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1.
Nat Commun ; 11(1): 4110, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807790

RESUMO

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.


Assuntos
Metaloproteinase 13 da Matriz/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Biotecnologia/métodos , Doenças Cardiovasculares/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Mutantes , Miócitos de Músculo Liso/efeitos dos fármacos , Progéria/metabolismo , Progéria/patologia , Proteômica/métodos
2.
Int J Nanomedicine ; 15: 3771-3790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547027

RESUMO

Introduction: Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects. Materials and Methods: The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs. Results: L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 µL L-rapa at both 5 µM and 50 µM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 µM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy. Conclusion: Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.


Assuntos
Osteoartrite/terapia , Sirolimo/uso terapêutico , Ondas Ultrassônicas , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Condrócitos/efeitos da radiação , Colágeno Tipo II/metabolismo , Liberação Controlada de Fármacos , Cobaias , Humanos , Injeções Intra-Articulares , Interleucina-6/metabolismo , Lipossomos/ultraestrutura , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite/sangue , Osteoartrite/patologia , Proteoglicanas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sirolimo/administração & dosagem , Sirolimo/farmacologia
3.
Acta Chir Orthop Traumatol Cech ; 87(2): 90-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396508

RESUMO

INTRODUCTION Vitamin D-deficiency is known to cause nerve conduction impairments, cancer and chronic diseases, as well as the pathogenesis of osteoarthritis. Our goal with this study is to evaluate the cartilage healing by applying intraarticular 1α, 25 (OH) 2D3 at different doses in rats with normal vitamin D levels and metabolism, which we made focal chondral damage model in the knee joint. MATERIAL AND METHODS 35 male Sprague-Dawley rats aged 20-24 weeks were used in our study. Both knees of rats were cartilage defected surgically on day 0. Joint injections performed at 06:00 am on 0th and 2nd days and after second injection others performed on days 9-16 and 23 following a weekly period. RESULTS In the fourth week, hematoxylin eosin staining measurements showed statistically significant difference according to the groups (p < 0.01) Metalloproteinase-13 (MMP-13) in histological staining for evaluating cartilage healing and healing levels showed statistically significant differences between the groups at first week and fourth week (p < 0.05). DISCUSSION Vitamin D, which affects many tissues through its receptors, is believed to be chondroprotective and neuroprotective by decreasing the expression of MMP in cartilage fibroblast, macrophage, lymphocyte through its intracellular receptors. To the best of our knowledge, this is the first study known to be intraarticular use of 1α, 25-dihydroxyvitamin D3. Our study has been found to be safe and successful in terms of weight, systemic PTH and 1α, 25-dihydroxyvitamin D3 levels in rats during treatment as well as better healing of cartilage damage. Key words: vitamin D3 receptor, articular cartilage, orthopedics, nerve conduction.


Assuntos
Calcitriol/administração & dosagem , Cartilagem Articular/efeitos dos fármacos , Membro Posterior/lesões , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Cartilagem Articular/lesões , Modelos Animais de Doenças , Injeções Intra-Articulares , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley
4.
Am J Sports Med ; 48(7): 1647-1656, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32383968

