Association between elevated serum matrix metalloproteinase-2 and tumor necrosis factor-α, and clinical symptoms in male patients with treatment-resistant and chronic medicated schizophrenia.

BACKGROUND: Inflammation has an important role in the pathogenesis of schizophrenia. The aim of this study was to investigate the levels of tumor necrosis factor (TNF) and matrix metalloproteinase-2 (MMP-2) in male patients with treatment-resistant schizophrenia (TRS) and chronic medicated schizophrenia (CMS), and the relationship with psychopathology. METHODS: The study enrolled 31 TRS and 49 cm male patients, and 53 healthy controls. Serum MMP-2 and TNF-α levels were measured by the Luminex liquid suspension chip detection method. Positive and Negative Syndrome Scale (PANSS) scores were used to evaluate symptom severity and Repeatable Battery for the Assessment of Neuropsychological Status was used to assess cognitive function. RESULTS: Serum TNF-α and MMP-2 levels differed significantly between TRS, CMS and healthy control patients (F = 4.289, P = 0.016; F = 4.682, P = 0.011, respectively). Bonferroni correction demonstrated that serum TNF-α levels were significantly elevated in CMS patients (P = 0.022) and MMP-2 levels were significantly higher in TRS patients (P = 0.014) compared to healthy controls. In TRS patients, TNF-α was negatively correlated with age (r=-0.435, P = 0.015) and age of onset (r=-0.409, P = 0.022). In CMS patients, MMP-2 and TNF-α were negatively correlated with PANSS negative and total scores, and TNF-α was negatively correlated with PANSS general psychopathology scores (all P < 0.05). MMP-2 levels were positively correlated with TNF-α levels (P < 0.05), but not with cognitive function (P > 0.05). CONCLUSION: The results indicate the involvement of inflammation in the etiology of TRS and CMS. Further studies are warranted.

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

Objective: The 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 methods: In 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. Results: There 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 < 0.0001), and MMP-2 is negatively correlated with the edema volume (r = -0.2187, p < 0.05), NIHSS score (r = -0.2194, p < 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). Conclusion: The 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.

Extracellular matrix collagen biomarker levels in patients who underwent pulmonary endarterectomy.

OBJECTIVES: The role of extracellular matrix collagen biomarkers in chronic thromboembolic pulmonary hypertension (CTEPH) is not well known. Our goal was to investigate the matrix metalloproteinase (MMP)-2 and -9 protein levels in patients with CTETH. METHODS: This is a prospective, cross-sectional study. Patients with CTETH who underwent pulmonary endarterectomy comprise group 1, and the control group included patients who underwent lung surgery without pulmonary hypertension (group 2) between March 2020 and March 2021. In addition to serum levels of MMP-9, the pulmonary endarterectomy and control pulmonary artery tissue samples were measured by the enzyme-linked immunosorbent assay  4pl, cubic, quadratic and Western blot techniques. Levels of MMP-2, which consist of pro MMP-2/ß-actin and active MMP-2/ß-actin and MMP-9/ß-actin, were measured only in the tissue samples. RESULTS: Forty-eight patients were enrolled consecutively in group 1 (n: 24) and group 2 (n: 24). The serum concentrations of MMP-9 were similar in both groups. Similarly, a comparison of tissue sample levels of pro MMP-2/ß-actin (P = 0.496) and active MMP-2/ß-actin (P = 0.216) showed no significant difference between the groups. The tissue samples from patients with CTETH had significantly lower amounts of MMP-9/ß-actin compared to the control group (P = 0.001). CONCLUSIONS: This study indicates that serum levels of extracellular matrix collagen biomarkers were similar in patients with CTETH who were candidates for surgery and in patients who had non-pulmonary hypertension who underwent lung surgery. Differences in levels of MMP-9/ß-actin in tissue samples may play a role in pulmonary vascular remodelling in operable patients.

