High Levels Of Matrix Metalloproteinases Research Articles

Correlation analysis of serum MMP-1 and MMP-2 levels with lower extremity deep venous thrombosis after operation for lower limb fracture

To investigate the relationship between serum matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-2(MMP-2) and the formation of deep venous thrombosis(LDVT) in lower extremity patients after surgery for lower extremity fracture, and to analyze the value of MMP-1 and MMP-2 in predicting the occurrence of LDVT after lower extremity fracture. From June 2018 to December 2021, 352 patients who planned to receive surgical treatment of lower limb fracture in our hospital were selected as the research objects. Venous blood was collected at 1, 2 and 3 days after surgery, respectively, and serum MMP-1 and MMP-2 levels were detected. The incidence of LDVT during hospitalization was analyzed, and the risk factors of postoperative LDVT in patients with lower limb fracture surgery and the predictive value of MMP-1 and MMP-2 for LDVT were analyzed. LDVT occurred in 40 patients (LDVT group), the incidence of LDVT was 11.36%, and 312 patients did not occurred(no occurred group). The serum levels of MMP-1 and MMP-2 in LDVT group increased gradually after surgery; the serum levels of MMP-1 and MMP-2 in the no occurred group increased slightly after surgery at 2 days and then decreased at 3 days after surgery (P<0.01);the serum levels of MMP-1 and MMP-2 in LDVT group were higher than those in the no occurred group at 2 days and 3 days after surgery (P<0.05). Serum levels of MMP-1 and MMP-2 were positively correlated with serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor -α (TNF-α) in LDVT patients at 2 days and 3 days postoperatively (P<0.05). Operative time, MMP-1 and MMP-2 postoperative 3 days were related to the occurrence of LDVT after lower limb fracture (P<0.01). The area under the curve(AUC) predicted by MMP-1 and MMP-2 postoperative 3 days for LDVT after lower limb fracture was 0.738 and 0.744 respectively, and the AUC predicted by combined MMP-1 and MMP-2 was 0.910, which was higher than that predicted by single indicator(Z=2.819 and 2.025, P<0.05). High levels of MMP-1 and MMP-2 after lower extremity fracture are closely related to the occurrence of LDVT, and 3 d mMP-1 and MMP-2 after surgery maybe used as evaluation indexes for LDVT risk prediction.

A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases

Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.

Modelling the Effect of Matrix Metalloproteinases in Dermal Wound Healing

With over 2 million people in the UK suffering from chronic wounds, understanding the biochemistry and pharmacology that underpins these wounds and wound healing is of high importance. Chronic wounds are characterised by high levels of matrix metalloproteinases (MMPs), which are necessary for the modification of healthy tissue in the healing process. Overexposure of MMPs, however, adversely affects healing of the wound by causing further destruction of the surrounding extracellular matrix. In this work, we propose a mathematical model that focuses on the interaction of MMPs with dermal cells using a system of partial differential equations. Using biologically realistic parameter values, this model gives rise to travelling waves corresponding to a front of healthy cells invading a wound. From the arising travelling wave analysis, we observe that deregulated apoptosis results in the emergence of chronic wounds, characterised by elevated MMP concentrations. We also observe hysteresis effects when both the apoptotic rate and MMP production rate are varied, providing further insight into the management (and potential reversal) of chronic wounds.

Molecular biomarkers for objective assessment of symptomatic pulpitis: A systematic review and meta-analysis.