RESUMO

BACKGROUND: Femoroacetabular impingement (FAI) has been proposed as an etiologic factor in up to 50% of hips with osteoarthritis (OA). Inflammation is thought to be one of the main initiators of OA, yet little is known about the origin of intra-articular inflammation in FAI hips. HYPOTHESIS: Articular cartilage from the impingement zone of patients with FAI has high levels of inflammation, reflecting initial inflammatory process in the hip. STUDY DESIGN: Controlled laboratory study. METHODS: Head-neck cartilage samples were obtained from patients with cam FAI (cam FAI, early FAI; n = 15), advanced OA secondary to cam FAI (FAI OA, late FAI; n = 15), and advanced OA secondary to developmental dysplasia of the hip (DDH OA, no impingement; n = 15). Cartilage procured from young adult donors (n = 7) served as control. Safranin O-stained sections were assessed for cartilage abnormality. Tissue viability was detected by TUNEL assay. Immunostaining of interleukin 1ß (IL-1ß), catabolic markers (matrix metalloproteinase 13 [MMP-13], a disintegrin and metalloproteinase with thrombospondin motif 4 [ADAMTS-4], aggrecan antibody to C-terminal neoepitope [NITEGE]), and an anabolic marker (type II collagen [COL2]) was performed to evaluate molecular inflammation and metabolic activity. The average percentage of immunopositive cells from the total cell count was calculated. Kruskal-Wallis test followed by Steel-Dwass post hoc test was used for multiple comparisons. RESULTS: Microscopic osteoarthritic changes were more prevalent in cartilage of cam FAI and FAI OA groups compared with DDH OA and control groups. Cartilage in cam FAI and FAI OA groups, versus the DDH group, had higher expression of inflammatory molecules IL-1ß (69.7% ± 18.1% and 72.5% ± 13.2% vs 32.7% ± 14.4%, respectively), MMP-13 (79.6% ± 12.6% and 71.4% ± 18.8% vs 38. 5% ± 13.3%), ADAMTS-4 (83.9% ± 12.2% and 82.6% ± 12.5% vs 45.7% ± 15.5%), and COL2 (93.6% ± 3.9% and 92.5% ± 5.8% vs 53.3% ± 21.0%) (P < .001). Expression of NITEGE was similar among groups (cam FAI, 89.7% ± 7.7%; FAI OA, 95.7% ± 4.7%; DDH OA, 93.9% ± 5.2%; P = .0742). The control group had minimal expression of inflammatory markers. Inflammatory markers were expressed in all cartilage zones of early and late FAI but only in the superficial zone of the no impingement group. CONCLUSION: Cartilage from the impingement zone in FAI is associated with a high expression of inflammatory markers, extending throughout all cartilage zones. CLINICAL RELEVANCE: Inflammation associated with FAI likely has a deleterious effect on joint homeostasis. Further clinical and translational studies are warranted to assess whether and how surgical treatment of FAI reduces molecular inflammation.


Assuntos
Cartilagem Articular/patologia , Impacto Femoroacetabular/patologia , Osteoartrite do Quadril/etiologia , Biomarcadores/metabolismo , Cartilagem Articular/metabolismo , Feminino , Impacto Femoroacetabular/complicações , Impacto Femoroacetabular/metabolismo , Impacto Femoroacetabular/cirurgia , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite do Quadril/metabolismo , Osteoartrite do Quadril/patologia
5.
PLoS One ; 15(4): e0231501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330138

RESUMO

Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/ß-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.


Assuntos
Doenças das Cartilagens/metabolismo , Cartilagem Articular/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Idoso , Animais , Células Cultivadas , Condrócitos/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo
6.
J Bone Miner Metab ; 38(4): 491-500, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32146507

RESUMO

INTRODUCTION: To investigate the effect of different frequencies of whole body vibration (WBV) on articular cartilage of early knee osteoarthritis (OA) rats and determine whether WBV would influence the pathway of hypoxia-inducible factor-2α (HIF-2α) regulation-related genes after 8 weeks of treatment. MATERIALS AND METHODS: Forty 8-week-old OA rats were divided into five groups: sham control (SC); high frequency 60 Hz (HV1); high frequency 40 Hz (HV2); middle frequency 20 Hz (MV) and low frequency 10 Hz (LV). WBV (0.3 g) treatment was given 40 min/day and 5 days/week. After 8 weeks, rats were killed and knees were harvested. OA grading score: Osteoarthritis Research Society International (OARSI), and the expression of related genes: interleukin-1ß (IL-1ß), HIF-2α, matrix metalloproteinases-13 (MMP-13), and collagen type II alpha 1 (COL2A1), at both mRNA and protein levels were analyzed. RESULTS: After 8 weeks of WBV, our data showed that lower frequency (10 Hz) was more effective than the higher ones, yet they all suggested that WBV alleviates the erosion of knee articular cartilage in early OA. The expression of IL-1ß, HIF-2α and MMP-13 decreased with frequency and reached the lowest level at 10 Hz, the expression of COL2A1 increased with frequency and reached the highest level at 10 Hz. CONCLUSIONS: This study demonstrates that WBV could alleviate the degeneration of knee joints in an early OA rat model. WBV regulates related gene expression at both mRNA and protein levels. HIF-2α could be a therapeutic target. The effect of WBV is frequency dependent; the lower frequency shows better effects.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Osteoartrite do Joelho/metabolismo , Vibração , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite do Joelho/patologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
7.
Chem Biol Interact ; 322: 108968, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004530

