Plasma MMP-9 Research Articles

Astaxanthin, Compared to Other Carotenoids, Increases the Efficacy of Methotrexate in Rat Adjuvant Arthritis.

This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin's therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin's full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (β - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (β - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Slow-velocity eccentric-only resistance training improves symptoms of type 2 diabetic mellitus patients by regulating plasma MMP-2 and -9.

This study investigated the intervention effect of slow-velocity eccentric-only resistance training on type 2 diabetic mellitus (T2DM) patients based on the role of matrix metalloproteinase-2 and -9 (MMP-2 and -9) in regulating extracellular matrix homeostasis. 50 T2DM patients were randomly divided into the slow-velocity eccentric-only resistance training group (E) and control group (C). The E group performed eccentric-only resistance training 3 times a week, every other day for 10 weeks, while the C group did not. Blood samples were collected before and after training, and subjects were tested for changes in clinical parameters, insulin resistance indices [fasting insulin, homeostatic model assessment insulin resistance (HOMA-IR)], MMP-2 and -9, and hydroxyproline, and muscle strength (12-RM), respectively. After 10 weeks of training, the E group showed significant decreases in fasting glucose (P < .05), insulin (P < .05), insulin resistance indices (P < .05), hemoglobin A1c (HbA1c) (P < .01), triglycerides (P = .06) and MMP-2 (P < .05), while total cholesterol (P < .05), MMP-9 (P < .05), hydroxyproline (P < .01), Creatine Kinase (CK) (P < .05), and muscle strength (P < .001) significantly increased. There were no significant changes in the count of neutrophil, lymphocyte and platelet, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c). Compared with the C group, the E group showed a trend of a significant decrease in triglyceride (P < .05), lymphocyte count (P < .05), fasting glucose (P = .07), and plasma MMP-2 (P < .05), while MMP-9 (P < .05), hydroxyproline (P < .001), and muscle strength (P < .01) significantly increased. However, no significant changes were observed in insulin and insulin resistance indices, HbA1c, total cholesterol, HDL-c, LDL-c, CK, and other inflammatory indicators. Slow-velocity eccentric-only resistance training was beneficial for T2DM, but the potential role of MMP-2 and -9 in regulating extracellular matrix homeostasis is very different in T2DM patients.

Reduction in ACE2 expression in peripheral blood mononuclear cells during COVID-19 – implications for post COVID-19 conditions

BackgroundSevere COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC).MethodsThe IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10.ResultsForty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals.ConclusionsThis work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.

Molecular characteristics of non-human papillomavirus driven cervical adenocarcinoma and adenosquamous carcinoma.

e17532 Background: Cervical cancer is the fourth most common malignancy in women worldwide. Although infection from human papillomavirus (HPV) has been the major cause of cervical cancer, about 3-8% of cervical cancer cases are HPV-negative. Clinical data showed that patients with HPV-negative cervical cancer had significantly lower DFS than those with HPV-positive cervical cancer. The detection of HPV DNA tends to be lower in adenosquamous carcinoma (AC/ASC) than in squamous cell carcinoma. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative AC/ASC and verify the underlying potential mechanism. Methods: In this study, we aimed to exam the differential gene expression profiling by exome-capture RNA sequencing on formalin-fixed, paraffin-embedded tumor tissue of prospectively enrolled cervical AC/ASC patients (HPV-negative: HPV-positive: 1:1) and validate the selected biomarkers on the remaining (unmatched; n = 110) prospective cohort and the 274 retrospective cohort patients. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical AC/ASC tissues and HPV-negative cell lines were validated by Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical staining (IHC staining). Results: Exome-capture RNA sequencing on HPV-negative and age/grade matched HPV-positive AC/ASC (10:6) for discovery initially. We found differentially activated WNT pathway from HPV positive/negative AC/ASC in the prospective cohort. In the preliminary results of 28 prospective cohort patients, SOX17 and MMP7 highly expressed genes in HPV-negative (n = 13) then the HPV-positive (n = 11) cervical AC/ASC by IHC staining (p = 0.1029 and p = 0.0306, respectively). Moreover, plasma MMP7 levels were upregulated in HPV-negative AC/ASC (n = 10) compared with HPV-positive AC/ASC (n = 17) (p = 0.0086) by ELISA analysis in the prospective cohort. Conclusions: Further studies and more analyses will be continued to investigate the effects of changes in the expression of SOX17 and MMP7 related mechanisms, and targeting WNT/SOX17/MMP7 pathways specifically associated with HPV-negative AC/ASC to provide new insights into the early screening and effective treatment of HPV-negative AC/ASC.

