Matrix Metalloproteinase Activity Research Articles

Increased Elastase and Matrix Metalloproteinase Levels in the Pulmonary Arteries of Infants With Congenital Diaphragmatic Hernia

BackgroundPulmonary vascular disease (PVD) complicated with pulmonary hypertension (PH) is a leading cause of mortality in congenital diaphragmatic hernia (CDH). Unfortunately, CDH patients are often resistant to PH therapy. Using the nitrogen CDH rat model, we previously demonstrated that CDH-associated PVD involves an induction of elastase and matrix metalloproteinase (MMP) activities, increased osteopontin and epidermal growth factor (EGF) levels, and enhanced smooth muscle cell (SMC) proliferation. Here, we aimed to determine whether the levels of the key members of this proteinase-induced pathway are also elevated in the pulmonary arteries (PAs) of CDH patients. MethodsNeutrophil elastase (NE), matrix metalloproteinase-2 (MMP-2), epidermal growth factor (EGF), tenascin-C, and osteopontin levels were assessed by immunohistochemistry in the PAs from the lungs of 11 CDH patients and 5 normal age-matched controls. Markers of proliferation (proliferating cell nuclear antigen (PCNA)) and apoptosis (cleaved (active) caspase-3) were also used. ResultsWhile expressed by both control and CDH lungs, the levels of NE, MMP-2, EGF, as well as tenascin-C and osteopontin were significantly increased in the PAs from CDH patients. The percentage of PCNA-positive PA SMCs were also enhanced, while those positive for caspase-3 were slightly decreased. ConclusionsThese results suggest that increased elastase and MMPs, together with elevated tenascin-C and osteopontin levels in an EGF-rich environment may contribute to the PVD in CDH infants. The next step of this study is to expand our analysis to a larger cohort, and determine the potential of targeting this pathway for the treatment of CDH-associated PVD and PH. Type of StudyTherapeutic. Level of EvidenceLEVEL III.

Inhibitors of gastric acid secretion increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling.

The use of inhibitors of gastric acid secretion (IGAS), especially proton pump inhibitors (PPI), has been associated with increased cardiovascular risk. While the mechanisms involved are not known, there is evidence supporting increased oxidative stress, a major activator of matrix metalloproteinases (MMP), as an important player in such effect. However, there is no study showing whether other IGAS such as histamine H2-receptor blockers (H2RB) cause similar effects. This study aimed at examining whether treatment with the H2RB ranitidine promotes oxidative stress resulting in vascular MMP activation and corresponding functional and structural alterations in the vasculature, as compared with those found with the PPI omeprazole. Male Wistar rats were treated (4 weeks) with vehicle (2% tween 20), omeprazole (10 mg/Kg/day; i.p.) or ranitidine (100 mg/Kg/day; gavage). Then the aorta was collected to perform functional, biochemical, and morphometric analysis. Both ranitidine and omeprazole increased gastric pH and oxidative stress assessed in situ with the fluorescent dye dihydroethidium (DHE) and with lucigenin chemiluminescence assay. Both IGAS augmented vascular activated MMP-2. These findings were associated with aortic remodeling (increased media/lumen ratio and number of cells/μm2). Both IGAS also impaired the endothelium-dependent relaxation induced by acetylcholine (isolated aortic ring preparation). This study provides evidence that the H2RB ranitidine induces vascular dysfunction, redox alterations, and remodeling similar to those found with the PPI omeprazole. These findings strongly suggest that IGAS increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling, which helps to explain the increased cardiovascular risk associated with the use of those drugs.

FRET Sensor-Modified Synthetic Hydrogels for Real-Time Monitoring of Cell-Derived Matrix Metalloproteinase Activity using Fluorescence Lifetime Imaging.

