Tissue Inhibitors Of Matrix Metalloproteinases Research Articles

The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs.

Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.

The hepatoprotective effect of silibinin after hepatic ischemia/reperfusion in a rat model is confirmed by immunohistochemistry and qRT-PCR.

We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-β-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-β-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. Silibinin may have a beneficial effect on the protection of the liver.

Shear-Resistant, Biological Tethering of Nanostimulators for Enhanced Therapeutic Cell Paracrine Factor Secretion.

Mesenchymal stromal cells (MSCs) secreting multiple growth factors and immunomodulatory cytokines are promising for regenerative medicine. To further enhance their secretory activity, efforts have emerged to tether nanosized carriers of secretory stimuli, named nanostimulators, to the MSC surface by forming nonchemical bonds. Despite some successes, there is a great need to improve the retention of nanostimulators during transport through a syringe needle, where high shear stress exerted on the cell surface separates them. To this end, we hypothesize that poly(lactic-co-glycolic acid)-block-hyaluronic acid (PLGA-HA) conjugated with integrin-binding RGD peptides, denoted PLGA-HA-RGD, can form nanostimulators that remain on the cell surface stably during the injection. The resulting HA-CD44 and RGD-integrin bonds would synergistically increase the adhesion strength of nanostimulators. Interestingly, nanostimulators prepared with PLGA-HA-RGD show 3- to 6-fold higher retention than those made with PLGA-HA. Therefore, the PLGA-HA-RGD nanostimulators induced MSCs to secrete 1.5-fold higher vascular endothelial growth factors and a 1.2-fold higher tissue inhibitor of matrix metalloproteinase-1 as compared to PLGA-HA nanostimulators. Consequently, MSCs tethered with PLGA-HA-RGD nanostimulators served to stimulate endothelial cell activities to form a blood vessel-like endothelial lumen with increased length and number of junctions. The nanostimulator design strategy would also be broadly applicable to regulate, protect, and home a broad array of therapeutic or immune cells by tethering carriers with bioactive molecules of interest.

Activated matrix metalloproteinase 8 in serum predicts severity of acute pancreatitis

ObjectivesSevere acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs) are active in tissue destruction and inflammatory responses. We studied whether serum levels of activated MMP-8 (aMMP-8), MMP-9 and their regulators tissue inhibitor of matrix metalloproteinases (TIMP)-1, myeloperoxidase (MPO) and human neutrophil elastase (HNE) could predict the development of SAP. MethodsThe study comprised 214 AP patients (revised Atlanta classification: 142 mild, MAP; 54 moderately severe, MSAP; 18 SAP) referred to Helsinki University Hospital. A venous blood sample was taken within 72 h from the onset of symptoms. Serum levels of aMMP-8 were determined using immunofluorometric assay, and those of MMP-9, TIMP-1, MPO and HNE using enzyme-linked immunosorbent assay. AP groups were compared using Jonckheere-Terpstra test and predictive value for SAP was analyzed using receiver operating characteristics (ROC) analysis. ResultsSerum aMMP-8 levels were higher in SAP (median 657 ng/ml, interquartile range 542–738 ng/ml) compared to MSAP (358 ng/ml, 175–564 ng/ml; p < 0.001) and MAP (231 ng/ml, 128–507 ng/ml; p < 0.001). Similar trend was seen with TIMP-1 and MPO. In ROC analysis aMMP-8, MPO and TIMP-1 emerged as potential markers for the development of SAP (areas under ROC curves 0.83, 0.71 and 0.69, respectively). ConclusionsSerum aMMP-8 measured early in the course of AP (within 72 h of symptom onset) predicted the development of SAP.

Salivary Biomarkers and Oral Health in Liver Transplant Recipients, with an Emphasis on Diabetes.

