Production Of Matrix Metalloproteinases Research Articles

Dextran sulfate-based MMP-2 enzyme-sensitive SR-A receptor targeting nanomicelles for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an ordinarily occurring autoimmune disease with systemic inflammatory. Targeted drug delivery systems have many successful applications in the treatment of rheumatoid arthritis. In order to develop nanoparticles for targeted delivery of Celastrol (Cel) to rheumatoid arthritis and specific drug release, the dextran sulfate (DS) was modified as the targeting molecular by binding to the scavenger receptor of macrophage. The dextran-sulfate-PVGLIG-celastrol (DS-PVGLIG-Cel), named DPC, amphiphilic polymeric prodrug was synthesized and characterized. The resulting DPC@Cel micelles had the average size of 189.9 nm. Moreover, the micelles had ultrahigh entrapment efficiency (about 44.04%) and zeta potential of −11.91 mV. In the in vitro release study, due to the excessive production of matrix metalloproteinase-2 (MMP-2) at the inflammatory joint, the MMP-2 reactive peptide was used to crack in the inflammatory microenvironment to accelerate the release of Cel. The results have shown that the nanoparticles can effectively deliver Cel to activated macrophages and significantly improve the bioavailability. In vivo experiments showed that DPC@Cel have better anti-rheumatoid arthritis effects and lower systemic toxicity than free Cel. This study provided a new therapeutic strategy for the treatment of RA.

Pro-inflammatory mediators released by activated monocytes promote aortic valve fibrocalcific activity

BackgroundCalcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Valvular fibrocalcification is a characteristic pathological change. In diseased valves, monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities. However, the impact of activated monocytes on valular fibrocalcification remains unclear. We tested the hypothesis that pro-inflammatory mediators from activated monocytes elevate AVIC fibrogenic and osteogenic activities.Methods and resultsPicro-sirius red staining and Alizarin red staining revealed collagen and calcium depositions in cultured human AVICs exposed to conditioned media derived from Pam3CSK4-stimulated monocytes (Pam3 CM). Pam3 CM up-regulated alkaline phosphatase (ALP), an osteogenic biomarker, and extracellular matrix proteins collagen I and matrix metalloproteinase-2 (MMP-2). ELISA analysis identified high levels of RANTES and TNF-α in Pam3 CM. Neutralizing RANTES in the Pam3 CM reduced its effect on collagen I and MMP-2 production in AVICs while neutralizing TNF-α attenuated the effect on AVIC ALP production. In addition, Pam3 CM induced NF-κB and JNK activation. While JNK mediated the effect of Pam3 CM on collagen I and MMP-2 production, NF-κB was critical for the effect of Pam3 CM on ALP production in AVICs.ConclusionsThis study demonstrates that activated monocytes elevate the fibrogenic and osteogenic activities in human AVICs through a paracrine mechanism. TNF-α and RANTES mediate the pro-fibrogenic effect of activated monocytes on AVICs through activation of JNK, and TNF-α also activates NF-κB to elevate AVIC osteogenic activity. The results suggest that infiltrated monocytes elevate AVIC fibrocalcific activity to promote CAVD progression.