MMP-9 upregulation may predict hemorrhagic transformation after endovascular thrombectomy.

Hemorrhagic transformation (HT) is a serious complication after endovascular thrombectomy (EVT) for patients with acute ischemic stroke (AIS). We analyzed the plasma levels of MMP-9 before and after EVT and assessed the temporal changes of MMP-9 that may be associated with, and therefore predict, HT after EVT. We enrolled 30 AIS patients who received EVT, and 16 (53.3%) developed HT. The levels of MMP-9 in plasma collected from the arteries of AIS patients before and immediately after EVT were measured using ELISA. The percent change in MMP-9 after EVT (after/before) was calculated and compared between patients with and without HT. The median age of the AIS patients was 70 years, and 13 patients (43.3%) were men. The median National Institutes of Health Stroke Scale (NIHSS) scores of patients with HT were 18 on admission and 18 after EVT. The median NIHSS scores of patients without HT were 17 on admission and 11 after EVT. Patients with HT demonstrated significantly greater percentage increases in arterial MMP-9 levels after EVT. Patients with AIS who developed HT had significantly increased arterial MMP-9 levels after EVT, suggesting that the upregulation of MMP-9 following EVT could serve as a predictive biomarker for HT.

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade. We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively. bsPD-L1 was detected in 17/117GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis. Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Enteral Protease Inhibition Preserves Aortic Ultrastructure and Mechanics in Experimental Trauma/Hemorrhagic Shock

Introduction: Vascular compliance of large arteries is often overlooked in acute trauma/hemorrhagic shock (T/HS), as standard interventions, such as vasopressors, typically target systemic vascular resistance (SVR) regulated by small arterioles. However, patients may become refractory to vasopressors, and efforts to raise SVR may not restore mean arterial blood pressure (MAP), which is crucial for organ perfusion. We have previously reported compromised vascular compliance after T/HS in vivo with increased pulse wave velocity and ex vivo with diminished circumferential distensibility, that were both partially mitigated by enteral serine protease inhibition. To further elucidate the mechanisms behind these adverse changes, our aim was to directly assess the material stiffness, extracellular matrix (ECM) morphology, and matrix metalloproteinase (MMP) activity within the aortic wall tissue after T/HS, as well as to evaluate the effectiveness of enteral protease inhibition in this context.Methods: Anesthetized Wistar rats (350 - 400g) underwent laparotomy (trauma) and exsanguination to maintain a MAP of 35-40 mmHg for 90 minutes (shock). Animals were randomly assigned to receive either enteral gabexate mesilate protease inhibitor treatment (GM-treated) or vehicle-only (Untreated) via an orally-inserted catheter; investigators were blinded to the treatment assignation. At the conclusion of the shock period, animals were resuscitated with intravenous Lactated Ringer’s solution (LR) for two hours to achieve and maintain a MAP of at least 60 mmHg. A sham control group was also included for comparison. In all groups, the thoracic aorta was bisected, with one half sectioned for atomic force microscopy and histology and the other half homogenized for gelatin zymography. Liquid-phase force mapping was conducted on random areas (1600 μm2) of the medial layer in triplicate to determine the average Young’s modulus of the tissue. Collagen fibers were stained with picrosirius red, and elastin fibers were stained with Verhoeff Van Gieson. Results: After being subjected to T/HS and LR reperfusion, the aortic media of the Untreated group had a significantly higher average Young’s modulus than that of healthy sham vessels (862.7 kPa vs. 556.5 kPa, p &lt; 0.05). The GM-treated group, however, better preserved its material elasticity (~650 kPa). These stiffness values negatively correlate with corresponding animals’ final MAP values measured at the end of the reperfusion period (r2 = 0.5031), supporting an association between vascular compliance and hemodynamic stability. The area of collagen within the tunica media was found to be significantly decreased in the Untreated compared to the sham group (4.93% vs. 10.26%, p &lt; 0.05), but GM treatment was able to prevent collagen degradation (8.48%). Disruptions in elastin fibers were also observed at a higher frequency in the Untreated T/HS aorta compared to sham controls (3.3 vs. 1.7, p &lt; 0.05) or GM-treated aortas (3.3 vs. 1.6, p &lt; 0.05). Gelatin zymography revealed that enteral GM treatment also significantly attenuated elevated plasma MMP-9 (0.85 vs. 1.97 A.U., p &lt; 0.01) and tissue MMP-2 activity (0.86 vs. 1.80 A.U., p &lt; 0.05) seen following T/HS. Conclusions: Fluid-resuscitated traumatic hemorrhagic shock resulted in ultrastructural and biomechanical alterations in the aorta, indicating a loss in compliance. Enteral gabexate mesilate treatment effectively mitigated these pathological changes to the vasculature, suggesting the potential involvement of serine proteases in aortic ECM remodeling and large artery dysfunction in T/HS. Interventions against central artery impairment may be a promising strategy for improving blood pressure and survival in circulatory shock. Department of Defense Award W81XWH-17-2-0047. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study

Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p<0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p=0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5at hospital discharge) by 2.33 times per 1000ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Abstract 5392: Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis

Abstract Introduction: The Matrix metalloproteinases (MMPs) family are a collection of zinc and calcium-dependent endopeptidases. MMP-9 is instrumental in modifying the extracellular matrix (ECM) and generating bioactive molecules which influence a range of physiological functions. Cellular TNF-a, IL-8, VEGF, and FGF-2 can stimulate the production of MMP-9 in endothelial cells (EC), a process that controls healthy and disease-related angiogenesis. MMP-9 facilitates tumor metastasis and also is involved with wound healing. MMP-9 is generated by white blood cells, ECs, and several other cells. There’s a significant increase in plasma MMP-9 levels in patients suffering from colorectal cancer (CRC). The aim of this study was to assess plasma MMP-9 levels before and during the first month following MICR for CRC. Method: CRC patients enrolled in an IRB approved data/plasma bank who had undergone MICR for whom plasma samples were available from the following time points were deemed eligible for this study; preoperatively (PreOp) and on Postoperative Day (POD) 1, POD 3 and at least 1 later postop timepoint (POD 7-41). The demographic, clinical operative and pathology reports were reviewed. Blood specimens were collected, processed, and frozen. MMP-9 levels were measured in duplicate via ELISA. The Wilcoxon paired t-test was used for analysis and significance set at p&amp;lt;0.05. Results: 86 CRC MICR patients (69% colon,31% rectal; laparoscopic 69%, hand-assisted 31%; 47 males, 39 females; mean age 63.9± 14.3 years), met the entry criteria. The mean hospital stay was 6.5±3.0 days. The cancer stages were distributed as follows: stage I; (n=26), II; (n=25), III; (n=30), and IV; (n=4). Compared to the mean preop MMP-9 plasma levels (155.3±132.1,n=86; ng/ml), there was a significant increase on postoperative day (POD) 1 (292.6± 213.0; n=86, p&amp;lt;0.001), POD3 (232.1±205.9,n=78, p&amp;lt;0.01), POD7-13 (217.8±171.2, n=63, p&amp;lt;0.01), POD14-20 (228.7± 109.1,n=24,p=03). No difference was found at the POD 21-41 time points vs preop results. Non-significant increases in plasma MMP-9 levels were noted in the hand-assisted surgery group during the POD 3-27 period compared to the laparoscopic group. Conclusion: Postop plasma MMP-9 levels were significantly elevated (20% - 88%) vs preop levels for 3 weeks after MICR for CRC. The increased MMP-9 levels in the early postoperative period may be due to the acute inflammatory response, including increases in IL-1 and TNF mediated activation of neutrophils and macrophages. However, the spike during weeks 2-3 may be related to wound healing given MMP-9’s role in angiogenesis. This persistent elevation for 3 weeks after surgery may also enhance angiogenesis in residual cancer deposits postoperatively. Further studies are needed. Citation Format: Chandana S. K. Herath Mudiyanselage, Anuj R. Sharma, Neil Mitra, Aashutosh Sah, Xiaohong Yan, Pablo Palacios, Vesna Cekic, Richard L. Whelan. Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5392.