Salivary biomarkers have been linked to various systemic diseases. We examined the association between salivary biomarkers, periodontal health, and microbial burden in liver transplant (LT) recipients with and without diabetes, after transplantation. We hypothesized that diabetic recipients would exhibit impaired parameters. This study included 84 adults who received an LT between 2000 and 2006 in Finland. Dental treatment preceded transplantation. The recipients were re-examined, on average, six years later. We evaluated a battery of salivary biomarkers, microbiota, and subjective oral symptoms. Periodontal health was assessed, and immunosuppressive treatments were recorded. Recipients with impaired periodontal health showed higher matrix metalloproteinase-8 (MMP-8) levels (p < 0.05) and MMP-8/tissue inhibitor of matrix metalloproteinase 1 (TIMP1) ratios (p < 0.001) than recipients with good periodontal health. Diabetes post-LT was associated with impaired periodontal health (p < 0.05). No difference between groups was found in the microbial counts. Salivary biomarker levels did not seem to be affected by diabetes. However, the advanced pro-inflammatory state induced by and associated with periodontal inflammation was reflected in the salivary biomarker levels, especially MMP-8 and the MMP-8/TIMP-1 molar ratio. Thus, these salivary biomarkers may be useful for monitoring the oral inflammatory state and the course of LT recipients.

Autologous Adipose-Derived Mesenchymal Stem Cells Combined with Shockwave Therapy Synergistically Ameliorates the Osteoarthritic Pathological Factors in Knee Joint.

Adipose-derived mesenchymal stem cells (ADSCs) and shockwave (SW) therapy have been shown to exert a chondroprotective effect for osteoarthritis (OA). The results of this study demonstrated that autologous ADSCs had dose-dependent and synergistic effects with SW therapy (0.25 mJ/mm2 with 800 impulses) in OA rat knee joint. Autologous, high-dose 2 × 106 ADSCs (ADSC2 group) combined with SW therapy significantly increased the bone volume, trabecular thickness, and trabecular number among in the treatment groups. ADSC2 combined with SW therapy significantly reduced the synovitis score and OARSI score in comparison with other treatments. In the analysis of inflammation-induced extracellular matrix factors of the articular cartilage in OA, the results displayed that ADSC2 combined with SW therapy had a greater than other treatments in terms of reducing tumor necrosis factor-inducible gene (TSG)-6 and proteoglycan (PRG)-4, in addition to increasing tissue inhibitor matrix metalloproteinase (TIMP)-1 and type II collagen. Furthermore, ADSC2 combined with SW therapy significantly reduced the expression of inflammation-induced bone morphogenetic protein (BMP)-2 and BMP-6. Therefore, the results demonstrated that ADSC2 combined with SW therapy had a synergistic effect to ameliorate osteoarthritic pathological factors in OA joints.

Microenvironment Influence of a Novel Bioengineered Wound Product, APIS®: A Preliminary In Vitro Analysis of Inflammatory Marker and Growth Factor Secretion.

Objective Preliminary biological activity assessment of a novel bioengineered wound product (APIS®, SweetBio, Inc., Memphis, TN, USA), a synthesis of gelatin, Manuka honey, and hydroxyapatite, with in vitro indications to protect, instill balance to, and progress the wound microenvironment. Approach. The biological activity the bioengineered wound product (BWP) elicits on human cells in vitro was assessed by evaluating matrix metalloproteinase- (MMP-) related proteins expressed by macrophages and secretion of growth factors in fibroblasts. Cells were cultured with no treatment, stimulated with lipopolysaccharides (LPS), or seeded directly on the BWP for 24 hours. An additional 72-hour time point for the BWP was assessed to determine if the BWP maintained its activity compared to itself at 24 hours. Cell culture supernatants were assayed to quantify secreted protein levels. Results MMP-9 secretion from macrophages seeded on the BWP were nondetectable (P < 0.01), while a tissue inhibitor of MMP (TIMP-1) was detected. This decreased the overall MMP-9/TIMP-1 ratio secreted from macrophages seeded on the BWP compared to the controls. Additionally, the secretion of prohealing growth factors such as basic fibroblast growth factor (FGFb) and vascular endothelial growth factor (VEGF) was observed. Conclusion Results from this preliminary in vitro evaluation suggest that the BWP has the potential to instill balance to the wound microenvironment by reducing the MMP-9/TIMP-1 ratio secretion from macrophages and progress previously stalled chronic wounds towards healing by triggering the release of growth factors from fibroblasts.

Circulating MMP-7 and VEGF as potential predictive biomarkers for recurrent implantation failures.