Matrix remodeling plays central roles in a range of physiological and pathological processes and is driven predominantly by the activity of matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) proteins. Our understanding of how MMPs regulate cell and tissue dynamics is often incomplete as in vivo approaches are lacking and many in vitro strategies cannot provide high-resolution, quantitative measures of enzyme activity in situ within tissue-like 3D microenvironments. Here, we incorporate a Förster resonance energy transfer (FRET) sensor of MMP activity into fully synthetic hydrogels that mimic many properties of the native ECM. We then use fluorescence lifetime imaging to provide a real-time, fluorophore concentration-independent quantification of MMP activity, establishing a highly accurate, readily adaptable platform for studying MMP dynamics in situ. MCF7 human breast cancer cells encapsulated within hydrogels highlight the detection of MMP activity both locally, at the sub-micron level, and within the bulk hydrogel. Our versatile platform may find use in a range of biological studies to explore questions in the dynamics of cancer metastasis, development, and tissue repair by providing high-resolution, quantitative and in situ readouts of local MMP activity within native tissue-like environments.

Anti-inflammatory and antiresorptive effects of acyl substitution chromone derivatives in experimental model of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting mainly small and major joints. The development for new drugs for the treatment of RAs is constantly underway, while the purposeful synthesis of multi-targeted small molecules can be considered a promising direction for the synthesis of new anti-rheumatic drugs.The aim. To evaluate the anti-inflammatory and antiresorptive effects of acyl substituted chromone derivatives in experimental animal model for rheumatoid arthritis.Materials and methods. RА was modeled in rats by injection of a suspension of human type II collagen and a complete Freunds adjuvant (in a ratio of 1:1) under plantar aponeurosis of the hind limb of the animal. The analyzed substances under ciphers X3A7 and X3A9 at a dose of 20 mg/kg and the reference drug dexamethasone at a dose of 3 mg/kg were administered intraperitoneally for 28 days from the moment of RA modeling. On the 7th, 14th, 21st and 28th days of the experiment, the severity of the clinical manifestations of RA was determined. After 28 days, changes in the content of cytokines in the rats blood serum were assessed: tumor necrosis factor-α (TNF-α), interleukins (IL-1, IL-6, IL-10 and IL-12). Changes of myeloperoxidase activity and concentrations of matrix metalloproteinases (MMPs) of type 2 and 9 were determined in synovial tissues.Results. During the study, it was shown that the use of the tested compounds X3A7 and X3A9, as well as the reference, contributed to a decrease in the severity of clinical manifestations of RA, starting from the 14th day of the experiment. Subsequently, it was demonstrated that in animals treated with dexamethasone, the cytokine content in blood serum decreased in relation to untreated animals: TNF-α – by 57.8% (p <0.05), IL-1 – 64.1% (p <0.05), IL-6 – 59.1% (p <0.05) and IL-12 – 72.3% (p <0.05), with an increase in the level of IL-10 – by 75.4% (p <0.05). The cytokine profile of the blood serum changed similarly when the studied compounds were administered to animals. It worth be noting that against the background of the administration of dexamethasone, X3A7 and X3A9 substances, the activity of myeloperoxidase decreased by 41.7 (p <0.05), 61.7 (p <0.05) and 65.0% (p <0.05), respectively, while the concentration of MMP2 decreased by 24.0 (p <0.05), 38.5 (p <0.05) and 34.4% (p <0.05), respectively, and MMP9 – by 13.5 (p <0.05), 37.9 (p <0.05) and 35.6% (p <0.05).Conclusion. The study showed that the administration of the analyzed chromone derivatives X3A7 and X3A9 suppresses inflammatory reactions and resorptive processes in synovial tissues, which can serve as a basis for their further study as antirheumatic agents.

Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs.

One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. There are many etiological environmental factors influencing the development of chronic venous insufficiency (CVI), although genetic factors and family history of the disease play a key role. All these factors induce changes in the hemodynamic in the venous system of the lower limbs leading to blood stasis, hypoxia, inflammation, oxidative stress, proteolytic activity of matrix metalloproteinases (MMPs), changes in microcirculation and, consequently, the remodeling of the venous wall. The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. Particular emphasis has been placed on describing the role of inflammation and oxidative stress and the involvement of extracellular hemoglobin as pathogenetic factors of VV. Additionally, active substances used in the treatment of VV were discussed.