Implications of the Matrix Metalloproteinases, Their Tissue Inhibitors and Some Other Inflammatory Mediators Expression Levels in Children Obesity-Related Phenotypes.

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endo-peptidases engaged in many biological processes including adipogenesis, angiogenesis, and tissue remodeling. Fat tissue infiltration by peripheral leukocytes plays an important role in transition of fat tissue residual, non-inflammatory status into the pro-inflammatory one, resulting in fat tissue inflammation and expansion as well as production of many mediators like adipokines and cytokines. The aim of this study was to investigate the expression of MMPs, their endogenous tissue inhibitors (TIMPs), and selected inflammatory mediators in leukocytes and plasma of children with simple obesity to find their associations with obesity-related phenotypes. Twenty-six overweight/obese children and twenty-three healthy volunteers participated in the study. The leukocyte mRNA expression levels of MMP-2, -9, -12 -14, TIMP-1, -2, and IL-6 were analyzed by the real time quantitative PCR. Plasma MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios as well as the concentrations of MMP-9, TIMP-1, IL-1 beta, IL-6, TNF- alpha, leptin and resistin were tested by ELISA assays. Gelatin zymography was used to assess the activity of the leukocyte MMPs proteins. The obese children showed the following: a) increased expression of leukocyte TIMP-1 and slight elevation (close to statistical significance) of leukocyte MMP-9 (p = 0.054), the decline in MMP-2, b) elevation of plasma MMP-9, leptin, and MMP9/TIMP1 ratio, c) reduced expression of plasma TNF-alpha and MMP-2/TIMP-2 ratio. Several negative correlations were found: TIMP2 vs. ALT (r = -0.536), AST (r = -0.645) and TTG (r = -0.438), IL-6 vs. GGTP (r = -0.815), and MMP12 vs. TTG (r = -0.488), leptin vs. ALT (r = -0.569), MMP-9 vs. total cholesterol (r = -0.556). The only positive correlation was that of plasma leptin level vs. GGTP (r = 0.964). At the beginning of obesity development (children), possibly compensatory reactions prevail, reflected here by an increase in the expression of leukocyte MMPs inhibitor TIMP-1, decrease in the level of leukocyte MMP-2 and plasma MMP-2, MMP2/TIMP-2 ratio, low plasma TNF-alpha and negative correlations between the expression of TIMP-2 and liver (AST, ALT) or fat (TTG) inflammatory markers.

Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction

BackgroundLong-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development.MethodsParticipants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after.ResultsMMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0–253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%.ConclusionPlasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.

Predictive potential of various plasma inflammation-, angiogenesis-, and extracellular matrix remodeling-associated mediators for intra-amniotic inflammation and/or microbial invasion of the amniotic cavity in preterm labor.

To determine whether various inflammatory-, angiogenic/anti-angiogenic-, and extracellular matrix remodeling-associated proteins in plasma, alone or in combination with conventionalblood-based markers, can predict intra-amniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) in women with spontaneous preterm labor (PTL). A total of 193 singleton pregnant women with PTL (23-33weeks) were included in this retrospective cohort study. Plasma samples were obtained at the time of amniocentesis. Amniotic fluid (AF) was cultured for microorganism detection and consequent MIAC diagnosis. IL-6 levels were determined in AF and used to identify IAI (AF IL-6 ≥ 2.6ng/mL). Endostatin, haptoglobin, IGFBP-2/3, LBP, M-CSF, MMP-2/8, pentraxin 3, PlGF, S100A8/A9, and VEGFR-1 levels were assayed in plasma samples by ELISA. CRP levels and neutrophil-to-lymphocyte ratio (NLR) were measured. Plasma LBP, MMP-8, and S100A8/A9 levels, CRP levels, and NLR were significantly higher, and plasma IGFBP-2 and MMP-2 levels were significantly lower in women with IAI/MIAC than in those without this condition, whereas no baseline variables differed significantly between the two groups. Using a stepwise regression analysis, a noninvasive prediction model for IAI/MIAC was developed, which included plasma LBP, MMP-2, and MMP-8 levels (area under the curve [AUC], 0.785). The AUC for this prediction model was significantly or borderline greater than that of any single factor included in the model. IGFBP-2, LBP, MMP-2, MMP-8, and S100A8/A9 may represent valuable plasma biomarkers for predicting IAI/MIAC in women with PTL. Combination of LBP, MMP-2, and MMP-8 expression data can significantly improve the predictive potential for IAI/MIAC.

