Matrix metallopeptidase 9 contributes to the beginning of plaque and is a potential biomarker for the early identification of atherosclerosis in asymptomatic patients with diabetes.

Aims: To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) in vitro, early beginning of atherosclerosis in vivo in diabetic mice, and drug naïve patients with diabetes. Methods: Active human MMP9 (act-hMMP9) was added to HCASMCs and the expressions of MCP-1, ICAM-1, and VCAM-1 were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to diabetic KK.Cg-Ay/J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques was determined. Results: In vitro, act-hMMP9 increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM. Conclusion: MMP9 may contribute to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04424706.

Three-year follow-up of rheumatoid meningitis with matrix metalloprotease-9 levels in the serum and cerebrospinal fluid as indicators of disease activity: A case report.

Rheumatoid meningitis (RM) is an extra-articular complication of rheumatoid arthritis (RA). Although reports of RM sine arthritis exist, most patients with this presentation were diagnosed with RA within one year of RM onset. There are no established biomarkers reflecting the disease activity of RM. This case report highlights the elevation of matrix metalloprotease (MMP)-9 levels during the acute phase of RM and decline during remission. Additionally, this is the first case report of RA diagnosed three years after the onset of RM. It is important to further validate the utility of MMP-9 and conduct long-term follow-up of RM sine arthritis.

Safety of Three-Dimensional Conformal Radiotherapy on the Sheep with Pulmonary Cystic Echinococcosis: A Preliminary Study.

PURPOSE: Radiotherapy showed the potential to effectively kill the cysts of pulmonary cystic echinococcosis (CE). However, little is known about its safety. This study was designed to investigate the safety of three-dimensional conformal radiotherapy (3D-CRT) on the normal lung tissue adjacent to the cyst and blood of sheep naturally infected with pulmonary CE. METHODS: Twenty pulmonary CE sheep were randomly divided into control group (n = 5) and radiation groups with a dose of 30 Gray (Gy) (n = 5), 45 Gy (n = 5), and 60 Gy (n = 5), respectively. Animals in control group received no radiation. Heat shock protein 70 (Hsp70), tumor growth factor-ß (TGF-ß), matrix metalloproteinase-2 (MMP-2) and MMP-9 in the lung tissues adjacent to the cysts, which were considered to be closely related to the pathogenesis of CE, were evaluated after 3D-CRT. A routine blood test was conducted. RESULTS: The results showed that there were multiple cysts of various sizes with protoscoleces in the lung tissues of sheep, and necrotic cysts were found after 3D-CRT. 3D-CRT significantly increased the mRNA level of Hsp70, enhanced the protein level of TGF-ß and slightly increased the expression of MMP-2 and MMP-9 in lung tissues adjacent to the cysts. 3D-CRT did not significantly alter the amount of WBC, HB and PLT in sheep blood. CONCLUSIONS: The results suggested that 3D-CRT may suppress the inflammation and induce less damage of the normal lung tissues and blood. We preliminarily showed that 3D-CRT under a safe dose may be used to treat pulmonary CE.

An evaluation of matrix metalloproteinase-9 (Mmp-9) and tissue inhibitor metalloproteinase-1 (Timp-1) Serum levels and the Mmp-9/Timp-1 Ratio in Covid-19 patients.

Background: The progression of COVID-19 has different clinical presentations, which raises a number of immunological questions. Objectives: This study aimed to investigate MMP-9 and TIMP-1 levels in patients diagnosed with COVID-19 and whether the MMP-9/TIMP-1 ratio is associated with lung involvement in COVID-19. Methods: This study was conducted with 192 patients and 45 healthy controls. ELISA was used to measure the MMP-9 and TIMP-1. Results: The MMP-9 and TIMP-1 levels of the patients were found to be higher than those of the controls. MMP-9 and TIMP-1 were detected more in patients with lung involvement on chest CT scans than in those with no lung involvement on chest CT scans. A comparison of lung involvement levels revealed no difference was found between the groups. The MMP-9/TIMP-1 ratio was 5.8 in the group with lung involvement on chest CT scans and 6.1 in the group without lung involvement on chest CT scans. No difference was found between the two groups. A comparison with respect to lung involvement levels showed that the MMP-9/TIMP-1 ratio difference was found between the groups. Conclusion: Diagnostic and treatment methods targeting MMP-9 activity or neutrophil activation may be important in predicting lung involvement in COVID-19 and directing clinical outcomes.

