methods: Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot. Results: Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls. Conclusions: The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.

Background: High incidence of gastric cancer (GC), its aggressive clinical course, rapid tumor dissemination, low sensitivity to chemotherapy and lack of reliable laboratory diagnostic criteria urgently require a search for the most informative markers associated with key biologic properties of the tumors. Aim: Comparative analysis of galectin-3, matrix metalloproteinase (MMP)-2, and MMP-9 levels in peripheral blood of GC patients and healthy donors, assessment of association of these markers with clinical morphological characteristics of the disease, and prognosis of overall and relapse-free survival. Materials and methods: Sixty (60) primary treatment-nave GC patients (38 men, 22 women) aged 29 to 81 years and 90 healthy donors compatible with their age and sex were included into the study. Galectin-3 was measured in EDTA plasma, MMP-2 and MMP-9 in serum with standard direct enzyme immunoassay kits "Human MMP-2 (total)", "Human MMP-9 (total)", "Human Galectin-3" (RD Systems, USA). Results: Plasma galectin-3 concentration in the GC patients was significantly higher than in the healthy controls (median 12.9 and 10.6 ng/ml, respectively; p 0.0001). No difference in serum MMP-9 levels between GC patients and control subjects were found, while MMP-2 level in the control group was significantly higher, than in the GC patients (p = 0.039). No association between galectin-3, MMP-2, and MMP-9 blood levels in the GC patients could be identified. In contrast to GC patients, there was a positive correlation of plasma galectin-3 with age in the control group (rs = 0.51, p 0.005). No associations between the biomarkers levels in blood and clinical and morphological characteristics of GC were established, except MMP-9 being higher at Т4а invasion depth as compared to the earlier Т2 level. Marked differences in the overall survival depending on plasma galectin-3 levels were found, with the cut-off level of 12.9 ng/ml: the 5-year overall survival in the patients with low galectin-3 was better, than in those with its higher level (50 and 43%, respectively; however, the difference was non-significant, р 0.1). Both overall and relapse-free survival of the GC patients was higher in those with low ( 212 ng/ml) serum MMP-2: the 5-year overall survival in this group comprised 60% versus 23% in the patients with higher MMP-2 (p = 0.018). The difference in relapse-free survival was non-significant. Serum MMP-9 levels had no significant impact on the survival of GC patients. Conclusion: The ambiguous data on the clinical role of galectin-3, MMP-2, MMP-9 in GC obtained in this study indicate the necessity of further investigation of their possible utility for the diagnostics and prognosis of treatment results.

Study Design Experimental animal study. Purpose This study aims to investigate the effects of treatment with human neural stem cell (HNSC) secretomes on subacute spinal cord injury (SCI) post-laminectomy by analyzing interleukin-10 (IL-10), matrix metalloproteinase 9 (MMP9), transforming growth factor-β (TGF-β), and Basso–Beattie–Bresnahan (BBB) score locomotors as expressions of neurological recovery. Overview of Literature In the United States, SCI has a recovery rate of 0.08%, tetraplegia 58.7%, and paraplegia 40.6%. Therapeutic approaches to SCI have focused on modulating the secondary cascade to prevent neurological deterioration and glial scar formation. Increasing evidence has shown that the success of cell-based SCI therapy is attributed to the secretomes rather than the cells themselves, but the effect of treatment with HNSC secretomes in SCI is unclear. Methods This experimental study investigated 15 Rattus norvegicus rats that were divided into three groups: (1) normal, (2) SCI+non-secretome, and (3) SCI+secretome (30 μL, intrathecal Th10). Model subacute SCI post-laminectomy was performed in 60 seconds using an aneurysm Yasargil clip with a closing forceps weighing 65 g (150 kdyn). At 35 days post-injury, the specimens were collected, and the immunohistochemicals of IL-10, MMP9, and TGF-β were analyzed. Motor recovery was evaluated based on the BBB scores. Results The SCI post-laminectomy of rats treated with HNSC secretomes showed improvements in their locomotor recovery based on the BBB scores (p=0.000, mean=18.4) and decreased MMP9 (p=0.015) but had increased the levels of IL-10 (p=0.045) and TGF-β (p=0.01). Conclusions These results indicate that the factors associated with the HNSC secretomes can mitigate their pathophysiological processes of secondary damage after SCI and improve the locomotor functional outcomes in rats.

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.