Tobacco-derived and tobacco-free nicotine cause differential inflammatory cell influx and MMP-9 in mouse lung

BackgroundElectronic nicotine delivery systems (ENDS) or electronic cigarettes (e-cigarettes) aerosolize an e-liquid composed of propylene glycol (PG) and vegetable glycerin (VG) as humectants, flavoring chemicals, and nicotine. Nicotine naturally occurs in two isomers R- and S-nicotine, with tobacco-derived nicotine (TDN) composed of S-nicotine, and tobacco-free/synthetic nicotine (TFN) composed of a racemic mixture of R- and S-nicotine. Currently, there is limited knowledge of the potential differences in the toxicity of TFN versus TDN. We hypothesized that exposure of TFN and TDN salts to C57BL/6J mice would result in a differential response in lung inflammation and protease/ antiprotease imbalance.MethodsFive-week-old male and female C57BL/6J mice were exposed to air, PG/VG, PG/VG with TFN salts (TFN), or PG/VG with TDN salts (TDN) by nose-only exposure. Lung inflammatory cell counts, cytokine/chemokine levels, and matrix metalloproteinase (MMP) protein abundance and activity levels were determined by flow cytometry, ELISA, immunoblotting, and gel zymography, respectively.ResultsExposure to the humectants (PG/VG) alone increased cytokine levels- IL-6, KC, and MCP-1 in the BALF and KC levels in lung homogenate of exposed mice. While no change was observed in the cytokine levels in lung homogenate of TDN aerosol exposed mice, exposure to TFN aerosols resulted in an increase in KC levels in the lungs of these mice compared to air controls. Interestingly, exposure to TDN aerosols increased MMP-9 protein abundance in the lungs of female mice, while exposure to TFN aerosol showed no change. The metabolism of nicotine or the clearance of cotinine for TFN exposure may differ from that for TDN.ConclusionExposure to humectants, PG/VG alone, induces an inflammatory response in C57BL/6J mice. TFN and TDN salts show distinct changes in inflammatory responses and lung proteases on acute exposures. These data suggest variable toxicological profiles of the two forms of nicotine in vivo. Future work is thus warranted to delineate the harmful effects of synthetic/natural nicotine with humectants to determine the potential toxicological risks for users.

Effect of Nisin-based pretreatment solution on dentin bond strength, antibacterial property, and MMP activity of the adhesive interface

ObjectiveTo evaluate the effect of a Nisin-based dentin pretreatment solution on microtensile bond strength, antibacterial activity, and matrix metalloproteinase (MMP) activity of the adhesive interface. Materials and methods100 human molars were sectioned to expose dentin. The teeth were assigned to five groups (n = 20), according to the dentin pretreatment: 0.5%, 1.0%, or 1.5% Nisin; 0.12% chlorhexidine (positive control), and no solution (negative control), and divided into 2 subgroups: no aging, and thermomechanical aging. Specimens were etched with 37% H3PO4 for 15 s and submitted to the dentin pretreatment. Then, they were bonded with an adhesive (Adper Single Bond 2) and a resin composite for microtensile bond strength (μTBS) evaluation. Antibacterial activity against Streptococcus mutans was qualitatively examined using an agar diffusion test. Anti-MMP activity within hybrid layers was examined using in-situ zymography. Data were analyzed with two-factor ANOVA and post-hoc Tukey’s test (α = 0.050). ResultsFor μTBS, significant differences were identified for the factors “solutions” (p = 0.002), “aging” (p = 0.017), and interaction of the two factors (p = 0.002). In the absence of aging, higher μTBS was observed for the group 0.5% Nisin. In the presence of aging, all groups showed similar μTBS values. All Nisin concentrations were effective in inhibiting the growth of S. mutans. Endogenous MMP activity was more significantly inhibited using 0.5% and 1.0% Nisin (p < 0.050). Conclusion0.5% and 1.0% Nisin solutions do not adversely affect resin-dentin bond strength and exhibit a potential bactericidal effect against S. mutans. Both concentrations effectively reduce endogenous gelatinolytic activity within the hybrid layer. Clinical relevanceThe use of 0.5% and 1.0% Nisin solutions for dentin pretreatment potentially contributes to preserving the adhesive interface, increasing the longevity of composite restorations.

Engineered Multifunctional Zinc-Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery.

Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.

Transcriptional Profiling of Muscle in Females With Distal Radius Fracture and Functional Sarcopenia.

Skeletal muscle and bone interact with each other in mechanical and biochemical ways. This study aimed to investigate the molecular mechanisms of interaction between muscle and bone by analyzing the transcriptional profiles of total RNA from the muscle tissue of females with distal radius fractures. A total of 30 female participants (mean age 71.1 ± 8.9 years) with distal radius fractures were recruited. Participants were categorized into 2 groups: the NORM group consisted of participants with T score of the areal bone mineral density (aBMD) of the femoral neck higher than -1.0, handgrip strength greater than 18kg, and gait speed faster than 1.0 m/s (n = 10). Otherwise, participants with T score of the aBMD of the femoral neck equal to or less than -1.0, handgrip strength lower than 18kg, and gait speed slower than 1.0 m/s (n = 20) were categorized into EXP group. Pronator quadratus muscle samples were obtained from all participants. Total RNA was extracted from frozen muscle samples and sequenced. The gene ontology analysis demonstrated that the potential interactions between attached muscle function and the density of the associated bone would be linked with collagen biosynthetic activity and maintenance of extracellular matrix structures. The analysis of the pathway, network, and protein class exhibited that integrin signaling, inflammatory reactions, matrix metalloproteinase (MMP) activity, and extracellular matrix protein structure had possible associations with the molecular background of muscle-bone interaction. Through integrin signaling, MMP activity, inflammatory reactions, and collagen biosynthesis, muscle and bone may mutually interact with one another.

Acid challenge exacerbates activation of matrix metalloproteinases in permanent teeth undergoing radiotherapy.

The aim of this study was to investigate the effect of acid challenge on the activation of matrix metalloproteinases (MMPs) in the Dentinoenamel junction of primary and permanent teeth submitted to radiotherapy. For this purpose, a total of 178 dental fragments obtained from molars were used, and randomly divided into 2 groups (primary and permanent teeth) / 4 experimental subgroups (irradiated and non-irradiated, demineralized and non-demineralized). The fragments were exposed to radiation, with a dose fraction of 2 Gy, for 5 consecutive days, until a total dose of 60 Gy was reached, with a total of 30 cycles, for 6 weeks. To determine the activity of MMPs on the dentinoenamel junction (DEJ), in situ zymography assays on 0.6mm dental fragments were performed. To assess whether MMP activity would be impacted by an acidic environment, the fragments were placed in a demineralizing solution (pH of 4.8). The finding was that irradiation activated MMPs in DEJ and these effects were more evident in permanent when compared with primary teeth. When the effect of an acid challenge on MMPs activity was investigated, demineralization was observed not to increase MMPs activity in non-irradiated teeth, but it did increase MMPs activity in irradiated teeth. In conclusion, an acid challenge was found to exacerbate activation of MMPs in DEJ of permanent teeth submitted to irradiation, but not in primary teeth.

Glutamine Protects against Mouse Abdominal Aortic Aneurysm through Modulating VSMC Apoptosis and M1 Macrophage Activation.

Glutamine (Gln), known as the most abundant free amino acid, is widely spread in human body. In this study, we demonstrated the protective effects of glutamine against mouse abdominal aortic aneurysm (AAA) induced by both angiotensin II (AngII) and calcium phosphate (Ca3(PO4)2) in vivo, which was characterized with lower incidence of mouse AAA. Moreover, histomorphological staining visually presented more intact elastic fiber and less collagen deposition in abdominal aortas of mice treated by glutamine. Further, we found glutamine inhibited the excessive production of reactive oxide species (ROS), activity of matrix metalloproteinase (MMP), M1 macrophage activation, and apoptosis of vascular smooth muscle cells (VSMCs) in suprarenal abdominal aortas of mice, what's more, the high expressions of MMP-2 protein, MMP-9 protein, pro-apoptotic proteins, and IL-6 as well as TNF-α in protein and mRNA levels in cells treated by AngII were down-regulated by glutamine. Collectively, these results revealed that glutamine protected against mouse AAA through inhibiting apoptosis of VSMCs, M1 macrophage activation, oxidative stress, and extracellular matrix degradation.