Recurrent implantation failure (RIF) is considered to be one of the major limiting factors of assisted reproductive technology (ART) programme success. The current study focused on the investigation of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), cytokines and cell adhesion molecules in peripheral blood (PB) and follicular fluid (FF) obtained from 44 women aged between 25 and 39 years old and undergoing intracytoplasmic sperm injection (ICSI). These women were divided into two groups: 22 RIF women with embryo implantation failures after the transfer of at least four fresh or frozen-thawed good quality embryos in a minimum of three ICSI cycles, and 22 ICSI success women (controls) who achieved a clinical pregnancy at their first ICSI attempt. The PB and FF samples were obtained from each patient on the day of oocyte retrieval. MMP-1, -2, -3, -7, -9, TIMP-1, -2, vascular endothelial growth factor (VEGF), leukaemia inhibitory factor (LIF), vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecules 1 (ICAM1) were analyzed using enzyme-linked immunosorbent assay of PB and FF. Our results showed significant decreases in PB MMP-7 and PB VEGF in the RIF group compared with controls [281.11 (33-614) pg/ml vs 119.92 (27-441) pg/ml; P-value = 0.030] and [82.54 (25.94-210.20) pg/ml vs 30.93 (13.62-193.33) pg/ml; P-value = 0.022; respectively]. Receiver operating characteristic (ROC) curve analysis showed informative area under the curve values for PB MMP-7, as well as for PB VEGF, making them able to be proposed as biomarkers of the RIF. Therefore, circulating MMP-7 and VEGF seem to play an interesting role in embryo implantation in in vitro fertilization (IVF)/ICSI cycles and could be proposed as circulating biomarkers of the RIF. These results could be helpful for clinicians and patients to choose the best rescue strategy and treatment to minimize implantation failure in women undergoing IVF/ICSI procedures after the first attempt.

Genetic variants of tissue inhibitors of matrix metalloproteinase 1 (rs4898) and 2 (rs8179090) in diverticulosis.

Diverticulosis affects approximately 60% of population after 60th year of age. Diverticular disease is symptomatic diverticulosis characterized by abdominal pain, flatulence and bloating, and bowel habits change. Age and lifestyle are risk factors for diverticulosis, additionally genetic predisposition is postulated. The aim of the study was to assess whether tissue inhibitors of matrix metalloproteinase (TIMP) 1 rs4898 and TIMP2 rs8179090 genetic variants are related to colonic diverticulosis. The study included 220 patients, 100 with colon diverticulosis diagnosed on colonoscopy and 120 controls. TIMP1 rs4898 and TIMP2 rs8179090 variants were examined using PCR-restriction fragments length polymorphism from a blood sample. Allele T of TIMP1 rs4898 was more frequent in male patients with diverticulosis than in controls (P < 0.01), whereas in women there were no differences in its distribution, both in heterozygotes and homozygotes or in homozygotes separately, proving a recessive effect. TIMP2 s8179090 allele G frequency was 0.95 in cases and controls, there were no CC homozygotes identified, and no associations with diverticulosis showed. TIMP1 rs4898 allele T may be a genetic determinant of the risk of diverticulosis in men.

Matrix metalloproteinases and chronic rhinosinusitis with nasal polyposis. Unravelling a puzzle through a systematic review.

The expression of metalloproteinases (MMPs) in chronic rhinosinusitis with nasal polyposis (CRSwNP) was reviewed in order to investigate their possible use as therapeutical targets and/or biomarkers. The differences between CRSwNP and normal controls or CRS without NP, as well as the effects of various treatments on MMPs, tissue inhibitors of MMPs (TIMPs) and MMP/TIMP ratios were considered as primary outcomes. Additional factors reported to affect MMP expression levels were noted as secondary outcomes. Data regarding inflammatory subtypes, patients’ clinical characteristics, controls, laboratory method(s) and origin of samples were also pooled. Studies on 10 or fewer patients or on specimens other than nasal and serum were excluded. Forty-three studies were included. Tissue sample origin, allergic rhinitis, smoking, infection, medication intake and primary or recurrent disease should be considered as confounding factors for MMP levels. MMP-1 and -7 were consistently found to be significantly higher in CRSwNP patients than controls. CRSwNP endotypes with distinctly different inflammation patterns seem to present similar MMP-related remodelling patterns. The existing literature has revealed several population and methodology related confounding factors and remains inconclusive regarding the roles of MMPs in CRSwNP pathophysiology and their possible clinical usefulness as biomarkers and therapeutical targets.