Кристаліндукований остеоартрит: роль кристалів основного фосфату кальцію

Кристали основних фосфатів кальцію вже давно асоціюються з патогенезом остеоартриту. Основні фосфати кальцію з великою частотою визначаються в синовіальній рідині і суглобовому хрящі при цьому захворюванні. У той час як осадження основних фосфатів кальцію розглядається багатьма вченими як наслідок прогресуючого перебігу остеоартриту, з’явилися суттєві докази того, що ці кристали можуть виступати активними патогенними медіаторами остеоартриту. «Кристали основних фосфатів кальцію» — загальний термін для опису декількох видів фосфатів кальцію, у тому числі карбонатапатиту, гідроксиапатиту, три- і октакальцієвих фосфатів, кристалів вітлокіта магнію. Кристали основних фосфатів кальцію патогенетично пов’язані з остеоартритом, кальцинуючим тендинітом, гострим кристалічним артритом та атеросклерозом. Кристали кальцію визначаються в синовіальній рідині в 65 % випадків остеоартриту колінного суглоба, вони з високою частотою виявляються в гіаліновому хрящі при остеоартриті, а також у 100 % пацієнтів у суглобовому хрящі при проведенні операції тотального ендопротезування. Кристали основних фосфатів кальцію також були виявлені в синовіальній рідині та синовіальній мембрані пацієнтів із легким, помірним і тяжким ураженням колінного суглоба при артроскопії. Основні фосфати кальцію проявляють множинні біологічні ефекти in vitro, у тому числi здатність стимулювати мітогенез, продукцію простагландинів, цитокінів і матриксних металопротеїназ у різних типах клітин, включаючи синовіоцити, хондроцити і макрофаги. Кристали основних фосфатів кальцію також обумовлюють запалення при остеоартриті шляхом прямої взаємодії з вродженою імунною системою. У цьому огляді обговорюються останні досягнення в цій галузі і підбиваються підсумки сучасного розуміння ролі кристалів основних фосфатів кальцію в патогенезі остеоартриту. Погляди на роль кристалів основних фосфатів кальцію в патогенезі остеоартриту продовжують розширюватися, проте вже сьогодні існує достатньо експериментальних і клінічних доказів найважливішої ролі кальційумісних кристалів у розвитку цього захворювання і прогресуючій дегенерації суглобового хряща.

Characterization of stilbenes, in vitro antioxidant and cellular anti-photoaging activities of seed coat extracts from 18 Paeonia species

Paeonia is famous as ornamental, medicinal plant, and edible oil crop in China. The seeds of peonies are rich in unsaturated fatty acids, monoterpene glycosides, sterols and stilbenes which have antioxidant and anti-inflammatory effects, etc. In this study, the composition and content of stilbenes in the seed coat extracts (SCE) from 50 populations of 18 species and two subspecies of Paeonia were determined by high performance liquid chromatography - diode array detection (HPLC-DAD). The results showed that the composition and content of stilbenes, especially suffruticosol B and gnetin H, differed significantly between Paeonia species, while there were small differences between populations of the same species. All the samples were clustered into two groups according to the stilbenes in SCE. The difference between the two groups was mainly reflected in the content of suffruticosol B and gnetin H. Furthermore, all samples showed high antioxidant activity, which was significantly positively correlated with the total polyphenol content. The SCE of P. anomala and P. lactiflora at different concentrations could effectively inhibit the production of matrix metalloproteinase − 1 (MMP-1) in keratinocytes, and then achieve the effect of inhibiting cell aging. This study provided a valuable reference for the value-added utilization of Paeonia seed coat.

Platelet-rich plasma inhibits inflammation, apoptosis, and the NLRP3/Caspase-1 pathway and induces matrix metalloproteinases and proliferation of IL-1β-induced articular chondrocytes by downregulating T-box transcription factor 3

ObjectivesOsteoarthritis (OA) is a chronic joint disease characterized by osteoproliferation and the degeneration and destruction of articular cartilage. Platelet-rich plasma (PRP) is rich in various growth factors that have been reported to promote bone defect repair. This study examined the specific role and mechanism of PRP in OA.MethodsOA model cells were created by treating articular chondrocytes with IL-1β. After treatment of the model cells with PRP or/and a T-box transcription factor 3 (TBX3)-overexpression plasmid, TBX3 expression was monitored via RT-qPCR, western blotting, and immunofluorescence assays. IL-1β, IL-33, and Caspase-3 levels were detected with ELISA kits. Levels of NLRP3, Caspase-1, MMP9, MMP13, and COL2A1 expression were evaluated by western blotting, and cell proliferation was assessed by the CCK-8 assay.ResultsOur results showed that TBX3 expression was upregulated in IL-1β-induced articular chondrocytes. IL-1β stimulation induced inflammation and the production of matrix metalloproteinases, activated Caspase-3 and the NLRP3/Caspase-1 pathway, inhibited the proliferation of articular chondrocytes; however, all those affects mediated by IL-1β could be markedly reversed by PRP. We also found that PRP alleviated IL-1β-induced inflammation, apoptosis, and extracellular matrix degradation in articular chondrocytes by inhibiting TBX3. Our findings suggest that PRP alleviates OA progression in vitro by downregulating TBX3.ConclusionPRP suppressed OA progression in vitro by inhibiting TBX3, which may be its mechanism of action in treating OA.