Clinical and epidemiological implications of immune mechanisms in periodontitis

Periodontitis, considered a chronic inflammatory disease rather than a conventional bacterial infection, is characterized by a dysregulated immune response to the accumulation of bacterial biofilm in periodontal tissue. This inflammatory imbalance contributes to the loss of periodontal support and is influenced by factors such as unhealthy habits and systemic conditions. In Ecuador, the high prevalence of periodontal diseases reflects a significant problem, exacerbated by economic barriers, lack of access to adequate dental care and lack of knowledge about oral hygiene. The immune response to periodontitis involves both innate and adaptive immunity. Chronic inflammation, mediated by proinflammatory cytokines such as TNF-α and IL-1β, and the activity of matrix metalloproteinases (MMPs) are key determinants in the destruction of periodontal tissue. The interplay between microbial dysbiosis and inflammation reflects the need for therapeutic approaches that address both the control of bacterial biofilm and the modulation of the immune response. This study highlighted the complexity of periodontitis, underscoring the importance of strategies that integrate the understanding of chronic inflammation and the development of targeted therapies. The results indicated that personalization of treatment, based on individual profiles and specific biomarkers, influences the clinical outcomes of periodontal disease management. It is advisable to explore new technologies to effectively address this oral health challenge

Polydatin attenuated neuropathic pain and motor dysfunction following spinal cord injury in rats by employing its anti-inflammatory and antioxidant effects.

Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3mg/kg). Over 4weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function.

INPACT OF LAPONITE ON ENZYME ACTIVITY AND REDOX STATE OF THE TUMOR AND ORGANS OF THE DETOXIFICATION SYSTEM OF MICE WITH EhRLICH CARCINOMA

Summary. Laponite (Lap) is a synthetic clay mineral represented by disk-shaped nanoplatelets. The Lap (native or acid-activated) can be used for encapsulation of medical compounds, in particular anticancer drugs. Aim: to study the levels of the rate of superoxide radical (SR) generation, the activity of ribonucleases (RNases), gelatinases and ornithine decarboxylase (ODK) in tumor cells, liver and kidneys of intact mice and mice with Ehrlich carcinoma under the influence of Lap. Objects and methods: the purified gel-forming native Lap of the XLG class with the empirical formula Si8Mg5.45Li0.4H4O24Na0.7 was used. Acid activation of Lap (aLap samples) was done using sulfuric acid. The laboratory experiments were performed using outbred mice with transplanted Ehrlich carcinoma in ascites and solid forms. Determination of the rate of generation of SR was carried out by the method of electron paramagnetic resonance, RNases and matrix metalloproteinases activities were determined zymography in polyacrylamide gel, ODC activity was determined spectrophotometrically, statistical analysis of the results was performed using Student’s t-test. Results: the data on the rate of the superoxide generation and the activity of gelatinases in the liver tissue, the tumor tissue and the ascites fluid Ehrlich carcinoma were compared. The introducing of native Lap resulted in noticeable decrease in the rate of the superoxide generation in the liver tissue by 1.7 times as compared with the control group of mice, and in the ascites fluid by 1.5 times as compared with the mice group without Lap. Moreover, introducing of native Lap resulted in the decrease of the gelatinases activity by 2.4 times in the ascites fluid and 1.9 times in the solid Ehrlich carcinoma tissue. The less significant effects were observed for samples with incorporated aLap. No significant difference was found between the indicators of RNase and ODC activities under the influence of native Lap and aLap in intact and tumour-bearing mice. Conclusion: in a model experiment on outbred mice with Ehrlich carcinoma, it was determined that native Lap and aLap do not significantly affect the indicators of the redox state, the activity of RNases, gelatinases and ODC in tumor cells, liver and kidneys. It indicates the safety of using of these nanoplatelets for assistance of anticancer drug delivery.

Inhibitory effect of microRNA-21 on pathways and mechanisms involved in cardiac fibrosis development.