The Effect of Rubus idaeus Polyphenols Extract in Induced Endometriosis in Rats.

Endometriosis is a common gynecological condition with a complex physio-pathological background. This study aimed to assess the role of Rubus idaeus leaf extract (RiDE) as a potential therapeutic agent in reducing the size of the endometriotic lesions and modulate the plasma expression of MMP-2, MMP-9, and TGF-β1. The endometriotic lesions were induced in a rat model by the autologous transplant of endometrium. Thirty-six female rats, Wistar breed, with induced endometriosis, were divided into four groups and underwent treatment for 28 days. The CTRL group received 0.5 mL/day of the vehicle; the DG group received 1 mg/kg b.w./day dienogest; the RiDG group received 0.25 mL/kg b.w./day RiDE and the D+RiDG group received 1 mg/kg b.w./day dienogest and 0.25 mL/kg b.w./day RiDE, respectively. Rats' weight, endometriotic lesion diameter and grade, and plasma levels of MMP-2, MMP-9, and TGF-β1 were assessed before and after treatment. The administration of RiDE in association with dienogest vs. dienogest determined a lower weight gain and a reduction in diameter of the endometriotic lesions. RiDE administration restored MMP2 and MMP9 plasma levels to initial conditions. Rubus idaeus extract may help in reducing dienogest-associated weight gain, lower the size of endometriotic lesions, and have anti-inflammatory effects through MMP2 and MMP9 reduction.

Association of plasma MMP-2 levels and prognosis of patients with intracerebral hemorrhage: a prospective cohort study

ObjectiveThe role of MMP-2 in patients with ICH is controversial and the impact of plasma MMP-2 level on clinical outcome is still unclear.Materials and methodsIn this study, the peripheral venous blood was acquired from 93 patients with ICH and 88 healthy controls within 24 h of hospitalization and at enrollment. We retrospectively investigated plasma MMP-2 levels of patients and healthy controls. The edema volume, the NIHSS score, the GCS score, and mRS were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma MMP-2 levels with clinical outcomes. In addition, the plasma MMP-14 levels and complement C4 level were tested to explore the relationship with plasma MMP-2 level.ResultsThere was a significant reduction of plasma MMP-2 levels in ICH patients than that in healthy controls (38.02 ± 1.71 vs. 54.03 ± 2.15, p &amp;lt; 0.0001), and MMP-2 is negatively correlated with the edema volume (r = −0.2187, p &amp;lt; 0.05), NIHSS score (r = −0.2194, p &amp;lt; 0.05), blood leucocyte count (r = −0.2549, p = 0.012), and complement C4 level (r = −0.2723, p = 0.005). There is positive correlation between MMP-2 level and GCS score (r = 0.2451, p = 0.01) and MMP-14 level (r = 0.7013, p = 0.005). The multivariate analysis revealed that reduced plasma MMP-2 level is associated with elevated edema volume (OR = 0.2604, 95% CI [0.07 to 0.84], p = 0.02).ConclusionThe plasma MMP-2 level in patients with ICH is significantly lower than that of healthy controls, and plasma MMP-2 level may be a prognostic factor. Plasma MMP-2 levels are correlated with the clinical outcomes of patients and negatively correlated with blood leucocyte count and complement C4 level in patients with ICH.

Expression of Matrix Metalloproteinases in the Circulating Immune Cells in Children with Helicobacter pylori Infection-Correlation with Clinical Factors.