Inflammatory biomarkers are potentially useful targets for pulpal diagnostic tests that can identify pulp status and predict vital pulp treatment (VPT) outcome, however, their accuracy is unknown. (1) Calculate sensitivity, specificity and diagnostic odds ratio (DOR) of previously investigated pulpitic biomarkers; (2) Determine if biomarker levels discriminate between clinical diagnoses of pulpitis based on the presence or absence of spontaneous pain (3) Evaluate if biomarker level can predict VPT outcome. Searches: PubMed/MEDLINE, Ovid SP, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, Embase, Web of Science and Scopus in May 2023. prospective and retrospective observational studies and randomized trials. Participants were humans with vital permanent teeth and a well-defined pulpal diagnosis. deciduous teeth, in vitro and animal studies. Risk of bias was assessed with modified-Downs and Black quality assessment checklist. Meta-analysis was performed using bivariate random effect model in Meta-DiSc 2.0 and RevMan and the quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Fifty-six studies were selected, reporting >70 individual biomolecules investigating pulpal health and disease at the gene and protein level. Most studies were of low and fair quality. Among the biomolecules investigated, IL-8 and IL-6 demonstrated a level of diagnostic accuracy with high sensitivity, specificity and DOR to discriminate between healthy pulps and those exhibiting spontaneous pain suggestive of IRP (low-certainty evidence). However, none was shown to have high DOR and the ability to discriminate between pulpitic states (very low certainty evidence). Limited data suggests high levels of matrix metalloproteinase 9 correlate with poorer outcomes of full pulpotomy. The inability of identified molecular inflammatory markers to discriminate between dental pulps with spontaneous and non-spontaneous pain should shift the focus to improved study quality or the pursuit of other molecules potentially associated with healing and repair. Low-quality evidence suggests IL-8 and IL-6 demonstrated level of diagnostic accuracy to discriminate between healthy pulps and those exhibiting spontaneous pain. There is a need for standardized biomarker diagnostic and prognostic studies focusing on solutions that can accurately determine the degree of pulp inflammation. PROSPERO CRD42021259305.

Current Smoking Determines the Levels of Circulating MPO and MMP-9 in Adults with Coronary Artery Disease and Obstructive Sleep Apnea.

(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.

Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis

Hypermobility involves excessive flexibility and systemic manifestations of connective tissue fragility. We propose a folate-dependent hypermobility syndrome model based on clinical observations, and through a review of existing literature, we raise the possibility that hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin. Cleavage of decorin leads ultimately to extracellular matrix (ECM) disorganization and increased fibrosis. This review aims to describe relationships between folate metabolism and key proteins in the ECM that can further explain the signs and symptoms associated with hypermobility, along with possible treatment with 5-methyltetrahydrofolate supplementation.

Dynamics of matrix metalloproteinase 9 in comorbid patients who had myocardial infarction with ST elevation

Aim. The aim of the work was to study for three years the dynamics of matrix metalloproteinase 9 in patients with comorbid pathology who had suffered a myocardial infarction with ST segment elevation. Materials and methods. The study included patients of both sexes older than 18 years. All of them signed an informed consent for participation in the study. The inclusion criteria, in addition to signing informed consent for participation in the study, were acute myocardial infarction with ST elevation (STEMI), PCI and implantation of 1-2 stents into the left coronary artery, the presence of hypertension, type 2 diabetes melitus. Patients younger than 18 years and older than 80 years with type 1 diabetes mellitus, the presence of oncological diseases at the time of the study or in the anamnesis, chronic obstructive pulmonary disease, chronic viral infections were not included. All diagnoses were established according current clinical recommendations. The patients were divided into two groups. The first group included patients with arterial hypertension and type 2 diabetes mellitus, the second group included patients who had suffered acute myocardial infarction with ST segment elevation, who had arterial hypertension and type 2 diabetes mellitus. Serum was used to assess the content of matrix metalloproteinase 9. A standard test kit was used ("Cloud-Clone Corp.", China) in accordance with the instructions. The calculations were carried out using Excel spreadsheets and the statistical software package Statistica 10 (StatSoftInc.) USA. Results. When studying the level of metalloproteinase 9 for 3 years in patients who had suffered a myocardial infarction, it was found that the level of MMP-9 was statistically significantly higher in patients at the time of hospitalization, then decreased by the first year after the index event and became comparable with patients who did not have MI. After 36 months from the start of the study, patients who had suffered a myocardial infarction had statistically significantly higher levels of matrix metalloproteinase 9, compared with their values by the end of the first year, however, these data are comparable to the level of MMP-9 in patients of the first group. The level of MMP-9 in the first group is comparable at all time stages of observation. Conclusion. The inflammatory marker MMP-9, under certain conditions, can serve as a good predictor for predicting fatal outcomes and repeated AMI in patients who have undergone MI.

Metalloproteinase-9 in the ocular surface of patients with implanted Boston type 1 keratoprosthesis.