The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia

BackgroundGenes involved in lung development may become dysregulated in adult life and contribute to the pathogenesis of lung diseases. Multiple genes regulate lung development, including Forkhead box protein P1-4 (FoxP1-4).MethodsWe examined the association between variants in the FoxP1-4 genes and lung function using data from a GWAS that included close to 400,000 individuals and 20 million SNPs.ResultsMore than 100 variants in the FoxP1 gene, but none in the FoxP2-4 genes, are associated with lung function. The sentinel variant in the FoxP1 gene associated with FEV1 was rs1499894 (C > T), while the sentinel variant in the FoxP1 gene associated with FVC was rs35480566 (A > G). Those with the T allele instead of the C allele for rs1499894, or the G allele instead of the A allele for rs35480566 had increased FoxP1 mRNA levels in transcriptomic data, higher FEV1 and FVC, and reduced odds of being diagnosed with idiopathic pulmonary fibrosis. Further, knockdown of FoxP1 in lung epithelial cells by RNA interference led to increased mRNA levels for matrix metalloproteinases 1, 2, 3 and pro-inflammatory cytokines IL-6 & IL-8, as well as reduced cell viability after exposure to cigarette smoke—all processes implicated in the pathogenesis of COPD and IPF.ConclusionsOur results suggest that the protein encoded by the FoxP1 gene may protect against the development of COPD and IPF. A causal role for FoxP1 in the pathogenesis of COPD and IPF may warrant further investigation, and FoxP1 may be a novel therapeutic target for these lung disorders.

Роль нейровоспаления в патогенезе глаукомной оптической нейропатии

This article reviews recent studies on the etiology and pathogenesis of primary open-angle glaucoma (POAG). POAG is now considered a neurodegenerative disease associated with neuroinflammation. Neuroglia plays a key role in the development of neuroinflammation. In impaired homeostasis, microglia is activated to prevent retinal alterations triggered by glutamate excitotoxicity. Macrophages, being still active, release cytokines in the extracellular space and produce matrix metalloproteinases. The result is an increased degradation of collagen fibers of the lamina cribrosa and development of glaucomatous optic neuropathy. Macroglia (astrocytes and Muller cells) are also involved in retinal immunoregulation. Astrocytes produce neurotrophic brain factor which promote the survival of damaged neurons. Additionally, these cells secrete fibrillar proteins that regenerate the extracellular matrix but form a glial scar, thereby inhibiting axonal transport and limiting the regeneration of damaged axons. The activation of microglia and macroglia in glaucoma precedes the loss of retinal ganglion cells. Determining the activity of retinal ganglion cells helps identify specific biomarkers of early glaucoma. Early diagnosis of POAG prevents irreversible damage. The authors discuss potential ways to regulate the activity of glia by stimulating the release of neurotrophic factors and suppressing glia hyperactivity. Keywords: primary open-angle glaucoma, neurodegenerative disease, neuroinflammation, macroglia, microglia, neurotrophic factors. For citation: Egorov E.A., Korelina V.E., Cherednichenko D.V., Gazizova I.R. Role of neuroinflammation in the pathogenesis of glaucomatous optic neuropathy. Russian Journal of Clinical Ophthalmology. 2022;22(2):116–121 (in Russ.). DOI: 10.32364/2311-7729-2022-22-2-116-121

Dieckol Inhibits the Effects of Particulate Matter 10 on Sebocytes, Outer Root Sheath Cells, and Cutibacterium Acnes-Pretreated Mice.

BackgroundParticulate matter (PM) is an air pollutant that can impair the human skin. Antioxidants have been tested to improve PM-induced skin inflammation.ObjectiveIn this study, we investigated the effects of dieckol on PM-induced inflammation on cultured human sebocytes, outer root sheath (ORS) cells, and mice pretreated with Cutibacterium acnes.MethodsWe cultured and treated the sebocytes and ORS cells with 5 µM of dieckol and 100 µg/ml of PM10 for 24 h. The C. acnes-pretreated mice received 5 µM of dieckol and 100 µg/ml of PM10. We measured cell viability using MTT assay. Real-time PCR and measurement of reactive oxygen species (ROS) and sebum production analyzed the effects.ResultsDieckol inhibited the upregulation of the gene expression of the inflammatory cytokines, matrix metalloproteinase (MMP), aryl hydrocarbon receptor, and nuclear factor kappa-light-chain-enhancer of activated B cells by PM10 in the cultured sebocytes and ORS cells and inhibited an increase in ROS production by PM10 in the cultured sebocytes. In addition, dieckol decreased the inflammatory cytokines, MMP, and sebum production in C. acnes-pretreated mice.ConclusionDieckol effectively reduced the expression of inflammatory biomarkers and the production of sebum in cultured sebocytes, ORS cells, and C. acnes-pretreated mice.