Effect of vascular endothelial growth factor-A165 on scleral remodeling of guinea pigs with form-deprivation myopia / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the effect of the intravitreal injection of vascular endothelial growth factor-A165(VEGF-A165)on the scleral remodeling of guinea pigs with form-deprivation myopia(FDM).METHODS: A total of 120 tricolor guinea pigs, aged three weeks, were randomly divided into 6 groups, with 20 in each group. The blank group did not undergo any intervention. In the FDM group, only the FDM model was established. In the phosphate buffer saline(PBS)group, 2.5 μL of PBS was injected into the vitreous cavity before establishing the FDM model. In the 1ng group, 5ng group, and 10ng group, VEGF-A165 was injected into the vitreous cavity at concentrations of 1, 5 and 10ng, respectively, before the establishment of the FDM model. The FDM model was established by covering the right eyes of guinea pigs with translucent balloons for 14d. The diopter and axial length of the right eyes were measured before and after covering. After 14d, the content of dopamine(DA)in retina was measured by high performance liquid chromatography. Additionally, the mRNA and protein expression levels of matrix metalloproteinase-2(MMP-2), tissue inhibitor of matrix metalloproteinase-2(TIMP-2), transforming growth factor(TGF)-β1, TGF-β2 and α-smooth muscle actin(α-SMA)in sclera were detected by reverse transcription polymerase chain reaction(RT-PCR)and Western blot.RESULTS: Before covering, there were no significant differences in the diopter and axial length of the right eyes of guinea pigs in all groups(P&#x003E;0.05). After 14d of modeling, when compared with the blank group, FDM group showed an increase in the degree of myopia in the right eye, a prolongation of the axial length, a decrease in the content of DA in the retina, and an increase in the expression of MMP-2, TGF-β2 and α-SMA in the sclera. Conversely, the expression of TIMP-2 and TGF-β1 were decreased(P&#x003C;0.01). However, in comparison to the FDM group, the degree of myopia in the 1ng, 5ng, and 10ng groups of guinea pigs decreased, the growth trend of axial length slowed, the content of DA in the retina increased, and the expression of MMP-2, TGF-β2 and α-SMA in the sclera decreased. Furthermore, the expression of TIMP-2 and TGF-β1 in the sclera increased(P&#x003C;0.01). As the concentration of intravitreal injection of VEGF-A165 increased, the degree of myopia in the right eye of guinea pigs gradually increased, and the axial length gradually prolonged. The content of DA in the retina gradually decreased, the expression of MMP-2, TGF-β2, and α-SMA in the sclera gradually increased, while the expression of TIMP-2 and TGF-β1 decreased gradually.CONCLUSION: Intravitreal injection of VEGF-A165 can increase the content of DA in the retina of FDM guinea pigs, affect the expression of MMP-2, TIMP-2, TGF-β1, TGF-β2 and α-SMA in the sclera, and inhibit scleral remodeling of guinea pigs. Notably, the VEGF-A165 at the concentration of 1ng showed the most significant efficacy.

Corrigendum: Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and ß-catenin pathway in vitro.

[This corrects the article DOI: 10.3389/fphar.2022.963589.].

Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and ß-catenin pathway in vitro.

Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified. Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and ß-catenin. Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and ß-catenin. Conclusion: Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/ß-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.

Assessment of serum concentrations of matrix metalloproteinase 1, matrix metalloproteinase 2 and tissue inhibitors of metalloproteinases 1 in atopic dermatitis in correlation with disease severity and epidermal barrier parameters.

INTRODUCTION: Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes, conditioning the integrity of skin cells, however, their role in the inflammatory process of atopic dermatitis (AD) and the direct effect on the epidermal barrier parameters remain unexplained. AIM: To assess MMP-1, MMP-2, tissue inhibitors of metalloproteinases (TIMP)-1 concentrations in blood serum in the context of transepidermal water loss (TEWL) and stratum corneum hydration in AD. Moreover, serum levels of MMPs and TIMP-1 were analysed in relation to the Eczema Area and Severity Index (EASI). MATERIAL AND METHODS: Forty-three AD patients and 22 control group subjects have been investigated. Serum concentrations of MMP-1, MMP-2, and TIMP-1 have been evaluated with ELISA. TEWL and stratum corneum hydration have been assessed with a TM300 Tewameter and a CM825 Corneometer. Skin lesions in patients with AD have been evaluated with the Eczema Area and Severity Index. RESULTS: MMP-1 and MMP-2 serum concentrations were significantly higher in the AD group. The results of TIMP-1 serum concentration were similar for both groups. The correlation between the serum concentration and the EASI was demonstrated only for MMP-2 for patients with severe and moderate AD. Patients with AD and TIMP-1 serum concentration greater than MMP-1 presented lower TEWL and higher epidermal hydration. CONCLUSIONS: The results of this study warrant further investigation. The predominance of TIMP-1 over MMP-1 in blood serum can potentially limit TEWL and maintain the proper water content of the epidermis. Future work is necessary to establish how reliable the role of MMP-2 concentration is as an indicator of the severity of AD.

Laser as a promising non-invasive technique to treat oral submucous fibrosis: A systematic review of the literature.