Decreased serum MMP-9 levels in patients with nontraumatic osteonecrosis of the femoral head.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) are involved in the pathological mechanism of osteonecrosis of the femoral head (ONFH). This study aimed to investigate the relationship of serum MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio with disease severity in patients with nontraumatic ONFH. METHODS: Serum levels of MMP-9 and TIMP-1 among 102 nontraumatic ONFH patients and 96 healthy individuals were determined by enzyme-linked immunosorbent assay (ELISA). Imaging severity was determined using the FICAT classification system. The Harris hip score (HHS) and visual analogue scale (VAS) were used to evaluate clinical progress. The correlations of serum MMP-9 and TIMP-1 levels with imaging severity and clinical progress was evaluated statistically. The diagnostic value of MMP-9 for NONFH disease severity was evaluated by examining receiver operating characteristic (ROC) curves. RESULTS: The serum MMP-9 levels and the MMP-9/TIMP-1 ratio were significantly increased in patients with ONFH compared to normal controls, and TIMP-1 levels did not differ between the two groups. Serum MMP-9 levels and the MMP-9/TIMP-1 ratio were positively correlated with FICAT stage and VAS and were negatively correlated with the HHS score. The ROC curve results indicated that MMP-9 could be used as a potential marker of nontraumatic ONFH imaging progression. CONCLUSIONS: We hypothesize that increased MMP-9 expression and an imbalance in the MMP-9/TIMP-1 ratio play a role in the development of ONFH and are correlate with the severity of ONFH. The determination of MMP-9 can be a useful tool to assess the severity of the disease in patients with nontraumatic ONFH.

Longitudinal Changes in BDNF and MMP-9 Protein Plasma Levels in Children after Cochlear Implantation.

Congenitally deaf children who undergo cochlear implantation before 1 year of age develop their auditory skills faster than children who are implanted later. In this longitudinal study, a cohort of 59 implanted children were divided into two subgroups according to their ages at implantation-below or above 1 year old-and the plasma levels of matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and pro-BDNF were measured at 0, 8, and 18 months after cochlear implant activation, while auditory development was simultaneously evaluated using the LittlEARs Questionnaire (LEAQ). A control group consisted of 49 age-matched healthy children. We identified statistically higher BDNF levels at 0 months and at the 18-month follow-ups in the younger subgroup compared to the older one and lower LEAQ scores at 0 months in the younger subgroup. Between the subgroups, there were significant differences in the changes in BDNF levels from 0 to 8 months and in LEAQ scores from 0 to 18 months. The MMP-9 levels significantly decreased from 0 to 18 months and from 0 to 8 months in both subgroups and from 8 to 18 months only in the older one. For all measured protein concentrations, significant differences were identified between the older study subgroup and the age-matched control group.

MMP-9/BDNF ratio predicts more severe COVID-19 outcomes.