RESUMO

Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases, and the risk of developing OA significantly increases with age as well as with concomitant diseases, such as diabetes. Advanced glycation end products (AGEs) accumulate in the body over time and are associated with increased expression of various molecules involved in the pathophysiology of OA. Prostaglandin E2 (PGE2), along with its precursor cyclooxygenase (COX)-2, plays an integral role in the pathogenesis of OA and is highly upregulated in response to AGEs. The most significant event in OA is excessive degradation of the cartilage extracellular matrix, which is composed primarily of type II collagen and aggrecan. In the present study, we investigated the involvement of the receptor for glucagon-like peptide (GLP)-1 in the response of chondrocytes to insult from AGEs using the selective GLP-1 agonist dulaglutide. Firstly, our results indicate that AGEs reduced the expression of the receptor for GLP-1 (GLP-1R) in human SW1353 chondrocytes. Interestingly, we found that treatment with dulaglutide could ameliorate deterioration of the components of the articular extracellular matrix (ECM), such as type II collagen and aggrecan, induced by AGEs through downregulation of matrix metalloproteinase (MMP)-3 and MMP-13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. We also found that dulaglutide exerted a potent inhibitory effect against the expression of several proinflammatory cytokines and chemokines closely associated with OA, as well as the production of reactive oxygen species (ROS). Finally, we showed that the effects of dulaglutide were mediated through the nuclear factor kappa-B (NF-κB) pathway. Our findings indicate that dulaglutide displayed a robust protective effect against AGEs-induced damage in chondrocytes, suggesting that it might be a possible therapeutic agent for the treatment of OA.


Assuntos
Agrecanas/metabolismo , Colágeno Tipo II/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Produtos Finais de Glicação Avançada/metabolismo , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Linhagem Celular , Quimiocinas/análise , Quimiocinas/metabolismo , Condrócitos/citologia , Condrócitos/metabolismo , Citocinas/análise , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
8.
Arthritis Rheumatol ; 72(7): 1123-1133, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32067417

RESUMO

OBJECTIVE: To investigate the effects of a young systemic environment and growth differentiation factor 11 (GDF-11) on aging cartilage. METHODS: A heterochronic parabiosis model (2-month-old mouse and 12-month-old mouse [Y/O]), an isochronic parabiosis model (12-month-old mouse and 12-month-old mouse [O/O]), and 12-month-old mice alone (O) were evaluated. Knee joints and chondrocytes from old mice were examined by radiography, histology, cell proliferation assays, immunohistochemistry, Western blotting, and quantitative reverse transcriptase-polymerase chain reaction 16 weeks after parabiosis surgery. GDF-11 was injected into 12-month-old mouse joints daily for 16 weeks. Cartilage degeneration, cell proliferation, and osteoarthritis-related gene expression were evaluated. RESULTS: Osteoarthritis Research Society International scores in old mice were significantly lower in the Y/O group than in the O/O and O groups (both P < 0.05). The percentage of 5-ethynyl-2'-deoxyuridine-positive chondrocytes in old mice was significantly higher in the Y/O group than in the other groups (P < 0.05). Type II collagen (CII) and SOX9 messenger RNA levels differed in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). RUNX-2, CX, and matrix metalloproteinase 13 levels were significantly lower in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). Similar results were obtained for protein expression levels and after GDF-11 treatment in vitro and in vivo. Phosphorylated Smad2/3 (pSmad2/3) levels were higher in the recombinant GDF-11-treated group than in the control group. CONCLUSION: A young systemic environment promotes chondrocyte proliferation and cartilage matrix synthesis in old mice. GDF-11, a "young factor," contributes to these effects through the up-regulation of pSmad2/3.