BACKGROUND: Oral submucous fibrosis (OSMF) is one of the common oral potentially malignant disorders that can result in severe morbidity. Depending upon the stage of disease, multiple management therapies exist which include medicinal and surgical approaches. Although the surgical approach is preferred in severe conditions, numerous studies have reported its post-surgical deteriorating outcomes including increased fibrotic changes. To reduce these post-surgical complications, Light amplification by stimulated emission of radiation (Laser) has been introduced and studied as a non-invasive technique to treat oral submucous fibrosis. However, there exists a lack of knowledge about 'which laser shows a better post-treatment outcome'. Accordingly, this review aims to answer this question. MATERIALS AND METHODS: A systematic review of the published literature was performed using an electronic search in PubMed/Medline, Science Direct, Web of Science, Embase, J- STAGE, Google Scholar, and Scopus databases, from 1952 till 2019 using keywords like, 'Oral submucous fibrosis', 'Treatment', 'Laser', 'Trismus', ' Fibrosis', 'Surgical', 'Non-invasive', and 'Postoperative results'. RESULTS: The search strategy revealed 20 relevant published studies in which laser had been used to treat 250 patients of OSMF. Effective results were found without any complications in all the cases after follow up. CONCLUSION: Observing the current literature, it can be concluded that laser might be used as a potential non-invasive approach in the management of OSMF, however, large scale studies are required to investigate the efficacy and other effects of this technology.

Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2-5.6-fold) and suppressed cyclin D expression (0.8-0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

Orosomucoid 1 promotes epirubicin resistance in breast cancer by upregulating the expression of matrix metalloproteinases 2 and 9.

Orosomucoid 1 (ORM1) has been shown to be upregulated in the serum of breast cancer patients; however, the expression and function of ORM1 in breast cancer remains unknown. We measured the expression of ORM1 in breast cancer tissues and cell lines using qRT-PCR. A colony formation assay was done to assess cell proliferation and Transwell and wound healing assays were performed to determine the migration and invasion capacity of the cells, respectively. In addition, a CCK-8 assay was used to measure epirubicin cytotoxicity and western blot assays were done to analyze the putative mechanisms of epirubicin sensitivity. We found that the expression of ORM1 was upregulated in breast cancer tissues and cell lines. The expression of ORM1 enhanced the proliferation and migration of the cell lines. In contrast, down-regulation of ORM1 inhibited the expression of MMP-2 and MMP-9 and activation of the AKT/ERK signaling pathway. Therefore, ORM1 may represent a potential therapeutic target for breast cancer and promote epirubicin resistance by regulating the expression of MMP-2 and MMP-9, as well as activating the AKT/ERK signaling pathway.

Human Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate Blood-Spinal Cord Barrier Disruption via the TIMP2/MMP Pathway After Acute Spinal Cord Injury.

After spinal cord injury (SCI), destruction of the blood-spinal cord barrier (BSCB) results in infiltration of blood cells, such as neutrophils and macrophages, leading to permanent neurological dysfunction. Previous studies have shown that human bone marrow mesenchymal stem cell (BMSC)-derived exosomes have a beneficial neuroprotective effect in SCI models. However, whether BMSC-Exos contribute to the integrity of the BSCB has not been clarified. The purpose of this study was to investigate the mechanism of BMSC-Exo-induced changes in the permeability of the BSCB after SCI. Here, we first used BMSC-Exos to treat an SCI rat model, showing that BMSC-Exos can inhibit BSCB permeability damage and improve spontaneous repair. Next, we found that tissue inhibitors of matrix metalloproteinase 2 (TIMP2) have been shown to play an important role in the function of BMSC-Exos by inhibiting the matrix metalloproteinase (MMP) pathway, thereby reducing the reduction of cell junction proteins. Therefore, we constructed siTIMP2 to knock out TIMP2 in BMSC-Exos, which caused the activity of BMSC-Exos to be significantly weakened. Finally, we constructed an in vitro model of BSCB with HBMECs and verified that TIMP2 in BMSC-Exos in vitro can also alleviate BSCB damage. This proof-of-principle study demonstrates that BMSC-Exos can preserve the integrity of the BSCB and improve functional recovery after SCI through the TIMP2/MMP signaling pathway.

Chemical composition and pharmacological bio-efficacy of Parrotiopsis jacquemontiana (Decne) Rehder for anticancer activity.