COVID-19 clinically manifests from asymptomatic to the critical range. Immune response provokes the pro-inflammatory interactions, which lead to the cytokines, reactive oxygen/nitrogen species, peptidases, and arachidonic acid metabolites enlargement and activation of coagulation components. Matrix metalloproteinases (MMPs) contribute to tissue destruction in the development of COVID-19. Due to the endothelial, systemic course of the disease, VEGF A participates actively in COVID-19 development, while neurotrophic and metabolic effects of BDNF recommends for the prediction of complications in COVID-19 patients. Searching for a marker that would improve and simplify the ranking in COVID-19, the study intended to evaluate the relationship of MMP-9 with VEGF A, BDNF, and MMP-8 with the COVID-19 severity. Upon admission to the hospital and before the therapy administration, 77 patients were classified into a mild, moderate, severe, or critical group. Due to the inflammatory stage in COVID-19, a comparison between groups showed related differences in leukocytes, neutrophils, lymphocytes, and platelets counts as anticipated. Only in seriously ill patients, there is a significant increase in the serum concentration of MMP-9, MMP-8, and VEGF A, while BDNF values did not show significant variations between groups. However, all those parameters positively correlated with each other. The ratio of MMP-9/BDNF markedly decreased in the severe and critically patients compared to the mild group. Testing the capability of this ratio to predict the COVID-19 stage by ROC curves, we found the MMP-9/BDNF could be a suitable marker for differentiating stages I/II (AUC 0.7597), stage I/III (AUC 0.9011), and stage I/IV (AUC 0.7727). Presented data describe for the first time the high-level systemic MMP-9/BDNF ratio in patients with COVID-19. This parameter could contribute to a more precise determination of the phase of the disease.

[Assessment of serum MMP-9, TIMP-1 levels and MMP-9/TIMP-1 ratio in migraine patients with and without aura].

Background and purpose: Matrix metalloproteinases (MMP) are the enzymes responsible for proteolytic ac-tivity of extracellular matrix proteins. Tissue inhibitors of metalloproteinases (TIMPs) are their endogenous inhibitors. MMP-9 acts on the basal membrane of cerebellar epithe-lium and is antagonized by TIMP-1. MMP-9/TIMP-1 ratio exhibits the net activity of MMP-9. These enzymes are thought to have a role in migraine physio-pathogenesis. Methods: Total of 50 treatment-naive migraine patients (25 with aura and 25 without aura) with no other diseases, were included. 25 healthy control subjects of cor-responding age and gender were enrolled. For MMP-9 and TIMP-1 analysis, one serum sample from control group and two samples from patients were collected (during headache and headache-free periods). The enzyme levels were quantitatively analyzed by competitive ELISA method. Duration and severity of the pain and duration of the disease were recorded. Results: There was no significant difference in MMP-9 levels between patient and control groups during headache and headache-free periods (p: 0,746, p: 0,243). TIMP-1 levels were significantly lower and MMP-9/TIMP ratios were higher comparing with the control group (p: 0.001). Positive correlation was obtained between the duration of pain and MMP-9 levels in the headache-free period for both patient groups (p<0.05). There was also a positive correlation between MMP-9/TIMP-1 ratio and severity of pain (p<0.05). Conclusion: In our study, low TIMP-1 levels of patients in both headache and headache-free periods suggest that disturbance of proteolytic protection has a role in neuro-inflammation and pain in migraine. Therefore, these enzymes could be potential targets in migraine therapies.

The potential role of serum expression profile of long non coding RNAs, Cox2 and HOTAIR as novel diagnostic biomarkers in systemic lupus erythematosus.

BACKGROUND: The role of the long non-coding RNAs (lncRNAs) in the pathogenesis of systemic lupus erythematosus (SLE) is mostly unknown, despite increasing evidence that lncRNAs extensively participate in physiological and pathological conditions. AIM: To detect the level of lncRNA-Cox2, HOTAIR, IL-6, and MMP-9 in the serum of SLE patients and to correlate these levels with disease activity and patients' clinical and laboratory data to evaluate the value of these biomarkers for SLE diagnosis and assessment of disease activity. METHODS: Blood samples from 58 SLE patients, and 60 healthy controls (HCs) were used for detection of lncRNAs-Cox2 and HOTAIR expression levels by real-time polymerase chain reaction. Both IL-6 and MMP-9 serum levels were assayed by enzyme-linked immunosorbent assay. Lupus activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: The serum expression levels of lncRNA-Cox2 and HOTAIR were significantly up-regulated in SLE patients vs HCs (fold change [median (IQR) was 1.29(0.81-1.71, P<0.0001) and 2.68(0.95-3.67), P = 0.038) for lncRNA-Cox2 and HOTAIR, respectively. Serum levels of both IL-6 and MMP-9 were significantly high in SLE patients compared with HCs (P≤0.001 for each). The up-regulated lncRNA-Cox2 was positively associated with the presence of neurological manifestations in SLE patients (P = 0.007). Furthermore, HOTAIR expression level had significantly positive correlation with IL-6 (r = 0.578, P<0.0001), MMP-9 level (r = 0.762, P<0.0001), nephritis grades (r = 0.296, P = 0.024) and proteinuria (r = 0.287, P = 0.035). LncRNA-Cox2 showed sensitivity and specificity 72.4%, and 100.0% respectively. HOTAIR sensitivity was 60.3%, and specificity was 100.0%. By multiple logistic regression analysis, lncRNA-Cox2 and HOTAIR were found as SLE independent predictors. CONCLUSION: LncRNA-COX2 and HOTAIR can be used as new non-invasive biomarkers for the diagnosis of SLE.