Role of estrogen receptor alpha in MEHP-induced proliferation and invasion of SH-SY5Y cells

Estrogen receptors are involved in regulating the proliferation and invasion process of neuroblastoma. As a kind of estrogen-like environmental endocrine disruptors (EEDs), whether mono-2-ethylhexyl phthalate (MEHP) can affect the proliferation and invasion of neuroblastoma cells via ERs is unknown. The present study aimed to explore the role of ERα in MEHP-induced proliferation, migration, and invasion of SH-SY5Y cells. SH-SY5Y cells were cultured in DMEM with 10 % FBS. Wild-type SH-SY5Y cells and ERα-knockdown SH-SY5Y cells were treated with MEHP (0, 10, 50, and 250 μM) for 12 h and 24 h. The viability of SH-SY5Y cells was detected with a CCK8 kit and cell cycle was measured by flow cytometry. Cell migration was measured using a scratch assay, and cell invasion was tested using a Transwell migration assay. The expression levels of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), ERα, and ERβ were detected with real-time qPCR and western blotting. MEHP promoted the proliferation of SH-SY5Y cells. The results also showed that MEHP significantly increased the relative migration distance of wild-type SH-SY5Y cells. Conversely, MEHP treatment did not increase the relative migration distance of ERα-knockdown SH-SY5Y cells, suggesting that MEHP promotes the migration of neuroblastoma through ERα. Similarly, MEHP significantly increased the relative number of invaded wild-type SH-SY5Y cells, while the MEHP-induced invasion effect was significantly decreased in ERα-knockdown SH-SY5Y cells. Moreover, the expression levels of PCNA, MMP-2, MMP-9, and ERα cells were upregulated by MEHP in wild-type SH-SY5Y, and the expression level of its tissue inhibitor TIMP-2 was downregulated. In contrast, the expression of PCNA, MMP-2, MMP-9, and ERα was significantly downregulated in ERα-knockdown SH-SY5Y cells, while the expression of TIMP-2 was significantly upregulated. In conclusion, MEHP can upregulate PCNA, MMP-2, and MMP-9, and downregulate TIMP-2, further promoting proliferation, migration, and invasion of neuroblastoma through ERα.

Apoptosis signal-regulating kinase 1 inhibition reverses deleterious indoxyl sulfate-mediated endothelial effects

AimsIndoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. Main methodsIS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. Key findingsIS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor β receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. SignificanceASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.

Additional diagnostic criteria for atrial cardiomyopathy in patients with lone atrial fibrillation

Aim . To determine additional diagnostic criteria for class I atrial cardiomyopathy (ACM) in patients with lone atrial fibrillation (AF). Material and methods . This cross sectional non-randomized clinical study included 170 stable patients &lt;60 years of age, of which 99 patients were selected. The inclusion criteria in the first group were the presence of lone AF with increased left atrial (LAVI) or right atrial volume index according to echocardiography without cardiovascular and pulmonary diseases, hypertension, and diagnostic criteria for heart failure (HF). The inclusion criterion in the second group was combination of AF and HF. The inclusion criterion in the third group was diagnostic criteria for HF (N-terminal pro-brain natriuretic peptide &gt;125 ng/ml) in patients with sinus rhythm. In all patients, the concentration of NT-proBNP, a soluble stimulating growth factor 2 (sST2), as well as creatinine and cystatin C with calculation of the glomerular filtration rate, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), and neutrophil gelatinase associated lipocalin (NGAL) was determined. Non-invasive angiography was performed. Results . According to ROC analysis, NT-proBNP, TIMP-1, NGAL as markers of class I ACM in patients with lone AF, showed unsatisfactory clinical significance. In patients with ACM and AF, regardless of the presence/ absence of HF, direct moderate relationship between sST2 and LAVI (r=0,470, p=0,012) and direct strong correlation between sST2 and NT-proBNP (r=0,726, p=0,004). Using ROC curve, for all available sST2 values, its diagnostic significance was obtained in the range from 5 to 16 ng/ml (AUC=0,98). Conclusion . The blood concentration of sST2 in the range from 5 to 16 ng/ml can be considered as an additional diagnostic criterion for class I ACM in patients with lone AF with a sensitivity of 98% and a specificity of 80%.

Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells.

Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and myocytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor β (TGFβ) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the gene expression of S1P receptors and enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA) mRNA expression, and protein translation due to increased glycogen synthase kinase 3β (GSK3β) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.

The Non-peptide Angiotensin-(1-7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats.

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1–7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1–7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1–7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1–7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

Berberine accelerated wound healing by restoring TrxR1/JNK in diabetes.

The high disability, mortality and morbidity of diabetic ulcers make it urgent to explore effective strategies for diabetic wound repair. TrxR1 plays a vital role in regulating redox homeostasis in various pathologies. In the present study, the effect of berberine (BBR) on diabetic wounds was investigated in streptozotocin (STZ)-induced diabetic rats and a high glucose (HG)-induced cell model, and the mechanism of BBR on TrxR1 was elucidated. BBR treatment remarkably accelerated wound healing and enhanced extracellular matrix (ECM) synthesis and significantly inhibited HG-induced HaCaT cell damage. Further analysis indicated that BBR activated TrxR1, suppressed its downstream JNK signaling, thereby inhibiting oxidative stress and apoptosis, promoted cell proliferation, down-regulated matrix metalloproteinase (MMP) 9 (MMP9) and up-regulated transforming growth factor-β1 (TGF-β1) and tissue inhibitors of MMP 1 (TIMP1), resulting in accelerated wound healing. Importantly, the enhancement of BBR on wound repair was further abolished by TrxR1 inhibitor. Moreover, in diabetic wounds induced by a combination of STZ injection and high-fat diet, BBR significantly increased wound closure rate and TrxR1 expression, and this was reversed by TrxR1 inhibitor. These data indicated that topical BBR treatment accelerated diabetic wound healing by activating TrxR1. Targeting TrxR1 may be a novel, effective strategy for restoring redox homeostasis and promoting diabetic wound healing.

Effect of hTIMP-1 overexpression in human umbilical cord mesenchymal stem cells on the repair of pancreatic islets in type-1 diabetic mice.

Mesenchymal stem cells (MSCs) have been suggested for pancreatic islet repair in Type 1 diabetes mellitus (T1DM). This study aimed to investigate the effect of human umbilical cord MSCs (hUC-MSCs) transfected with tissue inhibitors of matrix metalloproteinase (TIMP)-1 on the regeneration of β-cell islets in vitro and in vivo. hUC-MSCs were isolated, cultured, and transfected with lentiviruses for the overexpression of hTIMP-1. An in vitro coculture system of hUC-MSCs and streptozotocin-induced islets was established to examine the morphology, apoptosis, and insulin secretion of the cocultured islets. Diabetic mouse models were injected with lenti-TIMP-1-enhanced green fluorescent protein (EGFP)-hUC-MSCs to test the effect of hTIMP-1 on insulin levels and glucose tolerance in vivo. The expression of insulin and glucagon was evaluated by immunofluorescence staining. The results showed that coculture with hUC-MSCs or Lenti-TIMP-1-EGFP-hUC-MSCs improved islet viability rates. Lenti-TIMP-1-EGFP-hUC-MSC coculture increased the insulin and C-peptide secretion function of the cultured islets and increased the secretion of tumor necrosis factor-β1, interleukin-6, IL-10, and hTIMP-1. hUC-MSCs, especially those transfected with Lenti-hTIMP-1-EGFP, showed a strong protective effect in diabetic mice by alleviating weight loss and improving glucose and insulin metabolism. In addition, transplantation rescued islet histology and function in vivo. The overexpression of TIMP-1 by hUC-MSCs seems to exert beneficial effects on pancreatic islet cells. In conclusion, this study may provide a new perspective on the development of hUC-MSC-based cell transplantation therapy for T1DM.