Assuntos
Envelhecimento/genética , Proteínas Morfogenéticas Ósseas/farmacologia , Cartilagem Articular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fatores de Diferenciação de Crescimento/farmacologia , Osteoartrite do Joelho/genética , Parabiose , Adolescente , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Artroplastia do Joelho , Proteínas Morfogenéticas Ósseas/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno Tipo II/efeitos dos fármacos , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Colágeno Tipo X/efeitos dos fármacos , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Fatores de Diferenciação de Crescimento/metabolismo , Humanos , Técnicas In Vitro , Articulação do Joelho , Masculino , Metaloproteinase 13 da Matriz/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Osteoartrite do Joelho/metabolismo , Fosforilação , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOX9/efeitos dos fármacos , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteína Smad2/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/metabolismo , Joelho de Quadrúpedes , Adulto Jovem
9.
Anat Sci Int ; 95(3): 334-341, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32006224

RESUMO

We investigated the architecture of periodontal ligament regenerated by an enamel matrix derivative (EMD, Emdogain®) coating on the surface of hydroxyapatite (EMD-HA). Immediately after extraction of the maxillary first molar in rats, HA alone or EMD-HA was implanted into the socket. At 5 days, and 2 and 4 weeks after implantation, the specimens were examined by light and transmission electron microscopy, and immunohistochemistry for periostin and matrix metalloproteinase (MMP)-13. Histological observations revealed a large number of fibroblasts and well-developed blood capillaries in the fibrous connective tissue surrounding EMD-HA at 5 days. Ultrastructural analysis showed a distinct difference in the architecture of the fibrous connective tissue. As compared with the poorly constructed architecture of HA, EMD-HA had an orderly alignment of fibroblasts and bundled collagen fibers, with some fibroblasts in the cytoplasm showing collagen fiber phagocytosis. Periostin immunoreactivity was observed in the fibrous connective tissue around EMD-HA at each time point, but was not seen in HA at 5 days and 2 weeks. MMP-13 immunoreactivity was intensely localized in fibroblasts at 5 days and 2 weeks in EMD-HA. The present results indicate that EMD may greatly contribute to a well-developed architecture accompanied by orderly alignment of fibroblasts and bundled collagen fibers, through accelerated induction of periostin, maintenance of fibrillogenesis, and degradation of collagen fibers by extracellular proteinase and phagocytosis.


Assuntos
Tecido Conjuntivo/fisiologia , Proteínas do Esmalte Dentário/farmacologia , Esmalte Dentário , Durapatita/administração & dosagem , Maxila , Regeneração/efeitos dos fármacos , Extração Dentária , Alvéolo Dental , Animais , Moléculas de Adesão Celular/metabolismo , Colágeno/metabolismo , Tecido Conjuntivo/irrigação sanguínea , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/ultraestrutura , Fibroblastos , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Dente Molar , Ratos Wistar
10.
Arch Biochem Biophys ; 684: 108297, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035098

RESUMO

Although rheumatoid arthritis (RA) has long posed a major threat to global health, the mechanisms driving the development and progression of RA remain incompletely understood. In the present study, we investigated the effects of G protein-coupled receptor 43 (GPR43/FFAR2) in various aspects of the pathogenesis of RA. To our knowledge, this is the first study to demonstrate that GPR43 is expressed on human fibroblast-like synoviocytes (FLS). Furthermore, we show that GPR43 is upregulated in FLS exposed to tumor necrosis factor-α (TNF-α). Importantly, our findings demonstrate that activation of GPR43 using its specific agonist significantly suppressed expression of the following key factors of RA: cytokines, such as interleukin-6 (IL-6), IL-8, high mobility group protein 1 (HMG-1); chemokines, such as monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cellular adhesion molecule 1 (VCAM-1); markers of oxidative stress, such as production of reactive oxygen species (ROS) and 4-hydroxynoneal (4-HNE); degradative enzymes, such as matrix metalloproteinase-3 (MMP-3) and MMP-13; and activation of the nuclear factor-κB (NF-κB) inflammatory signaling pathway. These results suggest a promising potential role for GPR43 as a specific target in the treatment and prevention of RA.