Sodium, although essential for life, is a key factor in changes in vascular function and cardiovascular disease when consumed in excess. Sarcocornia spp., a halophyte plant with many nutritional benefits, presents itself as a promising substitute for the consumption of purified salt. Matrix metalloproteinases (MMPs) 2 and 9 are widely studied due to their action in physiological processes and as biomarkers at the diagnostic level due to their increased expression in inflammatory processes. This study aimed to evaluate whether replacing salt with Sarcocornia perennis (S. perennis) powder in healthy young people leads to an improvement in biochemical profiles and the attenuation of MMP-2 and MMP-9 activity. In the present study, 30 participants were randomized into a control group that consumed salt and an intervention group that replaced salt with powdered S. perennis. The evaluation of the biochemical parameters was carried out by the spectrophotometry method, and the evaluation of MMP activity was carried out by zymography. A significant decrease was observed in the intervention group in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and creatinine (p-value ≤ 0.05), along with lower but not significantly different mean values of triglycerides. Regarding MMP activity after the intervention, a lower mean value was observed for MMP-9 activity, with there being higher mean values for MMP-2 activity, both with p-values ≥ 0.05. The results confirmed that the consumption of S. perennis is a beneficial choice for health regarding the lipid profile. The evaluation of MMP activity indicated the potential of S. perennis in the regulation of MMP-9 activity in healthy individuals, along with the need for the further study of these proteases in individuals with pathologies.

Objective To investigate the expression and clinical significance of phosphatidylinoinosidine-3-kinase (PI3K) and matrix metalloproteinase 9 (MMP-9) in bronchoscopic alveolar lavage fluid of children with severe pneumonia in pediatric intensive care unit (PICU). Methods A total of 103 children with severe pneumonia admitted to PICU of the hospital from January 2021 to June 2022 were enrolled. All patients underwent fiberbronchoscopic alveolar lavage. Real-time fluorescence quantitative polymerase chain reaction was used to determine the expression of PI3K, and enzyme-linked immunosorption was used to determine the expression of MMP-9 in alveolar lavage fluid. The patients were followed up for 21 days after admission to evaluate the prognosis. Logistic regression analysis was used to analyze the factors affecting the prognosis. Pearson correlation was used to analyze the correlation between the expression levels of PI3K and MMP-9 in the bubble lavage solution and the child Critical Case Score (PCIS) and child Organ Dysfunction 2 (PELOD-2) Scores. The values of PI3K and MMP-9 expression levels in alveolar lavage fluid to predict the prognosis were analyzed by receiver operating curve (ROC). Results Among the 103 children, 29 cases had poor prognosis vs 74 cases had good prognosis. Logistic multivariate regression analysis showed that combined shock (OR = 4.104, 95%CI: 1.689 ~ 9.974), PELOD-2 score (OR = 4.764, 95%CI: 1.960 ~ 11.577), PCIS score (OR = 5.068, 95%CI: 2.085 ~ 12.318), PI3K (OR = 3.924, 95%CI: 1.614 ~ 9.536) and MMP-9 (OR = 3.873, 95%CI: 1.594 ~ 9.412) were the prognostic factors of PICU children with severe pneumonia (P < 0.05). Pearson correlation analysis showed that the expression levels of PI3K and MMP-9 in alveolar lavage fluid were negatively correlated with PCIS scores (r = -0.598, P = 0.000; r = -0.537, P = 0.000), PI3K and MMP-9 expression levels in alveolar lavage fluid were positively correlated with PELOD-2 scores (r = 0.546, P = 0.000; r = 0.571, P = 0.000). ROC curve results showed that the sensitivity of PI3K, MMP-9 and their combination to predict the prognosis of PICU children with severe pneumonia was 75.86% (95%CI: 56.08% ~ 88.98%), 72.41% (95%CI: 52.51% ~ 86.55%) and 82.76% (95%CI: 63.51% ~ 93.47%), the specificity was 75.68% (95%CI: 64.07% ~ 84.58%), 79.73% (95%CI: 68.47% ~ 87.85%), 89.19% (95%CI: 79.28% ~ 94.88%), and the AUC was 0.762 (95%CI: 0.666 ~ 0.859), 0.767 (95%CI: 0.670 ~ 0.873), 0.909 (95%CI: 0.848 ~ 0.971). Conclusion The expression of PI3K and MMP-9 in bronchoscopic alveolar lavage fluid was related to the prognosis of children with severe pneumonia in PICU, and the combination in predicting the prognosis was effective, so it has certain clinical value to use them as a sensitive indicator to predict the prognosis of children with severe pneumonia in PICU. [ABSTRACT FROM AUTHOR]