Consistent STAT3 (Single transducer and activator of transcription 3) activation is observed in many tumors and promotes malignant cell transformation. In the present investigation, we evaluated the anticancer effects of Parrotiopsis jacquemontiana methanol fraction (PJM) on STAT3 inhibition in HCCLM3 and MDA-MB 231 cells. PJM suppressed the activation of upstream kinases i.e. JAK-1/2 (Janus kinase-1/2), and c-Src (Proto-oncogene tyrosine-protein kinase c-Src), and upregulated the expression levels of PIAS-1/3 (Protein Inhibitor of Activated STATs-1/3), SHP-1/2 (Src-homology region 2 domain-containing phosphatase-1/2), and PTP-1ß (Protein tyrosine phosphatase 1 ß) which negatively regulate STAT3 signaling pathway. PJM also decreased the levels of protein products conferring to various oncogenes, which in turn repressed the proliferation, migration, invasion, and induced apoptosis in cancer cell lines. The growth inhibitory effects of PJM on cell-cycle and metastasis were correlated with decreased expression levels of CyclinD1, CyclinE, MMP-2 (Matrix metalloproteinases-2), and MMP-9 (Matrix metalloproteinases-9). Induction of apoptosis was indicated by the cleavage and subsequent activation of Caspases (Cysteine-dependent Aspartate-directed Proteases) i.e. caspase-3, 7, 8, 9, and PARP (Poly (ADP-ribose) polymerase) as well as through the down-regulation of anti-apoptotic proteins. These apoptotic effects of PJM were preceded by inhibition of STAT3 cell-signaling pathway. STAT3 was needed for PJM-induced apoptosis, and inhibition of STAT3 via pharmacological inhibitor (Stattic; SC-203282) abolished the apoptotic effects. Conclusively, our results demonstrate the capability of PJM to inhibit cancer cell-proliferation and induce apoptosis by suppressing STAT3 via upregulation of STAT3 inhibitors and pro-apoptotic proteins whereas the down-regulation of upstream kinases and anti-apoptotic protein expression. In future, one-step advance studies of PHM regarding its role in metastatic inhibition, immune response modulation for reducing tumor, and inducing apoptosis in suitable animal models would be an interesting and promising research area.

Investigation of the effect of melatonin administration on inflammatory mediators; MMP-2, TGF-ß and VEGF levels in rats with sepsis.

AIMS: Sepsis causes life-threatening tissue and organ dysfunctions caused by endogenous mediators in response to infection. Melatonin is a powerful endogenous anti-inflammatory agent and effective in reducing cellular damage. This study aimed to evaluate the changes in serum and liver tissue levels of VEGF, TGF-ß and MMP-2 in melatonin-treated septic rats. MATERIALS AND METHODS: Twenty-one Wistar-albino male rats were included in this study. Rats were randomly divided into three groups. Group 1 is sham-operated control (C) group, Group 2 is caecal ligation and puncture (CLP) group and Group 3 is melatonin-treated (10 mg/kg) (M-CLP) group. Serum and tissue samples were analysed. All procedures were carried out according to the ethical rules specified in Helsinki Declaration. RESULTS: Sera MMP-2 levels were found higher than tissue MMP-2 levels in C and CLP (respectively, P = .048, P = .01). In CLP and M-CLP, serum TGF-ß levels were higher than tissue TGF-ß levels(respectively, P = .05, P = .01). Serum VEGF levels in CLP were found to be significantly higher than both C and M-CLP(P < .01). CONCLUSION: MMP-2 levels may have increased because of the prevention of oxidative damage in sepsis, and this may increase the anti-inflammatory effect. Melatonin treatment may have a therapeutic effect against sepsis since it prevents the increase in serum VEGF level. A powerful endogenous antioxidant, may be a promising therapeutic agent on the mortality and morbidity of the disease, because of its lowering effect on serum VEGF, which is a poor prognostic factor in sepsis.

Host-Guest Interaction-Based Dual response core/shell nanoparticles as efficient siRNA carrier for killing breast cancer cells.