Assuntos
Receptores de Superfície Celular/metabolismo , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Aldeídos/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Quimiocinas/metabolismo , Humanos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/agonistas , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Mol Cell Biochem ; 466(1-2): 1-15, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31912277

RESUMO

Progressive alteration of the extracellular matrix (ECM) is the characteristic of hypertensive nephropathy (HN). Both mesangial and endothelial cells have the ability to synthesize and degrade ECM components, including collagens through the activation of matrix metalloproteinases (MMPs) in stress conditions, such as in hypertension. On the other hand, hydrogen sulfide (H2S) has been shown to mitigate hypertensive renal matrix remodeling. Surprisingly, whether H2S ameliorates receptor-mediated (urokinase plasminogen activator receptor-associated protein, uPARAP/Endo180) collagen dysregulation in Ang-II hypertension is not clear. The purpose of this study was to determine whether Ang-II alters the expression of Endo180, tissue plasminogen activator (tPA), MMPs, and their tissue inhibitors (TIMPs) leading to the dysregulation of cellular collagen homeostasis and whether H2S mitigates the collagen turnover. Mouse mesangial cells (MCs) and glomerular endothelial cells (MGECs) were treated without or with Ang-II and H2S donor GYY (GYY4137) for 48 h. Cell lysates were analyzed by Western blot and RT-PCR, and cells were analyzed by immunocytochemistry. The results indicated that, while Ang-II differentially expressed MMP-13 and TIMP-1 in MCs and in MGECs, it predominantly decreased tPA, Endo 180, and increased plasminogen activator inhibitor-1 (PAI-1), MMP-14, and collagen IIIA and IV in both the cell types. Interestingly, H2S donor GYY treatment normalized the above changes in both the cell types. We conclude that Ang-II treatment causes ECM remodeling in MCs and MGECs through PAI-1/tPA/Endo180 and MMP/TIMP-dependent collagen remodeling, and H2S treatment mitigates remodeling, in part, by modulating these pathways.


Assuntos
Células Endoteliais/metabolismo , Mesângio Glomerular/metabolismo , Hipertensão Renal/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Receptores de Colágeno/metabolismo , Estresse Fisiológico , Animais , Células Endoteliais/patologia , Mesângio Glomerular/patologia , Hipertensão Renal/patologia , Camundongos
12.
Microvasc Res ; 129: 103973, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31891716

RESUMO

Ischemic stroke represents a major cause of adult death and severe neurological disability worldwide. Reperfusion following brain ischemia produces an inflammatory cascade that increases brain damage. In this context, matrix metalloproteinases (MMPs) play an important role as pro-inflammatory mediators. The MMP 2 up-regulation seems to promote matrix degradation, blood-brain barrier (BBB) disruption and facilitates the influx of peripheral inflammatory cells to the brain after stroke. However, there are not studies about MMP-1 in this condition. The aim of this study is to evaluate the association of brain damage, inflammatory response and the immunostaining profile of matrix metalloproteinases 1 and 2 after transient global cerebral ischemia. Mice were submitted to bilateral common carotid arterial occlusion (BCCAo) during 25 min. After three days of reperfusion, the neurological deficit score was evaluated and the animals were euthanized. Brain samples were collected in order to analyze the histopathological damage, MMPs 1 and 2 immunostaining and cytokines and chemokines levels. Ischemic group showed neurological deficits associated with brain lesions, characterized by necrotic core and penumbra zone three days after reperfusion. Higher brain immunostaining of MMP-1 and MMP-2 was observed in BCCAo samples than in sham samples. Ischemic group also exhibited increased brain levels of the cytokines tumoral necrosis factor (TNF) and interleukin 1ß (IL-1ß), chemokine (C-X-C motif) ligand 1 (CXCL1), and chemokine (C-C motif) ligand 5 (CCL5) in comparison to sham group. Our results suggest that the MMP-1 and MMP-2 raise, associated with the up-regulation of inflammatory mediators, contributes to brain damage and neurological deficits after global brain ischemia followed by three days of reperfusion in mice.