Serum syndecan-4 correlates with blood pressure and cardiovascular parameters but not proinflammatory markers in healthy older women.

Aging is accompanied by a low-grade proinflammatory status that plays a role in age-related vascular alterations. Syndecan-4 (SDC4) is a key component of the endothelial glycocalyx, and its extracellular domain can be shed by matrix metalloproteinase-9 (MMP-9). In vitro studies demonstrated that MMP-9-mediated shedding of SDC4 is induced by tumor necrosis factor-α (TNF- α) in human endothelial cells. However, the relationship between circulating shed SDC4, systemic inflammation, and age-related vascular alterations remains unknown. Here, we used linear regression models to examine the associations of serum SDC4 levels with cardiovascular hemodynamic phenotypes, serum MMP-9, and serum TNF-α and inteleukin-6 in healthy older women (n = 74). Serum SDC4 was not associated with proinflammatory cytokines or arterial elasticity. Nevertheless, we found significant correlations of SDC4 with MMP-9, heart rate, left ventricular ejection time, systemic vascular resistance, and blood pressure. Our preliminary evidence suggests that systemic inflammation might not induce SDC4 shedding in healthy aging.

MMP-9, TIMP-1 and S100B protein as markers of ischemic stroke in patients after carotid artery endarterectomy.

Ischemic stroke is the main cause of permanent disability in adult patients. No commonly accepted method were discovered to predict stroke before the first symptoms. Activation of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMP) and S100B protein may be observe in patients with symptomatic carotid artery stenosis. Hemorrhagic transformation of ischemic stroke may be associated with changes in MMP, TIMP and S100B. AIM: The aim of this study was to determine if MMP-9, TIMP-1 and S-100B protein may markers of forthcoming ischemic stroke in patients undergoing carotid endarterectomy. MATERIALS AND METHODS: Blood samples were taken and an analysis of circulating proteins (MMP-9, TIMP-1, S100B) 73 subsequent patients with carotid artery stenosis ≥70% (33 asymptomatic and 40 symptomatic), who were referred for potential revascularization. RESULTS: A statistically significant difference was found between MMP- 9 levels in patients with ischemic stroke compared to patients with asymptomatic carotid stenosis after endarterectomy. Also, average TIMP-1 levels in patients with ischemic stroke and stenosis ≥70% were statistically significantly higher than the average levels in patients after endarterectomy. In terms of S-100B, a higher mean value was observed in patients with stroke than in endarterectomy group. No statistical differences were found in the levels of that proteins in the hemorrhagic transformation of ischemic stroke. CONCLUSIONS: Increased levels of MMP-9, TIMP-1 and S-100B in patients with ischemic stroke compared to patients with asymptomatic carotid stenosis after endarterectomy showed that abovementioned proteins may be a good predictive factor of ischemic stroke in patients undergoing carotid endarterectomy.

Matrix metalloproteinase-9 and substance-P as predictors for early-stage diagnosis of acute mountain sickness.