Polygonatum sibiricum polysaccharide inhibits IL-1β-induced inflammation in human chondrocytes

Osteoarthritis (OA) is a degenerative joint disease associated with inflammation. Polygonatum sibiricum polysaccharide (PSP) is a major group of active components isolated from Polygonatum sibiricum with broad activities including anti-inflammatory effect. However, the role of PSP in OA is unclear. In the present study, we aimed to investigate the effects of PSP on IL-1β-induced inflammatory response in primary human OA chondrocytes. The results showed that PSP improved cell viability of chondrocytes in response to IL-1β induction. The increased levels of several inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in IL-1β-induced chondrocytes were attenuated by PSP in a dose-dependent manner. The IL-1β-induced production of pro-inflammatory cytokines, TNF-α and IL-6, were mitigated by PSP in chondrocytes. Besides, PSP also suppressed the production of matrix metalloproteinases (MMPs), including MMP-1, MMP-3 and MMP-13 in IL-1β-stimulated chondrocytes. Furthermore, the IL-1β-induced activation of NF-κB signaling pathway in chondrocytes was also prevented by PSP. These findings suggested that PSP alleviated IL-1β-induced inflammatory response in chondrocytes via inhibiting NF-κB signaling pathway.

Aqueous Extracts of Pleurotus ostreatus and Hericium erinaceus Protect against Ultraviolet A-Induced Damage in Human Dermal Fibroblasts.

Pleurotus ostreatus (PO) and Hericium erinaceus (HE) have been traditionally used to treat various diseases, owing to their antioxidant, antimicrobial, neuroprotective, and antitumor effects. However, few studies have been reported on their antiaging effects. In this study, the antioxidant and antiaging activities of PO and HE aqueous extracts were investigated in ultraviolet A (UVA)-induced human dermal fibroblast cells (HDFs). The antioxidant properties of PO and HE aqueous extracts were measured by total polyphenol and ergothioneine content, and their antioxidant activity was analyzed with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical-scavenging assays. To demonstrate the antiaging effect of PO and HE aqueous extracts in UVA-induced HDFs, the secretion and mRNA expression of matrix metalloproteinase-1 (MMP-1), procollagen type I (PC1), and elastase were assessed by enzyme-linked immunosorbent assay (ELISA) and real-time PCR, respectively. The total polyphenol content in each extract was 13.6 and 11.7 mg gallic acid equivalents/g dry weight (DW), respectively, and the total ergothioneine content in each extract was 3.43 and 2.18 mg/g DW, respectively. The PO and HE extracts increased DPPH and ABTS radical-scavenging activity in a dose-dependent manner. In UVA-damaged HDFs, the extracts increased PC1 production but decreased MMP-1 production and elastase-1 activity. Furthermore, the mRNA levels of PC1, MMP-1, and elastase were recovered in the PO- and HE-treated UVA-irradiated HDFs compared to those in the irradiated control group. PO and HE aqueous extracts may be potentially used as a promising antiphotoaging agent.

CD147 Levels in Blood and Adipose Tissues Correlate with Vascular Dysfunction in Obese Diabetic Adults.