Background. Impaired homeostasis of the retinal tissue in diabetes primarily involves microglia, which triggers a cascade of inflammatory reactions, one of the main mechanisms of diabetic retinopathy (DR). The purpose of the study was to determine the state of microglia in experimental DR and the effect of the tyrosine protein kinase blocker imatinib. Materials and methods. In 45 three-month-old male Wistar rats, diabetes was simulated by a single injection of streptozotocin (50 mg/kg; Sigma-Aldrich). The rats were divided into 3 groups: controls; short-acting insulin; insulin and imatinib (Grindex, Latvia). Immunohistochemically, CD68-positive cells were detected in the retina, and the levels of ionized calcium-binding adapter molecule 1 (Iba-1) and matrix metalloproteinase 9 (MMP-9) was evaluated by immunoblotting. Results. The retinal content of Iba-1 progressively increased and exceeded the initial level by 2.0 times after 7 days, and by 3.55 times after 28 days (p < 0.05). The insulin introduction inhibited the Iba-1 increase, which, although exceeding the initial level by 1.8 times, was significantly lower than the protein level in the control group after 28 days. The administration of imatinib together with insulin prevented the accumulation of Iba-1 in the retinal tissue: the protein content did not differ from the initial level (p > 0.05). CD68-positive cells in the retina were noted in the vessels of the choroid plexus throughout the observation, from the 14th day — in the dilated venules of the outer plexiform layer (monocytic pool), and from day 28 — diffusely in the parenchyma of the inner layers (microglial pool). The latter had either a rounded or a ramified shape, which corresponded to the morphology of amoeboid (phagocytic) or activated microglia. Tyrosine protein kinase blockade prevented the microglial activation in the retina. Signs of inflammation in the form of retinal MMP-9 increase and fibrotic retinal proliferations were absent on the 28th day when using insulin and imatinib. Conclusions. The blockade of retinal inflammation and microglial activation by imatinib indicated the prospects of tyrosine protein kinases inhibition in DR and substantiated the prospect of further research with the clarification of such an effect on other mechanisms of DR development. [ABSTRACT FROM AUTHOR]

(1) Background: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), in which a rupture of atherosclerotic plaques and oxidative stress play a role in the initiation and progression of the disorder. Circulating levels of myeloperoxidase (MPO), as an oxidative stress marker, as well as matrix metalloproteinase-9 (MMP-9), as a destabilizer of plaques, are known to be elevated in patients with CAD and are associated with worse prognosis. Some studies have suggested that OSA is associated with MPO and MMP-9, but the effect of OSA on these biomarkers in cardiac cohorts is unknown. (2) Aims: We addressed the determinants of high MPO and MMP-9 in a CAD cohort with concomitant OSA. (3) Materials and Methods: The current study was a secondary analysis of the RICCADSA trial that was conducted in Sweden between 2005 and 2013. A total of 502 revascularized CAD patients with OSA (apnea–hypopnea index [AHI] ≥ 15 events/h; n = 391) or no-OSA (AHI < 5 events/h; n = 101), based on a home sleep apnea test, and who had blood samples at baseline were included in the analysis. The patients were dichotomized into a high or low MPO and MMP-9 groups, based on the median cut-off values. (4) Results: The mean age of the participants was 63.9 (±8.6), and 84% of the study cohort were men. Median values of MPO and MMP-9 levels were 116 ng/mL and 269 ng/mL, respectively. In different multivariate linear and logistic regression models, neither OSA nor OSA severity in terms of AHI and oxygenation indices were associated with the high MPO and MMP-9 levels. Current smoking was significantly associated with both high MPO (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06–2.84; p = 0.030) and high MMP-9 levels (OR 2.41, 95% CI 1.44–4.03; p < 0.001), respectively. Other significant determinants were revealed as beta blocker use (OR 1.81, 95% CI 1.04–3.16; p = 0.036) for high MPO as well as male sex (OR 2.07, 95% CI 1.23–3.50; p = 0.006) and calcium antagonist use (OR 1.91, 95% CI 1.18–3.09; p = 0.008) for high MMP-9 levels. (5) Conclusions: Current smoking, but not OSA, was significantly associated with high MPO and MMP-9 levels in this revascularized CAD cohort. Smoking status should be seriously taken into consideration while evaluating the effects of OSA and its treatment on long-term adverse cardiovascular outcomes in adults with CAD. [ABSTRACT FROM AUTHOR]

Simple Summary: The crucial role of tumor-associated macrophages (TAMs) in the disease progression of various types of tumors, including esophageal squamous cell carcinoma (ESCC), has been well established. To investigate the close interplay between cancer cells and TAMs, we previously established a direct co-culture system. Our aim was to identify useful molecular markers whose expression is regulated by interactions with cancer cells and TAMs, to predict patient prognoses, or to gain a deeper understanding of the ESCC mechanism. Our method revealed that direct contact with macrophages stimulated matrix metalloproteinase 9 (MMP9) production in ESCC cells, and that MMP9 played an integral role in cancer cell migration and invasion in vitro. Moreover, MMP9 expression in ESCC cells was significantly correlated with high infiltration of TAMs and poor clinical outcomes in immunohistochemical analysis. Our study suggests the potential for TAMs or MMP9 as important prognostic markers or therapeutic ESCC targets. Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front ("cancer cell MMP9") was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features. [ABSTRACT FROM AUTHOR]

Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis. [ABSTRACT FROM AUTHOR]

BackgroundMatrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma.Patients and methodsThis phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed.ResultsAndecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed.ConclusionAndecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma.Implications for practiceThe combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.