To characterize the presence of ocular surface inflammation, using matrix metalloproteinase 9 (MMP-9) as a marker, in the ocular surface of eyes with implanted Boston Keratoprosthesis type 1 (KPro). Patients with implanted KPro at a single tertiary center were recruited to assess ocular inflammation. MMP-9 was measured using InflammaDry® test in both eyes of each patient. The non-KPro eye served as control. Rate of positivity of MMP-9 was compared between groups. Possible associations between ocular surface inflammation and the development of postoperative complications were evaluated using univariate statistical analysis. Fifty eyes from 25 patients were included. The mean age was 50 years old. Non-inflammatory indications for KPro were predominant among patients. Eighty eight percent of KPro eyes had a positive test for MMP-9 while only 25% of control eyes were positive (p<001). The most common complications were retroprosthetic membrane, epithelial defects, and sterile corneal melt. The presence of a strong positive result was associated to a higher frequency of complications (80% of eyes) compared to a faint positive test (54%) and a negative test (33%). The KPro device appears to increase MMP-9 levels in the ocular surface. High MMP-9 levels may be associated with higher risk of complications. MMP-9 testing can be useful to assess subclinical ocular surface inflammation with a potential role in the postoperative care of KPro patients.

Evaluation of the Salivary Matrix Metalloproteinase-9 in Women With Polycystic Ovaries Syndrome and Gingival Inflammation: A Case-Control Study.

Background Polycystic ovary syndrome (PCOS) is an endocrine disease of women of reproductive age that impacts their oral and systemic well-being. This study aimed to compare the gingival inflammation indices and matrix metalloproteinase-9 (MMP-9) of non-obese women with PCOS. Materials and methods This is a case-control study in which 78 women were referred to the Babol Clinic Hospital in Northern Iran between 2018 and 2019. They were divided into three groups:26 women with PCOS and gingivitis, 26 women with PCOS with no gingivitis, and 26 women with no PCOS and no gingivitis as a control group. After recording the anthropometric and demographic variables, fasting saliva samples were taken from all participants before any periodontal intervention. These samples were transferred to Babol Molecular Cell Research Center under highly guaranteed cold-chain conditions to measure the serum levels of MMP-9. Periodontal status was evaluated for Gingival Index (GI), Plaque Index (PI), and Bleeding on Probing (BOP). Analysis of variance was used to compare the mean results for these indices. The significance level was considered when p ≤ 0.05. Results All the gingival indices were significantly higher for women with PCOS with gingivitis compared to the results for women from the other two groups. Similarly, women with PCOS showed high salivary MMP-9 levels but were within the normal reference ranges. Conclusion The gingival indices (GI, PI, and BOP) and salivary MMP-9 are higher in women with PCOS, regardless of the gingival status.

Synergistic Protective Effect of Interactions of Quercetin with Lycopene Against Ochratoxin A-Induced Ulcerative Colitis.

Ulcerative colitis is a type of inflammatory bowel disease responsible for the inflammation of the innermost lining of the colon and rectum. The present study's objective is to determine the potential synergistic impact of quercetin (QR) and lycopene (LP) in ulcerative colitis (UC) induced in rats by ochratoxin A (OTA) by biochemical and morphological alterations. QR and LP were administered alone and in combination with the OTA for 7days. OTA administration caused UC generation, resulting in significant changes in body weight percentage, disease activity index (DAI), macroscopic evaluation, colon weight/length ratio, and histological score. In addition to the above parameters, it also leads to elevated oxidative stress, i.e. increased malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), and hydroxyproline levels and decreased superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Histological changes in the colon architecture were also observed suggestive of extensive mucosal damage. In addition, a high level of matrix metalloproteinase 7 (MMP7) was observed in immunohistochemistry, and a high level of gene expression of osteopontin (OPN), runt-related transcription factor 2 (RUNX2), MMP-7, and interleukin-6 (IL-6) was observed in OTA administered animals. The combination of QR and LP significantly restored the per cent body weight loss and DAI score and improved macroscopic and histological changes, colon weight/length ratio, and macroscopic damages. It also improved the biochemical parameters to near-normal levels, i.e. reduced MDA, NO, MPO, and hydroxyproline levels and increased SOD and GSH levels. In addition, OPN, Runx2, MMP-7, and IL-6 gene expression decreased compared to the OTA-induced UC group. Outcomes of the present study indicate the potential of QR + LP as anti-inflammatory and immunomodulatory agents against OTA-induced UC in rats.