INTRODUCTION: Although acute mountain sickness (AMS) can be a life-threatening condition, early diagnosis is difficult due to vague and non-specific symptoms. The aim of this study is to investigate biochemical markers that can detect high-altitude diseases in advance. Eight different biomarkers (BNP, HIF-1α, NGAL, MMP-3, MMP-9, SESN2, substance P (SP), and U-II) were studied, and their relationship with AMS was investigated. METHODS: Of the 84 mountaineers who participated in the mountaineering training organized by the Turkish Mountaineering Federation in the Rize Kaçkar Mountains in 2018, 52 volunteered to participate in the study. Twelve hours after the participants reached an altitude of 2200 m (exposed to moderate hypoxia), their vital parameters were measured, and blood samples were taken for biochemistry tests. Vital signs and Lake Louise (LL) AMS scores were recorded every 24 h during the following 72 h. The participants were divided into two groups according to their LL scores: those with AMS and those without (AMS+ and AMS -), and the vital parameters and biomarker levels of both groups were compared and evaluated. RESULTS: Of the volunteers participating in the study, 35 (67.3%) were male and 17 (32.7%) were female, although there was no gender difference in terms of susceptibility to AMS. Among the investigated markers in the AMS + group, MMP-9 and SP were statistically significantly higher (p = 0.037 and p = 0.038, respectively). There were no statistical differences between AMS- and AMS+ groups with regard to heart rate, oxygen saturation, and systolic and diastolic blood pressure values (p = 0.507, p = 0.929, p = 0.955, p = 0.572, respectively). CONCLUSION: There were significant differences between the AMS- and AMS+ groups in terms of MMP-9 and SP. However, differences in physical indexes between the groups were not statistically significant. This could provide objective indexes for scanning and screening individuals susceptible to AMS in the early stages of rapid ascending.

Plasma Matrix Metalloproeteinase-9 Is Associated with Seizure and Angioarchitecture Changes in Brain Arteriovenous Malformations.

Both angiogenesis and inflammation contribute to activation of matrix metalloproeteinase-9 (MMP-9), which dissolves the extracellular matrix, disrupts the blood-brain barrier, and plays an important role in the pathogenesis of brain arteriovenous malformations (BAVMs). The key common cytokine in both angiogenesis and inflammation is interleukin 6 (IL-6). Previous studies have shown elevated systemic MMP-9 and decreased systemic vascular endothelial growth factor (VEGF) in BAVM patients. However, the clinical utility of plasma cytokines is unclear. The purpose of this study is to explore the relationship between plasma cytokines and the clinical presentations of BAVMs. Prospectively, we recruited naive BAVM patients without hemorrhage as the experimental group and unruptured intracranial aneurysm (UIA) patients as the control group. All patients received digital subtraction angiography, and plasma cytokines were collected from the lesional common carotid artery. Plasma cytokine levels were determined using a commercially available, monoclonal antibody-based enzyme-linked immunosorbent assay. Subgroup analysis based on hemorrhagic presentation and angiograchitecture was done for the BAVM group. Pearson correlations were calculated for the covariates. Means and differences for continuous and categorical variables were compared using Student's t and χ2 tests respectively. Plasma MMP-9 levels were significantly higher in the BAVM group (42,945 ± 29,991 pg/mL) than in the UIA group (28,270 ± 17,119 pg/mL) (p < 0.001). Plasma MMP-9 levels in epileptic BAVMs (57,065 ± 35,732; n = 9) were higher than in non-epileptic BAVMs (35,032 ± 28,301; n = 19) (p = 0.049). Lower plasma MMP-9 levels were found in cases of BAVM with angiogenesis and with peudophlebitis. Plasma MMP-9 is a good biomarker reflecting ongoing vascular remodeling in BAVMs. Angiogenesis and pseudophlebitis are two angioarchitectural signs that reflect MMP-9 activities and can potentially serve as imaging biomarkers for epileptic BAVMs.

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

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

Doxycycline can reduce glycocalyx shedding by inhibiting matrix metalloproteinases in patients undergoing cardiopulmonary bypass: A randomized controlled trial.