CD147 is a glycoprotein that stimulates the production of matrix metalloproteinases (MMPs), known contributors to cardiovascular risk. The activity of CD147 protein depends on its glycosylation. However, it is unclear whether CD147 protein expression or glycosylation are influenced by the diabetic milieu characterized by hyperglycemia and abundant glycation-end-products (AGEs). We examined the circulating and visceral adipose tissue (VAT) levels of CD147 and their correlation with vascular function in obese, obese diabetic, and non-obese controls (n = 40, each). The circulating levels of CD147 and the glycosylated CD147 protein in VAT were considerably higher in obese, particularly obese diabetic subjects compared to controls. Obese diabetics had the lowest brachial and arteriolar vasoreactivity and the highest carotid pulse-wave velocity (PWV, a measure of arterial stiffness) among the three groups. CD147 correlated positively with body mass index (BMI), total and visceral fat mass, PWV, and plasma levels of glucose, insulin, MMPs, and AGEs and negatively with brachial artery and VAT-arteriolar vasoreactivity and nitric oxide production. Multivariate regression revealed that BMI, body fat mass, insulin, and glucose levels significantly predicted CD147. Our data suggest that higher levels of CD147 in obese subjects, particularly those with diabetes, are linked to vascular dysfunction and several cardiometabolic risk factors.

Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues.

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.

The Protective Effect of Carotenoids, Polyphenols, and Estradiol on Dermal Fibroblasts under Oxidative Stress.

Skin ageing is influenced by several factors including environmental exposure and hormonal changes. Reactive oxygen species (ROS), which mediate many of the effects of these factors, induce inflammatory processes in the skin and increase the production of matrix metalloproteinases (MMPs) in dermal fibroblasts, which leads to collagen degradation. Several studies have shown the protective role of estrogens and a diet rich in fruits and vegetables on skin physiology. Previous studies have shown that dietary carotenoids and polyphenols activate the cell’s antioxidant defense system by increasing antioxidant response element/Nrf2 (ARE/Nrf2) transcriptional activity and reducing the inflammatory response. The aim of the current study was to examine the protective effect of such dietary-derived compounds and estradiol on dermal fibroblasts under oxidative stress induced by H2O2. Human dermal fibroblasts were used to study the effect of H2O2 on cell number and apoptosis, MMP-1, and pro-collagen secretion as markers of skin damage. Treatment of cells with H2O2 led to cell death, increased secretion of MMP-1, and decreased pro-collagen secretion. Pre-treatment with tomato and rosemary extracts, and with estradiol, reversed the effects of the oxidative stress. This was associated with a reduction in intracellular ROS levels, probably through the measured increased activity of ARE/Nrf2. Conclusions: This study indicates that carotenoids, polyphenols, and estradiol protect dermal fibroblasts from oxidative stress-induced damage through a reduction in ROS levels.

A Practical Approach for the In Vitro Safety and Efficacy Assessment of an Anti-Ageing Cosmetic Cream Enriched with Functional Compounds

(1) Background: Cosmeceuticals are topical products applied to human skin to prevent skin ageing and maintain a healthy skin appearance. Their effectiveness is closely linked to the compounds present in a final formulation. In this article, we propose a panel of in vitro tests to support the efficacy assessment of an anti-ageing cream enriched with functional compounds. (2) Methods: biocompatibility and the irritant effect were evaluated on reconstructed human epidermis (RHE) and corneal epithelium (HCE) 3D models. After a preliminary MTT assay, normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) were used to evaluate the extracellular matrix (ECM) protein synthesis, and interleukin-6 (IL-6) and metalloproteinase-1 (MMP-1) production. (3) Results: data collected showed good biocompatibility and demonstrated the absence of the irritant effect in both 3D models. Therefore, we demonstrated a statistical increase in collagen and elastin productions in NHDF cells. In HaCaT cells, we highlighted an anti-inflammatory effect through a reduction in IL-6 levels in inflammatory stimulated conditions. Moreover, the reduction of MMP-1 production after UV-B radiation was demonstrated, showing significant photo-protection. (4) Conclusion: a multiple in vitro assays approach is proposed for the valid and practical assessment of the anti-ageing protection, anti-inflammatory and biocompatible claims that can be assigned to a cosmetic product containing functional compounds.

Angiopoietin-like protein 2 deficiency promotes periodontal inflammation and alveolar bone loss.