HIV Increases the Risk of Cigarette Smoke-Induced Emphysema Through MMP-9.

HIV is associated with an increased risk for emphysema. Matrix metalloproteinase 9 (MMP-9) is a lung tissue remodeling enzyme associated with emphysema. We previously found MMP-9 activity increases with increases in oxidative stress and that HIV increases alveolar oxidative stress. We hypothesized that HIV proteins would increase the risk of cigarette smoke-induced emphysema due to MMP-9. HIV-1 transgenic rats and wild-type littermates were exposed to cigarette smoke or sham for 8 weeks. Lung compliance and histology were assessed. Bronchoalveolar lavage (BAL), primary alveolar macrophages (AM), and serum samples were obtained. A rat alveolar macrophage cell line was exposed to the HIV protein Tat, and MMP-9 levels were assessed by Western immunoblotting. MMP-9 protein expression and activity were assessed in AM from the HIV rat model by ELISA and cytoimmunofluoresence, respectively. Serum from human subjects with and without HIV and tobacco dependence was assessed for MMP-9 levels. MMP-9 expression was significantly increased in rat alveolar macrophages after Tat exposure. HIV-1 transgenic rats developed emphysema while wild-type littermates did not. MMP-9 expression was also increased in the serum, BAL, and AM of HIV-1 transgenic rats after exposure to cigarette smoke compared with wild-type rats. In parallel, serum samples from HIV+ smokers had higher levels of MMP-9 than subjects without HIV and those who did not smoke. The combination of HIV and cigarette smoke increases MMP-9 expression in experimental rat HIV models and human subjects. HIV and cigarette smoke both induce alveolar oxidative stress and thereby increase MMP-9 activity.

Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.

The Predictive Values of MMP-9, PLTs, ESR, and CRP Levels in Kawasaki Disease with Cardiovascular Injury.

Objective To explore the levels of matrix metalloproteinase-9 (MMP-9), platelets (PLTs), C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) and their predictive values in Kawasaki disease (KD) with cardiovascular injury. Methods 128 children were diagnosed with KD in the Lanzhou University Second Hospital. 75 patients had coronary artery lesion (CAL), while 53 patients did not. The levels of MMP-9, PLTs, and CRP and ESR in the two groups were determined. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve and the Youden index (YI) were used to evaluate the efficacy of MMP-9, PLTs, ESR, and CRP for predicting CALs in KD. Results The mean age of the patients was 2.7 ± 2.03 years (range, 2 months to 11 years). There were 87 boys (67.97%) and 41 girls (32.03%). In contrast to the NCAL group, the CAL group had obviously higher levels of MMP-9, PLTs, and CRP and an obviously higher ESR (P < 0.05). MMP-9 showed a linear positive correlation with ESR (P < 0.05) and CRP (P < 0.05). The AUC of the combined detection of the four indicators was 0.877, the sensitivity was 85.07% and the specificity was 78.95%. Conclusion MMP-9, PLTs, ESR, and CRP are important indicators for a CAL in KD. The efficacy of the combined detection of MMP-9, PLTs, ESR and CRP is better than that of any single indicator for predicting a CAL in KD.

Clinical and histopathological effects of ointment prepared from kombucha floating cellulose layer on wound healing and the activity of matrix metalloproteinase 1 in diabetic rats