Cardiac fibrosis is a pivotal cardiovascular disease (CVD) process and represents a notable health concern worldwide. While the complex mechanisms underlying CVD have been widely investigated, recent research has highlighted microRNA-21's (miR-21) role in cardiac fibrosis pathogenesis. In this narrative review, we explore the molecular interactions, focusing on the role of miR-21 in contributing to cardiac fibrosis. Various signaling pathways, such as the RAAS, TGF-β, IL-6, IL-1, ERK, PI3K-Akt, and PTEN pathways, besides dysregulation in fibroblast activity, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs cause cardiac fibrosis. Besides, miR-21 in growth factor secretion, apoptosis, and endothelial-to-mesenchymal transition play crucial roles. miR-21 capacity regulatory function presents promising insights for cardiac fibrosis. Moreover, this review discusses numerous approaches to control miR-21 expression, including antisense oligonucleotides, anti-miR-21 compounds, and Notch signaling modulation, all novel methods of cardiac fibrosis inhibition. In summary, this narrative review aims to assess the molecular mechanisms of cardiac fibrosis and its essential miR-21 function.

A porcine model of thoracic aortic aneurysms created with a retrievable drug infusion stent graft mirrors human aneurysm pathophysiology

ObjectiveAneurysm pathophysiology remains poorly understood, in part from the disparity of murine models with human physiology and the requirement for invasive aortic exposure to apply agents used to create aneurysm models. A retrievable drug infusion stent graft (RDIS) was developed to isolate the aortic wall intraluminally for drug exposure. We hypothesized that an RDIS could deliver aneurysm-promoting enzymes to create a porcine model of thoracic aneurysms without major surgical exposure. MethodsRetrievable nitinol stent graft frames were designed with an isolated drug delivery chamber, covered with polytetrafluoroethylene, and connected to a delivery wire with a drug infusion catheter installed to the outer chamber. Institutional Animal Care and Use Committee-approved Yorkshire pigs (n = 5) underwent percutaneous access of the femoral artery, baseline aortogram and stent placement in the thoracic aorta followed by 30-minute exposure to a cocktail of elastase, collagenase, and trypsin. After aspiration of excess drug, stent retrieval, and femoral artery repair, animals were recovered, with angiograms at 1 and 4 weeks followed by explant. Histological analysis, in situ zymography, and multiplex cytokine assays were performed. ResultsThe RDIS isolated a segment of anterior aorta angiographically, while the center lumen preserved distal perfusion during drug treatment (baseline femoral mean arterial pressure, 70 ± 14 mm Hg; after RDIS, 75 ± 12; P = .55). Endovascular induction of thoracic aneurysms did not require prior mechanical injury and animals revealed no evidence of toxicity. Within 1 week, significant aneurysmal growth was observed in all five animals (1.4 ± 0.1 cm baseline to 2.9 ± 0.7 cm; P = .002) and only within the treated region of the aorta. Aneurysms persisted out to 4 weeks. Aneurysm histology demonstrated loss of elastin and collagen that was otherwise preserved in untreated aorta. Proinflammatory cytokines and increased matrix metalloproteinase activity were increased significantly within the aneurysm. ConclusionsAn RDIS achieves isolated drug delivery while preserving distal perfusion to achieve an endovascular porcine model of thoracic aneurysms without major surgery. This model may have value for surgical training, device testing, and to better understand aneurysm pathogenesis. Most important, although the RDIS was used to simulate aortic pathology, this tool offers intriguing horizons for focused therapeutic drug delivery directly to aneurysms and, more broadly, focused locoregional drug delivery to vessels and vascular beds.