Human periodontitis is a highly prevalent inflammatory disease that leads to connective tissue degradation, alveolar bone resorption, and tooth loss. Angiopoietin-like 2 (ANGPTL2) regulates chronic inflammation in various diseases and is functionally involved in maintaining tissue homeostasis and promoting tissue regeneration, but there is limited information about its function in periodontitis. Here we investigated the expression and explicit role of ANGPTL2 in periodontitis. Immunohistochemistry and quantitative real-time PCR (qRT-PCR) were used to detect the ANGPTL2 expression in periodontal tissues and periodontal ligament cells (PDLCs). A ligature-induced periodontitis model was generated in wild-type and ANGPTL2 knockout mice. qRT-PCR and enzyme-linked immunosorbent assay were used to assess the production of inflammatory cytokines and matrix metalloproteinases (MMPs) in cultured PDLCs. Western blot was performed to detect proteins in relevant signaling pathways. Increased ANGPTL2 expression was observed in inflamed periodontal tissues and PDLCs. ANGPTL2 deficiency promoted alveolar bone loss with enhanced osteoclastogenesis and inflammatory reactions in ligature-induced periodontitis. Downregulation of ANGPTL2 remarkably enhanced expression levels of interleukin (IL)-6, IL-8, MMP1, and MMP13 in Porphyromonas gingivalis lipopolysaccharide-induced PDLCs, whereas ANGPTL2-overexpressing PDLCs showed opposite trends. ANGPTL2 downregulation activated STAT3 and nuclear factor-κB pathways and blocked Akt signaling under inflammatory environment. Treatment with a STAT3 inhibitor partially suppressed the inflammatory reaction of PDLCs mediated by ANGPTL2 knockdown. Our study provides the first evidence of an anti-inflammatory effect of ANGPTL2 in murine periodontitis. The findings demonstrate the critical and protective role of ANGPTL2 in alveolar bone loss and periodontal inflammation.

Eisenia bicyclis Extract Repairs UVB-Induced Skin Photoaging In Vitro and In Vivo: Photoprotective Effects.

Chronic exposure to ultraviolet B (UVB) is a major cause of skin aging. The aim of the present study was to determine the photoprotective effect of a 30% ethanol extract of Eisenia bicyclis (Kjellman) Setchell (EEB) against UVB-induced skin aging. By treating human dermal fibroblasts (Hs68) with EEB after UVB irradiation, we found that EEB had a cytoprotective effect. EEB treatment significantly decreased UVB-induced matrix metalloproteinase-1 (MMP-1) production by suppressing the activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling and enhancing the protein expression of tissue inhibitors of metalloproteinases (TIMPs). EEB was also found to recover the UVB-induced degradation of pro-collagen by upregulating Smad signaling. Moreover, EEB increased the mRNA expression of filaggrin, involucrin, and loricrin in UVB-irradiated human epidermal keratinocytes (HaCaT). EEB decreased UVB-induced reactive oxygen species (ROS) generation by upregulating glutathione peroxidase 1 (GPx1) and heme oxygenase-1 (HO-1) expression via nuclear factor erythroid-2-related factor 2 (Nrf2) activation in Hs68 cells. In a UVB-induced HR-1 hairless mouse model, the oral administration of EEB mitigated photoaging lesions including wrinkle formation, skin thickness, and skin dryness by downregulating MMP-1 production and upregulating the expression of pro-collagen type I alpha 1 chain (pro-COL1A1). Collectively, our findings revealed that EEB prevents UVB-induced skin damage by regulating MMP-1 and pro-collagen type I production through MAPK/AP-1 and Smad pathways.

Photoprotective Effect of Artemisia sieversiana Ehrhart Essential Oil Against UVB-induced Photoaging in Mice.

Photoaging refers to the extrinsic aging resulting from ultraviolet (UV) irradiation, which impacts skin appearance and is accompanied by the risk of skin carcinoma. Developing natural products as photoprotective agents is of great interest in cosmetic industry nowadays. The present study aimed at investigating the possible use of Artemisia sieversiana Ehrhart essential oil (AEO) for the prevention of photoaging induced by UVB. AEO was characterized by chamazulene, which accounted for 38.92% among total 51 identified compounds. In invitro assays, AEO was found to be a moderate antioxidant and good UVB filter with photostability. A UVB-induced photoaging mice model was established with three AEO formulations (0.1%, 0.5% and 1.5%, w/w) topically applied prior to UVB irradiation. The activities of catalase, particularly superoxide dismutase of skin increased, while malondialdehyde content decreased in AEO groups as compared with model controls. The production of matrix metalloproteinases (MMP-1 and MMP-3) and depletion of hydroxyproline in skin were inhibited by AEO in a dose-dependent manner. Histological evaluation indicated that AEO decreased epidermal thickness, inflammatory cell infiltration, collagen degradation and elastin aberrance. These findings indicated that AEO could be a promising sunscreen agent in protecting the skin against photoaging.