Introduction: High blood glucose results in high levels of matrix metalloproteinases. Clinical and histopathological effects of the kombucha ointment on the healing of diabetic wounds were evaluated.&#x0D; Materials and methods: This study was conducted at research Lab, Department of Micobiology, Falavarjan of Branch Islamic Azad University, Isfahan, Iran from October 2019 to September 2020. A 6 mm diameter ulcer was aseptically created on the back of forty-eight rats with streptozotocin-induced diabetes. The animals were randomly divided into 4 groups: the group that was treated with base ointment, the group that was treated with 10% kombucha ointment, the group that was treated with 20% kombucha ointment, and the group that received no ointment treatment. Then the rats in each group were divided to 4 sampling groups that were sampled on the second, fifth, tenth, and fourteenth days. Microscopic features, inflammation and vasculature and fibroblast infiltration, as well as the matrix metalloproteinase 1(MMP1) were evaluated on days 2, 5, 10, 14 after wound healing.&#x0D; Results: 20% kombucha ointment let to inflammation and an angiogenesis decrease compared to those in the basic group and 10%-kombucha-ointment group. Also 20% kombucha ointment led to an increase in vascular remodeling and penetration of fibroblasts. MMP1 levels increased on the second (p &lt; 0.001) and fifth days after wounding when treatrd with 10% and 20% kombucha ointment (p &gt; 0.05). The expression of MMP1 decreased on the ten and fourteenth days when using 20% kombucha ointment compared to the control, placebo, and 10% kombucha ointment groups (p &gt; 0.05).&#x0D; Discussion: The histopatological finding indicated that both quantity and time duration of the treatment had significant effects on a degree of inflammation and angiogenesis.&#x0D; Сonclusion: Ointment prepared from 20% scoby improved the healing of diabetic ulcers within 14 days.

A human coronavirus OC43-derived polypeptide causes neuropathic pain.

Human coronaviruses have been recently implicated in neurological sequelae by insufficiently understood mechanisms. We here identify an amino acid sequence within the HCoV‐OC43 p65‐like protein homologous to the evolutionarily conserved motif of myelin basic protein (MBP). Because MBP‐derived peptide exposure in the sciatic nerve produces pronociceptive activity in female rodents, we examined whether a synthetic peptide derived from the homologous region of HCoV‐OC43 (OC43p) acts by molecular mimicry to promote neuropathic pain. OC43p, but not scrambled peptides, induces mechanical hypersensitivity in rats following intrasciatic injections. Transcriptome analyses of the corresponding spinal cords reveal upregulation of genes and signaling pathways with known nociception‐, immune‐, and cellular energy‐related activities. Affinity capture shows the association of OC43p with an Na+/K+‐transporting ATPase, providing a potential direct target and mechanistic insight into virus‐induced effects on energy homeostasis and the sensory neuraxis. We propose that HCoV‐OC43 polypeptides released during infection dysregulate normal nervous system functions through molecular mimicry of MBP, leading to mechanical hypersensitivity. Our findings might provide a new paradigm for virus‐induced neuropathic pain.

An Investigation of Molecular Targeting of MMP-9 for Endometriosis Using Algal Bioactive Molecules

Endometriosis is a chronic inflammatory disease that occurs due to the presence of endometrial tissue outside the uterine cavity. It affects from 5% to 10% of women of reproductive age. High levels of matrix metalloproteinase (especially MMP-9) have been observed in women suffering from endometriosis. Thus, the aim of this study was to investigate the naturally anti-inflammatory compounds available from an algal source that can target the MMP-9 by various in silico approaches. The target 1L6J (Crystal structure of human matrix metalloproteinase MMP-9) structure was retrieved from the PDB database. Five compounds such as Eckol, Sargafuran, Vitamin E, Docosahexaenoic acid, Fucoidan and Elagolix were selected based on ‘Lipinski’s rule of five’ using the PubChem database. The pharmacokinetics, ADMET properties and biological activity of these compounds were predicted computationally using databases such as PreADME, SWISS-ADME, pkCSM and PASS. Comparative analysis of the bioactive compounds with the target was performed by AutoDock 4.2.6. Using LigPlot v.2.2, the target residues interacting with the compounds were visualised in a 2D manner. Based on the results, Eckol exhibited the highest binding energy value of −7.82 kcal/mol, whereas the Elagolix (control drug) showed a binding energy of −4.88 kcal. We conclude that Eckol can be a potent inhibitor of target MMP-9 with least side effects when compared to the control drug. Hence, this compound can be effectively explored by further in vitro and in vivo studies to develop more effective treatments for Endometriosis.

Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Identification of Fungal Bioactive Compounds Targeting MMP-9 for Endometriosis- An In silico Approach

Background: Endometriosis is a chronic inflammatory disease of the female reproductive system characterized by the presence of endometrial tissue outside the uterus that affects 5 to 10% of women of reproductive age, which is approximately 176 million women in the world. The women suffering from endometriosis have been reported to have high levels of matrix metalloproteinase (especially MMP-9) which regulates the inflammatory process. Thus, the aim of this study is to investigate the naturally available anti-inflammatory fungal compounds that can target the MMP-9 by various in silico approaches.&#x0D; Methodology: A wide variety of anti-inflammatory bioactive compounds were screened and five compounds were further selected based on ‘Lipinski’s rule of five’ using the PubChem database. The bioavailability, pharmacokinetics, ADMET properties and biological activity of these compounds were predicted computationally using databases such as SWISS-ADME, PubChem, pkCSM and PASS. The target 1L6J (Crystal structure of human matrix metalloproteinase MMP-9) structure was retrieved from the PDB database. Comparative analysis of the bioactive compounds with the target was performed by AutoDock 4.2.6 and further visualisation of the target residues interacting with the compounds was performed using LigPlot v.2. 2. tool.&#x0D; Results: Based on the docking results, the compounds namely, Ergosterol peroxide, Lovastatin, Javanicin, Asperlin and Ergothioneine exhibited binding energy value of -10.25 kcal/mol, -8.4 kcal/mol, -7.64 kcal/mol, -7.07 kcal/mol and -6.19 kcal/mol respectively whereas Elagolix (control drug) exhibited binding energy value of -4.88 kcal/mol, thus, indicating that the selected bioactive compounds were seen to have better binding energy comparative to the control drug. &#x0D; Conclusion: Ergosterol peroxide derived from edible mushroom might act as a potential lead compound for designing a therapeutic drug for treating endometriosis and this compound can further be explored to evaluate its level of toxicity and efficacy in the wet laboratory studies by in vitro and in vivo methods.

The Role of Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Background: Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that accumulate in large numbers during many pathologic conditions, including cancer, infectious diseases, trauma, and sepsis. Given that MDSCs are an important element of a cellular network regulating immune responses, their recovery early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) seems to be related to regulating graft-versus-host disease (GVHD) and/or immune reconstitution. However, the nature of these cells remains controversial in terms of clinical allo-HSCT. Therefore, we conducted a large prospective analysis of patients undergoing allogeneic HSCT for hematologic malignancies to evaluate MDSC recovery and function in the proinflammatory milieu post-transplant, and its immune suppressive mechanisms.Methods: We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allo-HSCT. Further, we investigated differentially expressed genes between G-MDSCs and M-MDSCs by transcriptome resequencing and characterized the molecular functions using carboxyfluorescein succinimidyl ester (CFSE) assay.Results: The high M-MDSC group had a higher infection rate within 100 days, worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS) compared to those with low M-MDSC group. The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated subtypes of MDSCs showed that matrix metalloproteinase-9 (MMP-9) was expressed much more highly in M-MDSCs than in G-MDSCs. The high expression of MMP-9 (P<0.001)and its upstream genes, including ARRB2 (P = 0.010) and F2RL1 (P = 0.024), in M-MDSC was confirmed using qRT-PCR. Moreover, MMP-9 concentrations in cell lysates (P < 0.001) and in culture supernatants (P = 0.001) were much higher in M-MDSCs than G-MDSCs, as shown by ELISA.Importantly, M-MDSCs isolated from patients post-HSCT had a higher capacity to suppress T cell responses than did G-MDSCs, and MMP-9 blockade more forcefully inhibited the immunosuppressive effect of M-MDSCs than that of G-MDSCs. Ultimately, the patients with high serum levels of MMP-9 had significantly higher infections within 100 days (P = 0.015), TRM by 1 year (P = 0.001) and a trend toward reduced EFS (P = 0.055) compared to those with low MMP-9.Conclusion: Our data demonstrated that early expansion of M-MDSCs was associated with early infections and poorer clinical outcomes than was expansion of G-MDSCs. Post-HSCT M-MDSCs exhibited increased levels of matrix metalloproteinase-9 (MMP-9), which might play a key role in worsening post-transplant infections and, ultimately, survival outcomes. DisclosuresKim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Protease-Antiprotease Imbalance in Bronchiectasis.

Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.