H. pylori gastritis is strongly associated with the upregulation of the expression of several matrix metalloproteinases (MMPs) in the gastric mucosa. However, the role of MMP-2 and MMP-9, and their inhibitors (tissue inhibitors of metalloproteinases -TIMPs) produced by immune cells in infected children have not been clearly defined. Moreover, the effects of H. pylori eradication therapy on MMPs and TIMPs production has not been evaluated. A total of 84 children were studied: 24-with newly diagnosed H. pylori gastritis, 25-after H. pylori eradication therapy (17 of them after successful therapy), 24-with H. pylori-negative gastritis, and 11-controls. Plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 by ELISA; MMPs and TIMPs expression in lymphocytes; neutrophils and monocytes in peripheral blood by multiparameter flow cytometry; and mucosal mRNA expression levels of MMPs and TIMP-1 in gastric biopsies by RT-PCR were evaluated. Children with H. pylori-related gastritis showed the following: (1) increased MMP-2 and TIMP-2 plasma levels, (2) increased intracellular expression of MMP-2 in the circulating lymphocytes and neutrophils, (3) low frequencies of circulating TIMP-1+ and TIMP-2+ leukocytes, and (4) high expression of mRNA for MMP-9 along with low expression of mRNA for MMP-2 in the gastric mucosa. Unsuccessful H. pylori eradication was associated with the following: (1) high plasma levels of MMP-9 and TIMP-1, (2) increased pool of TIMP-1+ lymphocytes as well as high expression of MMP-9 in circulating lymphocytes, and (3) high expression of mRNA for MMP-9 in the gastric mucosa. Our data suggest that MMPs are important contributors to stomach remodelling in children with H. pylori-related gastritis. Unsuccessful H. pylori eradication is associated with increased MMP-9 in plasma, circulating lymphocytes, and gastric mucosa.

CD4 dim CD8 bright T cells are inversely associated with neuro-inflammatory markers among people with HIV.

HIV-associated neuroinflammation persists in the brain despite suppressive combination antiretroviral therapy (cART). We evaluated associations between a subset of CD8 + T cells, termed CD4 dim CD8 bright T cells, and soluble markers of immune activation and/or neuroinflammation in the cerebrospinal fluid (CSF) and plasma of people with HIV (PWH). Fifteen cART-naive PWH were enrolled and underwent blood draw, lumbar puncture for CSF collection, and neuropsychological tests at week 0 (pre-cART) and 24 weeks after cART initiation. CSF and peripheral blood T cells were evaluated with flow cytometry and soluble markers of immune activation were measured by multiplex and singleplex assays. Spearman bootstrap correlation coefficients with 10 000 resamples were computed and reported with corresponding 95% confidence intervals (CIs) for each marker of interest and T-cell type. The frequency of CSF CD4 dim CD8 bright T cells at week 0 was inversely related with CSF neopterin. In contrast, at week 24, CSF CD4 - CD8 + T cells were positively correlated with CSF s100β, a marker of brain injury. In the blood, at week 0, CD4 dim CD8 bright T cells were inversely correlated with MCP-1, IP-10, IL-8, IL-6, G-CSF, and APRIL and positively correlated with plasma RANTES and MMP1. At week 0, the frequency of blood CD4 - CD8 + were positively correlated with CRP and BAFF. CD4 dim CD8 bright T cells are associated with some anti-inflammatory properties, whereas CD4 - CD8 + T cells may contribute to inflammation and injury. Assessing the contrast between these two cell populations in neuroHIV may inform targeted therapeutic intervention to reduce neuroinflammation and associated neurocognitive impairment.

MMP-2 Associates With Incident Heart Failure and Atrial Fibrillation: The ARIC Study.