BACKGROUND: Cardiopulmonary bypass (CPB) leads to shedding of the glycocalyx of endothelial cells, resulting in a series of complications such as tissue edema and coagulatory and microcirculatory dysfunctions. Matrix metalloproteinases (MMPs) can cause glycocalyx shedding in a variety of pathological processes, but their role in the process of CPB is still unclear. We hypothesized that the MMPs inhibitor doxycycline would reduce glycocalyx shedding by inhibiting MMPs during CPB. METHODS: Thirty-six patients were randomized to receive either 100 mg oral doxycycline (an MMPs inhibitor) or a matching placebo pill twice a day for three days before CPB. The primary outcome was the concentration of plasma syndecan-1. Secondary outcomes included heparan sulphate, MMP-2, MMP-9, ratio of urinary albumin to creatinine, and short-term clinical outcomes. In order to further prove that MMPs in plasma caused the glycocalyx shedding, human umbilical vein endothelial cells were cultured with plasma obtained from cardiac surgery patients before or after CPB (with or without MMPs inhibitor GM6001). The change in glycocalyx content was detected by immunofluorescence. RESULTS: CPB resulted in an increase of MMPs and shedding of the glycocalyx. Plasma syndecan-1 was higher in the control group than in the doxycycline group (median difference:15.04 µg/L; 95% CI: 9.14-20.94 µg/L; P < 0.001). Similar to syndecan-1, plasma heparan sulphate, MMP-2, and MMP-9 concentrations in the doxycycline group were significantly lower than those in the control group during CPB. Doxycycline was also correlated with a reduction in the ratio of urinary albumin to creatinine and improved the short-term clinical outcomes of patients. Endothelial cells cultured with plasma from patients after CPB showed significant shedding of syndecan-1 and heparan sulphate (post-CPB group vs pre-CPB group, P < 0.001). GM6001 was shown to reduce shedding of syndecan-1 and heparan sulphate by inhibiting MMPs (post-CPB + GM6001 group vs post-CPB group, P < 0.001). CONCLUSION: Doxycycline can reduce glycocalyx shedding by inhibiting MMPs during CPB.

Changes of FSTL1 and MMP-9 levels in patients with acute cerebral infarction and its relationship with hemorrhagic transformation.

BACKGROUND: hemorrhagic transformation is a serious complication of acute ischemic stroke, which may lead to poor prognosis and delayed use of anticoagulant therapy. METHODS: 125 patients with cerebral infarction from December 2019 to December 2020 in the Second Affiliated Hospital of Zhejiang University were selected. All patients did not receive intravascular therapy, intravenous thrombolysis and other reperfusion treatment; and the relevant laboratory data were collected within 24 h after admission. At the same time, 15 healthy subjects were selected as the research objects for prospective analysis. Hemorrhagic transformation (HT) was defined as a condition in which computed tomography (CT) did not indicate bleeding at admission, but follow-up magnetic resonance imaging (MRI) or CT showed hemorrhage. The patients were divided into HT group (n = 50) and non-HT group (n = 75) according to whether there was HT after admission. The concentrations of FSTL1 and MMP-9 in peripheral blood of the two groups were detected. RESULTS: The concentrations of FSTL1 and MMP-9 in acute cerebral infarction (ACI) group were significantly higher than those in control group. However the HT group had a higher concentration of FSTL1 and MMP-9 than the non-HT group. The serum FSTL1 and MMP-9 were independent risk factors for hemorrhagic transformation. The area under the ROC curve of FSTL1 and MMP-9 in diagnosis of HT was 0.809 and 0.856 respectively, and their combined value was 0.923. CONCLUSION: The high levels of FSTL1 and MMP-9 had strong correlation with HT in ACI patients.

Correlation Analysis of Acute Coronary Syndrome with Serum IL-18, MMP-9, hs-CRP, and Plasma FIB.