How to overcome multiple obstacles to achieve the efficient and safe delivery of therapeutic genes is still the key to gene therapy. To address this issue, a cationic carrier consisting of polyamide-amine (HPAA-peptide-Fc) modified by an enzyme-responsive polypeptide as the core and hyperbranched polyglycerol derivative (CD-HPG) as the shell was synthesized by self-assembly. The obtained HPAA-peptide-HPG could form the compact nanocomplex with siPlk1, thus confirming the stable load of genes and subsequent targeted gene delivery. And the nanogenes could significantly induce apoptotic effect via the down-expression of Plk1 protein in breast cancer cells. Moreover, compared to polyethylenimine, HPAA-peptide-HPG exhibited superior biocompatibility through hemolysis and cell viability assays because of the shielding function of CD-HPG, thereby being beneficial to increasing the circulation time of the complex when administrated in vivo. Such an efficient and safe gene delivery complex (HPAA-peptide-HPG) presents a good example of rational design of cationic supramolecular vesicles for stimulus-responsive siRNA transport, which should be encouraged in cancer gene therapy.

Serum Anti-Collagen IV IgM and IgG Antibodies as Indicators of Low Vascular Turnover of Collagen IV in Patients with Long-Term Complications of Type 2 Diabetes.

Thickening of the vascular basement membrane (BM) is a fundamental structural change in the small blood vessels in diabetes. Collagen type IV (CIV) is a major component of the BMs, and monitoring the turnover of this protein in type 2 diabetes (T2D) can provide important information about the mechanisms of vascular damage. The aim of the study was through the use of non-invasive biomarkers of CIV (autoantibodies, derivative peptides, and immune complexes) to investigate vascular turnover of CIV in patients with long-term complications of T2D. We measured serum levels of these biomarkers in 59 T2D patients with micro- and/or macrovascular complications and 20 healthy controls using an ELISA. Matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) were also tested. In the T2D group, significantly lower levels of CIV markers and significantly higher levels of MMP-2 and MMP-9 were found compared to controls. A significant positive correlation was found between IgM antibody levels against CIV and MMP-2. These findings suggest that vascular metabolism of CIV is decreased in T2D with long-term complications and show that a positive linear relationship exists between MMP-2 levels and CIV turnover in the vascular wall.

Relationship between metalloproteinase-2 and -9 levels in plasma and vaginal secretion with preterm birth.

OBJECTIVE: To study the association of plasma and vaginal levels of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9), determined between 20+0 and 25+6 weeks of gestation, with preterm birth and its predictive value. STUDY DESIGN: All 129 cases of preterm birth (cases) and 258 randomly selected term patients (control group) were included in a cohort study with a nested case-control design. Inclusion criteria were living in Ribeirão Preto, Brazil, and gestational age 20+0 to 25+6 at enrollment. Exclusion criteria were multiple fetuses, congenital malformations or chromosome syndromes, and loss to follow-up. Maternal age, parity, smoking, and previous preterm birth were included as covariates. A blood sample and vaginal secretion were obtained for the determination of MMP-2 and MMP-9; the patients were screened for urinary tract infection and bacterial vaginosis, and cervical length was measured by ultrasound. The cut-off values for matrix metalloproteinases were calculated using receiver operating characteristic (ROC) curves for logistic regression analysis (crude and adjusted odds ratios). RESULTS: According to the WHO, in this study, preterm subtypes included 3.8 % extremely preterm, 6.9 % very preterm, and 89.2 % late preterm births. The plasma MMP-9 cut-off was 63.25 ng/mL and the area under the ROC curve was 0.725 (standard error 0.03; 95 % confidence interval, 0.677-0.769). The cut-off for plasma MMP-2 was 239.4 ng/mL and the area under the ROC curve was 0.585 (standard error 0.03, 95 % confidence interval, 0.521-0.649). Crude odds ratios showed an increased risk of preterm birth associated with plasma MMP-2 (odds ratio, 1.75; 95 % confidence interval, 1.14-2.68) and plasma MMP-9 (odds ratio, 3.26, 95 % confidence interval, 2.09-5.07); no association was detected for vaginal MMP-2 or 9. For plasma, adjusted odds ratios were 1.42 (95 % confidence interval, 0.80-2.53) for MMP-2 and 2.71 (95 % confidence interval, 1 .52-4.83) for MMP-9, along with an increased risk in other covariates. CONCLUSION: Elevated plasma MMP-9 levels and decreased MMP-2 levels were positively associated with preterm birth. Plasma MMP-9 level increased nearly three times the preterm risk.

Use of Glycated Hemoglobin (A1c) as a Biomarker for Vascular Risk in Type 2 Diabetes: Its Relationship with Matrix Metalloproteinases-2, -9 and the Metabolism of Collagen IV and Elastin.