Effect of Gancao Fuzi Decoction on osteoarthritis and proteomics of articular cartilage in rats

The rat osteoarthritis model was replicated by injection of sodium iodoacetate into the knee joint cavity, and the effects of Gancao Fuzi Decoction on rat osteoarthritis and the proteome of articular cartilage were investigated. Sixty SD rats weighing 230-250 g were randomly divided into normal group, model group, glucosamine sulfate group, and Gancao Fuzi Decoction high, medium and low dose groups. Osteoarthritis model was induced by intra-articular injection of sodium iodoacetate(3 mg on each leg) in all groups except the normal group. After modeling, each administration group was given intragastric administration for 1 month. During the administration period, joint pain test and joint width measurement were performed every week to observe the autonomous behavior of rats. Enzyme linked immunosorbent assay(ELISA) method was used to detect the contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), matrix metalloproteinase-3(MMP-3), and matrix metalloproteinase tissue inhibitor(TIMP-1) in rat joint lavage fluid. Hematoxylin-eosin(HE) staining was used to observe bone and joint morphology. Nano-LC-LTQ-Orbitrap system was used to detect arti-cular cartilage proteins. The results showed that, compared with the model group, Gancao Fuzi Decoction could significantly improve joint pain and joint swelling in osteoarthritis rats, significantly reduce the contents of TNF-α, IL-1β and MMP-3 in the joint cavity la-vage fluid, increase the content of TIMP-1, and relieve inflammatory diseases such as enlarged joint space, rough cartilage edge, different thickness of cartilage layer, and disordered arrangement of chondrocytes. After comparing the proteins between the groups, 273 differential proteins were screened out. KEGG analysis found that the above differential proteins involved 43 signaling pathways such as systemic lupus erythematosus, among which 11 signaling pathways were related to osteoarthritis. The above results indicated that Gancao Fuzi Decoction had a preventive effect on osteoarthritis, and its mechanism of action may be accomplished by regulating the protein expression of osteoarthritis-related signal pathways.

Long-term exposure to butyric acid induces excessive production of matrix metalloproteases in human gingival fibroblasts

ObjectiveThe purpose of this study was to clarify the relationship between bacteria-induced butyric acid and periodontal disease progression. DesignNormal human gingival fibroblasts were exposed to butyric acid (0, 1, 5, 10, and 15 mM) adjusted to a pH of 7.2–7.4 using sodium hydroxide for 0–96 h and cell viability was evaluated. In addition, the effects of butyric acid on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in gingival fibroblasts were analyzed by real-time RT-PCR, ELISA, western blotting, and stromelysin zymography. ResultsButyric acid reduced the viability of gingival fibroblasts in a concentration- and time-dependent manner. Furthermore, butyric acid promoted production of MMP-1, MMP-3, and MMP-10 in gingival fibroblasts and suppressed TIMP-2 protein production. ConclusionsButyric acid promoted overproduction of MMPs, resulting in a disruption of the balance between MMPs and TIMPs expression in gingival fibroblasts. Our study suggests that the butyric acid produced by causative bacteria stimulates excessive MMP expression in periodontal tissue, leading to destruction of the tissue.

Racial difference in atrial size and extracellular matrix homeostatic response to hypertension: Is this a potential mechanism of reduced atrial fibrillation in African Americans?

BackgroundAtrial fibrillation (AF) is less common in African Americans (AA) than Caucasians (C) despite a higher prevalence of risk factors such as hypertension (HTN).ObjectiveTest the hypothesis that differences in extracellular matrix (ECM) between AA and C in response to HTN might attenuate atrial enlargement and alter myocardial fibrosis.MethodsECM-related plasma biomarkers and echo data were collected from 326 C and 129 AA subjects with no history of AF, stratified by the presence of HTN, HTN with left ventricular hypertrophy (LVH), or HTN with LVH and heart failure with preserved ejection fraction (HFpEF).ResultsLeft atrial size was significantly smaller and the extent of enlargement in the presence of HTN was less in AA despite similar ventricular relative wall thickness, echocardiographic measures of diastolic function, and 6 minute-walk-test. AA had significantly lower levels of collagen I telopeptide and higher levels of collagen I propeptide among all strata, suggesting unique collagen homeostasis. Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP) showed a distinctive response to HTN in AA, with significantly lower levels of MMP-2, MMP-3, and MMP-8 in AA with HTN and significantly lower levels of TIMP-1 and TIMP-3 in AA with HTN and AA with LVH. AA had significantly lower levels of NT-pro-BNP in all strata.ConclusionThis cross-sectional study demonstrates a racial disparity in ECM blood biomarkers and atrial remodeling in response to HTN and in the development of LVH and HFpEF that may partly help explain the decreased risk of AF in AA.