Assuntos
Encéfalo/enzimologia , Citocinas/metabolismo , Ataque Isquêmico Transitório/enzimologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Necrose , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
13.
Am J Med Sci ; 359(1): 17-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785770

RESUMO

BACKGROUND: The purpose of this study was to demonstrate the role of renin-angiotensin system (RAS)-related components, vascular endothelial growth factor (VEGF) and atrial metalloproteinase-13 (MMP-13) in synovial tissue and synovial fluid from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). MATERIALS AND METHODS: Thirty-four patients with RA and 41 patients with OA were included in the study. Renin, angiotensin-converting enzyme (ACE), VEGF and MMP-13 protein levels in the synovial fluid were measured by enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction analysis, western blot analysis and immunohistochemistry were used to quantify renin, ACE, angiotensin type 1 and type 2 receptors, VEGF and MMP-13 in OA and RA. Additionally, the correlation was determined by Pearson's coefficient. RESULTS: In synovial fluid, expression levels of renin, ACE, VEGF and MMP-13 in patients with RA were significantly higher than those in patients with OA. In synovial tissue, the RAS components VEGF and MMP-13 were also elevated in patients with RA. The results of immunohistochemistry in synovial tissue also showed that the RAS components VEGF and MMP-13 were significantly increased in patients with RA. Notably, the Pearson coefficient demonstrated that the levels of the RAS components were positively correlated with the expression of VEGF and MMP-13 in OA and RA. CONCLUSIONS: The present results suggest that RAS-related components in RA and OA, including renin, ACE, angiotensin type 1 and type 2 receptors, are associated with increased expression of VEGF and play an important role in angiogenesis. Furthermore, there was a significant positive correlation between the expression of VEGF and MMP-13.


Assuntos
Artrite Reumatoide/metabolismo , Regulação da Expressão Gênica , Osteoartrite/metabolismo , Sistema Renina-Angiotensina/fisiologia , Idoso , Artrite Reumatoide/complicações , Feminino , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite/complicações , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Renina/genética , Renina/metabolismo , Líquido Sinovial/química , Líquido Sinovial/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Dis Model Mech ; 12(12)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848143

RESUMO

Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect affecting children worldwide, and is classified by age of onset, location and degree of spine curvature. Although rare, IS with onset during infancy is the more severe and rapidly progressive form of the disease, associated with increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remains elusive. Here, we demonstrate the role of PRMT5 in the infantile IS phenotype in mouse. Conditional genetic ablation of PRMT5 in osteochondral progenitors results in impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of these several markers of endochondral ossification revealed increased type X collagen (COLX) and Ihh expression, coupled with a dramatic reduction in Mmp13 and RUNX2 expression, in the vertebral growth plate and in regions of the intervertebral disc in the Prmt5 conditional mutant mice. We also demonstrate that PRMT5 has a continuous role in the intervertebral disc and vertebral growth plate in adult mice. Altogether, our results establish PRMT5 as a critical promoter of terminal hypertrophic chondrocyte differentiation and endochondral bone formation during spine development and homeostasis.This article has an associated First Person interview with the first author of the paper.


Assuntos
Proteína Morfogenética Óssea 4/genética , Condrócitos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Escoliose/genética , Alelos , Animais , Proteína Morfogenética Óssea 4/metabolismo , Cartilagem/metabolismo , Diferenciação Celular , Proliferação de Células , Condrogênese , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Cruzamentos Genéticos , Deleção de Genes , Proteínas Hedgehog/metabolismo , Homeostase , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Mutação , Osteogênese/genética , Fenótipo , Regiões Promotoras Genéticas , Células-Tronco/citologia
15.
BMC Vet Res ; 15(1): 419, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752879