Background and objectives: HbA1c measurements may be useful not only in optimizing glycemic control but also as a tool for managing overall vascular risk in patients with diabetes. In the present study, we investigate the clinical significance of HbA1c as a biomarker for hyperglycemia-induced vascular damages in type 2 diabetes (T2D) based on the levels of matrix metalloproteinases-2, -9 (MMP-2, MMP-9), anti-collagen IV (ACIV), and anti-elastin (AE) antibodies (Abs) IgM, IgG, and IgA, and CIV-derived peptides (CIV-DP) reflecting collagen and elastin turnover in the vascular wall. The aim is to show the relationship of hyperglycemia with changes in the levels of vascular markers and the dynamics of this relationship at different degrees of glycemic control reported by HbA1c levels. Materials and Methods: To monitor elastin and collagen IV metabolism, we measured serum levels of these immunological markers in 59 patients with T2D and 20 healthy control subjects with an ELISA. Results: MMP-2, MMP-9, and the AEAbs IgA levels were significantly higher in diabetic patients than in control subjects, whereas those of the AEAbs IgM, ACIVAbs IgM, and CIV-DP were significantly lower. MMP-9 levels were significantly lower at HbA1c values >7.5%. Conclusions: A set of three tested markers (MMP-2, MMP-9, and AEAbs IgA) showed that vascular damages from preceding long-term hyperglycemia begin to dominate at HbA1c values ≥7.5%, which is the likely cut-point to predict increased vascular risk.

Myocardial injection of a thermoresponsive hydrogel with reactive oxygen species scavenger properties improves border zone contractility.

The decrease in contractility in myocardium adjacent (border zone; BZ) to a myocardial infarction (MI) is correlated with an increase in reactive oxygen species (ROS). We hypothesized that injection of a thermoresponsive hydrogel, with ROS scavenging properties, into the MI would decrease ROS and improve BZ function. Fourteen sheep underwent antero-apical MI. Seven sheep had a comb-like copolymer synthesized from N-isopropyl acrylamide (NIPAAm) and 1500 MW methoxy poly(ethylene glycol) methacrylate, (NIPAAm-PEG1500), injected (20 × 0.5 mL) into the MI zone 40 min after MI (MI + NIPAAm-PEG1500) and seven sheep were MI controls. Cardiac MRI was performed 2 weeks before and 6 weeks after MI + NIPAAm-PEG1500. BZ wall thickness at end systole was significantly higher for MI + NIPAAm-PEG1500 (12.32 ± 0.51 mm/m2 MI + NIPAAm-PEG1500 vs. 9.88 ± 0.30 MI; p = .023). Demembranated muscle force development for BZ myocardium 6 weeks after MI was significantly higher for MI + NIPAAm-PEG1500 (67.67 ± 2.61 mN/m2 MI + NIPAAm-PEG1500 vs. 40.53 ± 1.04 MI; p < .0001) but not significantly different from remote myocardium or BZ or non-operated controls. Levels of ROS in BZ tissue were significantly lower in the MI + NIPAAm-PEG1500 treatment group (hydroxyl p = .0031; superoxide p = .0182). We conclude that infarct injection of the NIPAAm-PEG1500 hydrogel with ROS scavenging properties decreased ROS and improved contractile protein function in the border zone 6 weeks after MI.

Prognostic Role of Matrix Metalloproteinases 2, 7, 8, 9 and Their Type 1 Tissue Inhibitor in Blood Serum of Patients with Kidney Cancer.

The study compared the levels of MMP-2,7,8,9, and TIMP-1 in blood serum of healthy people (N=97) and patients with primary renal cell carcinoma (N=93) to assess relevance of these markers to prognosis of overall survival of these patients, which were followed-up over 1 to 45 months (median 26 months). To evaluate the survival with the Kaplan-Meier estimator, the median values of examined markers in the total group of patients were taken as the threshold levels. This estimator showed that the high levels of serum MMP-7 and MMP-8 were indicative for unfavorable prognosis in the total group of patients with renal cell cancer. Of them, the most significant marker was the level of MMP-7: at its low level (<6.3 ng/ml), a 3-year survival was 93%, whereas survival dropped down to 51% at a higher value of this marker (p<0.001). For MMP-8, the threshold level was 51 ng/ml, and the corresponding survivals were 78 and 58% (p<0.01). The level of MMP-7 was also prognostically significant for the patients with stage I kidney cancer: during a 3-year follow-up, all the patients with low MMP-7 were alive, while the 3-year survival of the patients with a high level of MMP-7 was only 72% (p=0.02). There were the declining trends for survival at high TIMP-1 and low MMP-2. In contrast, the level of MMP-9 virtually did not correlate with survival of the patients with renal cell cancer.