MMP (matrix metalloproteinase)-2 participates in extracellular matrix regulation and may be involved in heart failure (HF), atrial fibrillation (AF), and coronary heart disease. Among the 4693 ARIC study (Atherosclerosis Risk in Communities) participants (mean age, 75±5 years; 42% women) without prevalent HF, multivariable Cox proportional hazard models were used to estimate associations of plasma MMP-2 levels with incident HF, HF with preserved ejection fraction (≥50%), HF with reduced ejection fraction (<50%), AF, and coronary heart disease. Mediation of the association between MMP-2 and HF was assessed by censoring participants who developed AF or coronary heart disease before HF. Multivariable linear regression models were used to assess associations of MMP-2 with measures of left ventricular and left atrial structure and function. Compared with the 3 lower quartiles, the highest MMP-2 quartile associated with greater risk of incident HF overall (adjusted hazard ratio, 1.48 [95% CI, 1.21-1.81]), incident HF with preserved ejection fraction (1.44 [95% CI, 1.07-1.94]), incident heart failure with reduced ejection fraction (1.48 [95% CI, 1.08-2.02]), and incident AF (1.44 [95% CI, 1.18-1.77]) but not incident coronary heart disease (0.97 [95% CI, 0.71-1.34]). Censoring AF attenuated the MMP-2 association with HF with preserved ejection fraction. Higher plasma MMP-2 levels were associated with larger left ventricular end-diastolic volume index, greater left ventricular mass index, higher E/e' ratio, larger left atrial volume index, and worse left atrial reservoir and contractile strains (all P<0.001). Higher plasma MMP-2 levels associate with diastolic dysfunction, left atrial dysfunction, and a higher risk of incident HF and AF. AF is a mediator of MMP-2-associated HF with preserved ejection fraction risk.

Plasma MMP-9/TIMP-1 ratio serves as a novel potential biomarker in Alzheimer's disease.

This study aimed to explore the diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for Alzheimer's disease (AD). This retrospective study was performed in a cohort consisting of patients with AD (AD group) and cognitive normal subjects (HC group). Cerebrospinal fluid (CSF) classic biomarkers including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) levels, and plasma MMP-9 and TIMP-1 levels were measured by commercially available ELISA kits, respectively. The differential diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio was evaluated using the receiver operating characteristic curve analysis. It was observed that significantly elevated levels of plasma MMP-9 and MMP-9/TIMP-1 ratio in patients with AD than HC. Both MMP-9 and MMP-9/TIMP-1 ratios were negatively correlated with CSF Aβ42/Aβ40 ratio and positively correlated with CSF p-tau in AD group. ROC curve analysis showed better diagnostic accuracy of MMP-9/TIMP-1 ratio than MMP-9 for AD at a cutoff value of 1.35 with an area under the curve of 0.906 and sensitivity and specificity of 95.8% and 75%, respectively. Our findings encourage the use of plasma MMP-9/TIMP-1 ratio as a biomarker in the diagnosis of AD.

Promoting AMPK/SR-A1-mediated clearance of HMGB1 attenuates chemotherapy-induced peripheral neuropathy

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of chemotherapy with poorly understood mechanisms and few treatments. High-mobility group box 1 (HMGB1)-induced neuroinflammation is the main cause of CIPN. Here, we aimed to illustrate the role of the macrophage scavenger receptor A1 (SR-A1) in HMGB1 clearance and CIPN resolution.MethodsOxaliplatin (L-OHP) was used to establish a CIPN model. Recombinant HMGB1 (rHMGB1) (his tag) was used to evaluate the phagocytosis of HMGB1 by macrophages.ResultsIn the clinic, HMGB1 expression and MMP-9 activity were increased in the plasma of patients with CIPN. Plasma HMGB1 expression was positively correlated with the cumulative dose of L-OHP and the visual analog scale. In vitro, engulfment and degradation of rHMGB1 increased and inflammatory factor expression decreased after AMP-activated protein kinase (AMPK) activation. Neutralizing antibodies, inhibitors, or knockout of SR-A1 abolished the effects of AMPK activation on rHMGB1 engulfment. In vivo, AMPK activation increased SR-A1 expression in the dorsal root ganglion, decreased plasma HMGB1 expression and MMP-9 activity, and attenuated CIPN, which was abolished by AMPK inhibition or SR-A1 knockout in the CIPN mice model.ConclusionActivation of the AMPK/SR-A1 axis alleviated CIPN by increasing macrophage-mediated HMGB1 engulfment and degradation. Therefore, promoting HMGB1 clearance may be a potential treatment strategy for CIPN.1JEzHJvY7WaTcecv7_-Z6vVideo abstract