RESUMO

BACKGROUND: Osteoarthritis (OA), the most common form of arthritic disease, results from destruction of joint cartilage and underlying bone. It affects animals, including Asian elephants (Elephas maximus) in captivity, leading to joint pain and lameness. However, publications regarding OA pathogenesis in this animal are still limited. Therefore, this study aimed to investigate the effect of proinflammatory cytokines, including interleukin-1 beta (IL-1ß), IL-17A, tumor necrosis factor-alpha (TNF-α), and oncostatin M (OSM), known mediators of OA pathogenesis, and lipopolysaccharides on the expression of cartilaginous degrading enzymes, matrix metalloproteinase (MMP)-3 and MMP-13, in elephant articular chondrocytes (ELACs) cultures. Anti-arthritic drugs and the active compounds of herbal plants were tested for their potential attenuation against overproduction of these enzymes. RESULTS: Among the used cytokines, OSM showed the highest activation of MMP3 and MMP13 expression, especially when combined with IL-1ß. The combination of IL-1ß and OSM was found to activate phosphorylation of the mitogen-activated protein kinase (MAPK) pathway in ELACs. Lipopolysaccharides or cytokine-induced expressions were suppressed by pharmacologic agents used to treat OA, including dexamethasone, indomethacin, etoricoxib, and diacerein, and by three natural compounds, sesamin, andrographolide, and vanillylacetone. CONCLUSIONS: Our results revealed the cellular mechanisms underlying OA in elephant chondrocytes, which is triggered by proinflammatory cytokines or lipopolysaccharides and suppressed by common pharmacological or natural medications used to treat human OA. These results provide a more basic understanding of the pathogenesis of elephant OA, which could be useful for adequate medical treatment of OA in this animal.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/toxicidade , Elefantes/metabolismo , Lipopolissacarídeos/toxicidade , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Animais , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Regulação para Cima/efeitos dos fármacos
16.
Oxid Med Cell Longev ; 2019: 7189854, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781346

RESUMO

Intervertebral disc (IVD) degeneration (IDD) is a major cause of low back pain. The pathogenesis of IDD is associated with the disturbance of reactive oxygen species (ROS) equilibrium, inflammation, and matrix loss. Aspirin is a nonsteroidal anti-inflammatory drug that effectively inhibits inflammation and oxidative stress and has been widely used for the treatment of back pain. Therefore, we hypothesize that aspirin reverses the IDD process via antioxidative and anti-inflammatory effects on the AMPK signaling pathway. In vitro, aspirin diminished cellular oxygen free radicals (ROS, nitric oxide (NO)) and inflammatory cytokines (interleukin- (IL-) 1ß and IL-6 and tumor necrosis factor alpha (TNF-α)) induced by lipopolysaccharides (LPS) in nucleus pulposus cells (NPCs). We found that aspirin preserved the extracellular matrix (ECM) content of collagen type II (COL2) and aggrecan while inhibiting the expression of matrix-degenerating enzymes, including matrix metalloproteinase 3 and 13 (MMP-3 and MMP-13) and A disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS-4, ADAMTS-5). Aspirin significantly promoted the ratios of p-AMPK to AMPK and p-ACC to ACC expression in NPCs. Furthermore, pretreatment with the AMPK inhibitor compound C abrogated the antioxidant effects of aspirin. In vivo, an IDD model was established in Sprague-Dawley rats via percutaneous disc puncture with the 20-gauge needle on levels 8-9 and 9-10 of the coccygeal vertebrae. Imaging assessment showed that after aspirin treatment, improvements in disc height index (DHI) ranged from 1.22-fold to 1.54-fold and nucleus pulposus signal strength improved from 1.26-fold to 1.33-fold. Histological analysis showed that aspirin treatment prevented the loss of COL2 and decreased MMP-3 and MMP-13, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1ß, and TNF-α expression in the IVD tissues. These results suggest that treatment with aspirin could reverse the IDD process via the AMPK signaling pathway, which provides new insights into the potential clinical applications of aspirin, particularly for IDD treatment.


Assuntos
Aspirina/farmacologia , Degeneração do Disco Intervertebral/tratamento farmacológico , Núcleo Pulposo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Núcleo Pulposo/patologia , Ratos , Ratos Sprague-Dawley
17.
Int J Mol Sci ; 20(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652545

RESUMO

Inflammatory processes in the skin augment collagen degradation due to the up-regulation of matrix metalloproteinases (MMPs). The aim of the present project was to study the specific impact of MMP-3 on collagen loss in skin and its interplay with the collagenase MMP-13 under inflammatory conditions mimicked by the addition of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Skin explants from MMP-3 knock-out (KO) mice or from transgenic (TG) mice overexpressing MMP-3 in the skin and their respective wild-type counterparts (WT and WTT) were incubated ex vivo for eight days. The rate of collagen degradation, measured by released hydroxyproline, was reduced (p < 0.001) in KO skin explants compared to WT control skin but did not differ (p = 0.47) between TG and WTT skin. Treatment with the MMP inhibitor GM6001 reduced hydroxyproline media levels from WT, WTT and TG but not from KO skin explants. TNF-α increased collagen degradation in the WT group (p = 0.0001) only. More of the active form of MMP-13 was observed in the three MMP-3 expressing groups (co-incubation with receptor-associated protein stabilized MMP-13 subforms and enhanced detection in the media). In summary, the innate level of MMP-3 seems responsible for the accelerated loss of cutaneous collagen under inflammatory conditions, possibly via MMP-13 in mice.