AIM: This study attempted to investigate the diagnostic value of interleukin-18 (IL-18), matrix metalloproteinase-9 (MMP-9), high-sensitivity C-reactive protein (hs-CRP), and fibrinogen (FIB) in acute coronary syndrome (ACS) and their correlation with the degree of vascular lesions. MATERIALS AND METHODS: Altogether 206 patients with coronary heart disease admitted to our hospital were selected as research objects, including 136 patients with ACS (group A), 70 patients with stable angina pectoris (SAP) (group B), and 60 patients with noncoronary heart disease who had normal coronary angiography during the same period were selected as group C. The levels of IL-18, MMP-9, and hs-CRP in the serum were detected by enzyme-linked immunosorbent assay (ELISA), and the level of FIB in plasma was detected by automatic coagulation analyzer. RESULTS: Serum IL-18, MMP-9, hs-CRP, and plasma FIB levels in group A were significantly higher than those in group B and group C (p < 0.05). ROC curve and multivariate logistic regression showed that the sensitivity and specificity of combined diagnosis of ACS with serum IL-18, MMP-9, hs-CRP, and plasma FIB were 86.03% and 95.71%, respectively. Serum IL-18, MMP-9, hs-CRP, and plasma FIB were positively correlated with Gensini grading (p < 0.001). Serum IL-18, MMP-9, hs-CRP, and plasma FIB levels were positively correlated (p < 0.001). CONCLUSION: The combined detection of serum IL-18, MMP-9, hs-CRP, and plasma FIB has good diagnostic value for ACS, and these index levels are positively correlated with the degree of vascular lesions.

Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients.

To estimate the associations between dysnatraemia and inflammatory marker [including interleukin-6 (IL-6)], and tissue remodelling marker [matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1], the pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAP), and left ventricular end-diastolic pressure (EDP), and the prognostic relevance in patients with heart failure. The serum sodium level and circulating levels of IL-6, MMP-9, and TIMP-1 were measured in 173 heart failure patients. Dual heart catheterisation was performed to measure PCWP, mean PAP, and EDP. All-cause mortality was assessed during the follow-up period (mean 88 ± 49 months). Restricted cubic spline (RCS) regression showed a U-shaped association of serum sodium level with TIMP-1, with the lowest values in the 138-140 mmol/L range (P for effect = 0.042, P for non-linearity = 0.017). IL-6 and MMP-9 levels showed non-significant associations with serum sodium level. U-shaped associations of serum sodium level with PCWP (P for effect = 0.004, P for non-linearity = 0.001) and mean PAP (P for effect = 0.042, P for non-linearity = 0.017) were found with the RCS regression model. The random forest model revealed that TIMP-1, MMP-9, and IL-6 were important predictors for serum sodium levels. Restricted cubic spline Cox regressions demonstrated that TIMP-1 levels indicated a U-shaped, concaved, non-linear association with all-cause mortality (P for effect = 0.011, P for non-linearity = 0.022). Dysnatraemia is an index of TIMP-1 aggravation and elevated PCWP, mean PAP; hence, it is associated with worsening all-cause mortality.Clinical Trial Registration: UMIN000023840.

Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study.

We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34-0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.

Matrix metalloproteinases (MMP) 3 and 9 as biomarkers of severity in COVID-19 patients.

The molecular basis of the wide clinical heterogeneity of Coronavirus disease 2019 (COVID-19) is still unknown. Matrix metalloproteinases (MMPs) may have a role in the lung damage and regeneration that occur in severe patients. We studied serum MMP3 and MMP9 as potential biomarkers of COVID-19 severity, in 108 hospitalized patients with different World Health Organization (WHO) severity stage and in 48 controls. At hospital admission, serum MMP3 was increased in COVID-19 patients with a significant trend along the progression of the WHO stage, while serum levels of MMP9 were significantly increased in COVID-19 patients with no correlation with disease severity. At 1 week from hospitalization, MMP3 was reduced, suggesting an early pathogenic role of the protein in lung inflammation, while MMP9 levels were further increased, indicating a late role of the protein in the inflammatory process, specifically during the repairing phase. Furthermore, serum MMP9 was positively correlated with serum interleukin-6, myeloperoxidase, and circulating neutrophils and monocytes number. In conclusion, serum MMP3 may help to early predict the severity of COVID-19 and both proteins, MMP3 and MMP9, may contribute to define severe COVID-19 patients that may benefit from a targeted therapy on MMPs.