Abstract 10777: Circulating and Adipose Tissue Levels of CD147 Are Linked to Vascular Dysfunction in Obese Diabetic Adults

Background: Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) is a transmembrane glycoprotein that stimulates the production of matrix metalloproteinases (MMPs). These MMPs mediate vascular remodeling and are considered biomarkers for cardiovascular risk. The activity of CD147 depends mainly on its glycosylation, which varies significantly among different conditions. However, it is unclear if CD147 glycosylation or its role in MMP upregulation is influenced by the diabetic milieu characterized by high glucose levels and abundant glycation end products (AGEs). In this study, we sought to investigate the differential expression and glycosylation levels of CD147 in obese, diabetic (OB-T2D) individuals compared to non-OB controls. Methods: Blood and adipose tissue (AT) samples were obtained from OB-T2D individuals and controls (n=40, each). DEXA scanning was used for body composition analyses. Flow-induced dilation (FID) was assessed in vivo in the brachial artery and ex vivo in AT-isolated arterioles. Other cardiometabolic risk factors related to glucose and lipid metabolism and systemic inflammation were measured. Results: Circulating CD147 was considerably greater in OB individuals, mirroring the glycosylated CD147 and the N-acetylglucosaminyltransferase, MGAT5 protein levels in the AT. Within the OB-T2D group, AT and circulating CD147 correlated with higher body mass index, total and visceral fat percentage, fasting plasma glucose and insulin, insulin resistance measurement (HOMA-IR), glycosylated hemoglobin, systolic BP, and plasma levels of MMP2/9, AGEs (Carboxymethyl lysine and methyl-glyoxal-lysine dimer), C-reactive protein, interleukin 6, and tumor necrosis factor-alpha. AT-arteriolar FID was significantly lower in the OB-T2D individuals across all pressure gradients, while carotid pulse wave velocity (PWV) was higher, indicating arterial stiffness. CD147 correlated negatively with brachial artery and AT-arteriolar FID and flow-induced nitric oxide production and positively with PWV. Conclusion: Our findings imply that vascular dysfunction in OB-T2D patients is linked to higher levels of CD147 and its glycosylated fraction, which in turn is associated with other cardiometabolic risk factors.

LncRNA MIR31HG is induced by tocilizumab and ameliorates rheumatoid arthritis fibroblast-like synoviocyte-mediated inflammation via miR-214-PTEN-AKT signaling pathway.

Fibroblast-like synoviocytes (FLS) obtained from the joint synovium of rheumatoid arthritis (RA) patients exhibit hyperplasia and aggressive inflammatory phenotypes. This study was designed to explore the anti-inflammatory mechanism of IL-6R inhibitor, tocilizumab, in FLS-mediated inflammation in RA from the perspective of non-coding RNAs (ncRNAs). To this end, we sorted primary FLS obtained from the synovium of patients with RA and cultured them in vitro. The cells were then treated with tocilizumab and subjected to lncRNA- and miRNA-seq to identify the ncRNAs regulated by tocilizumab treatment using bioinformatic analysis and experimental verification. Tocilizumab treatment enhanced the expression of lncRNA MIR31HG and reduced that of micoRNA-214 (miR-214). In addition, miR-214 activated the AKT signaling pathway by directly targeting MIR31HG and PTEN. In addition, the tocilizumab-MIR31HG-miR-214-PTEN-AKT axis regulated the proliferation, migration, and production of inflammatory molecules and matrix metalloproteinases (MMPs) in RA-FLS. Furthermore, co-culture experiments showed that this axis could inhibit the inflammatory phenotype of macrophages and protect chondrocytes. In summary, our study shows that tocilizumab suppresses RA-FLS inflammation by regulating the MIR31HG-miR-214-PTEN-AKT pathway, and presents new insights on RA pathogenesis and potential targets for RA therapy.

MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity.

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.