THE PARTICULARITY PLASTIC CLOSURE OF WOUND DEFECTS IN PATIENTS WITH CHRONIC DIABETIC WOUNDS

Background. Chronic diabetic foot wounds and ulcers are serious complications of the course of diabetes mellitus (DM), which account for 85% of purulent-necrotic lesions of the lower extremities. Pathogenetic mechanisms of "chronization" of wounds in the form of hyperglycemia, neuropathy, and existing infection lead to metabolic disorders in the form of tissue hypoxia and activation of matrix metalloproteinase (MMP) proteolytic enzymes.&#x0D; Aim: to study the role of autologous plasminogen on healing processes in diabetic wounds by modulating MMP activity.&#x0D; Materials and methods. 45 patients with chronic diabetic wounds, who were divided into 2 groups, participated in the study. Patients of the control group (n=25) were treated according to standard methods. Autologous plasminogen applications were used for treatment in 20 patients of the main group.&#x0D; Results. On the 18th day of treatment, a 3.5-fold decrease in the activity of MMP-2,-9 and complete healing of wounds was noted in 16 patients. In 4 patients, the wound defects were closed by the method of autodermoplasty with complete engraftment of grafts. In the patients of the control group, the level of MMP activity remained stably high throughout the observation period.&#x0D; Conclusions. The use of applications of autologous plasminogen allows to modulate the activity of MMP and create favorable conditions for the healing of chronic diabetic wounds.

A research on the pathological mechanisms of aortic dissection

In this paper, the main content is to investigate which experimental methods are needed in the study of the case mechanism of aortic dissection and how to analyze the results by analyzing the experimental methods. The researchers used RNA sequencing, ChIP-Seq technology, transcription factor prediction, the dual-luciferase reporter assay, immunohistochemical staining, immunofluorescent staining, matrix metalloproteinases (MMP) activity staining, western blot and statistical analysis. The researchers used quantitative RT-PCR, In-Gel zymography, oxidant measurement by dihydroethidium, and flow cytometric analysis of inflammatory cells.

Matrix metalloproteinases system profile analysis and their endogenous inhibitors in children with periodontal diseases and various dysplasia phenotypes

Relevance. The search and development of modern non-invasive methods for early periodontal disease detection are of scientific and practical value for a personalized approach to disease course prognosis and explaining the choice of treatment tactics. Morphological immaturity, high intensity of anabolic processes, functional failure of neurohumoral, endocrine and immunological defence systems combined with an imbalance between the synthesis and degradation of extracellular matrix components in children with undifferentiated connective tissue disease (UCTD) significantly increases the risk of developing periodontal diseases. The available data on the activity of salivary matrix metalloproteinases (MMPs), which play a leading role in regulating connective tissue protein metabolism and bone remodelling mechanisms in children with UCTD of various degrees, are scarce and require further study.Purpose. The study aimed to explain the clinical, diagnostic and prognostic value of MMPs as markers of inflammatory periodontal diseases in children with UC TD and dysplastic disorders of various se verity.Material and methods. The study included 67 children with UCTD (main group) and 34 children of health groups I and II (comparison group) aged 12-17. The UCTD severity was established according to the diagnostic criteria by L. N. Abbakumova (2006) and a scale for assessing the significance of phenotypic and visceral signs. The main group was divided into two subgroups: Subgroup 1 (n = 38) – children with mild and moderate UCTD; Subgroup 2 (n=29) – children with severe UCTD. The studied groups had their periodontal status assessed, as well as the concentration of MMP-1, MMP-2, MMP-8, MMP-9 and their tissue inhibitors (TIMP-1, TIMP-2) in the oral fluid identified using the enzyme immunoassay, along with calculation done for the MMP ⁄ TIMP coefficients that set a balance between the degradation and synthesis of collagen.Results. The children with phenotypic signs of UCTD in the oral fluid appeared to show a statistically significant increase in the MMP-1, MMP-2, MMP-8, and MMP-9 levels and an imbalanced ratio in MMP-1⁄TIMP-1, MMP- 2⁄TIMP-2, MMP-8⁄TIMP-1, MMP-9⁄TIMP-1, compared with health groups I, II. An increase in the MMP-1, MMP-2, and MMP-8 concentrations, along with dominating expression of MMP-9 over TIMP-1 in the oral fluid of children of Subgroup 2, causes an increase in intensity and prevalence of periodontal diseases compared to the patients in Sub-group 1 and comparison group.Conclusion. Thus, when children with UCTD don’t demonstrate an increase in specific tissue inhibitors TIMP-1 and TIMP-2 in their oral fluid, along with an increase in the levels of the respective matrixins is the key pathogenetic factor in the degradation of extracellular matrix proteins, which causes a depressing impact on the proliferative activity in the periodontal set of tissues.

Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.