Assuntos
Colágeno/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Pele/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Dipeptídeos/farmacologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Proteólise , Pele/efeitos dos fármacos
18.
Med Sci Monit ; 25: 7488-7498, 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587011

RESUMO

BACKGROUND Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration and inflammation. We have previously clarified that a xanthan gum (XG) preparation exerts ameliorating effect on a rabbit OA model by regulating matrix metalloproteinase (MMP)-1 and MMP-3, which are critical proteins in the Wnt3a/ß-catenin pathway. Thus, it is reasonable to predict that the Wnt3a/ß-catenin pathway is involved in the treatment of OA with XG. MATERIAL AND METHODS The effect of XG in OA model animals were observed by hematoxylin and eosin staining (HE), Safranin O staining, and Fast Green staining. Articular cartilage degradation on the medial plateau sides was quantified using the modified Pritzker OARSI score. The levels of IL-6, TNF-alpha, and IL-1ß in synovial fluid were determined with ELISA. The protective effect of XG in rat chondrocytes was assessed by CCK8 assay. Moreover, activation of the Wnt3a/ß-catenin pathway and the expression of MMP13, ADAMTS5, aggrecan, and collagen II under the influence of XG was measured by Western blot and qRT-PCR. RESULTS Our results showed that XG reduced the OARSI score and the concentration of inflammatory cytokines in OA after intra-articular injection. XG acted on Wnt3a/ß-catenin in ATDC5 cells in a dose-dependent manner and exhibited a protective effect. XG also decreased the expression of MMP13 and ADAMTS5 and rescued the inhibition of aggrecan and collagen II expression in SNP-stimulated chondrocytes. CONCLUSIONS These results indicate that the effects of XG are related to the Wnt3a/ß-catenin pathway and XG suppresses matrix degradation by inhibiting the expression of MMPs and ADAMTS and promotes aggrecan and collagen II content in the ECM, indicating its favorable potential for use in OA therapy.


Assuntos
Osteoartrite/tratamento farmacológico , Polissacarídeos Bacterianos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína ADAMTS5/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Linhagem Celular , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Coelhos , Ratos , Ratos Sprague-Dawley , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
19.
Med Sci Monit ; 25: 7202-7208, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31587013

RESUMO

BACKGROUND Hypoxia promotes cancer progression. Hypoxia-inducible factor-1alpha (HIF-1alpha) has been reported to enhance tumor invasion and metastasis via activating downstream genes, such as matrix metalloproteinases (MMPs). The purpose of this study was to explore the probable roles of HIF-1alpha and MMP13 in the invasion and metastasis of ovarian cancer under hypoxic conditions. MATERIAL AND METHODS The expression of HIF-1alpha and MMP13 protein were detected with immunohistochemistry staining in ovarian cancer tissues, metastatic lesions, and normal fallopian tissues. Ovarian cancer A2780 cells were cultured under normoxic condition and hypoxic condition. mRNA and protein expression of HIF-1alpha and MMP13 were detected by RT-PCR and Western blot analysis. The effects of siRNA against HIF-1alpha on MMP13 expression were examined by RT-PCR and Western blot analysis. Transwell invasion assays were performed to test the invasive ability of A2780 cells. RESULTS Immunohistochemistry staining showed significantly higher expression of HIF-1alpha and MMP13 protein in ovarian cancer tissues and metastatic lesions than in normal fallopian tissues. HIF-1alpha and MMP13 expression were closely related. After exposure to hypoxia, mRNA and protein levels of HIF-1alpha and MMP13 were upregulated. siRNA effectively inhibited HIF-1alpha expression and MMP13 expression. The number of invading A2780 cells decreased after HIF-1alpha was silenced. CONCLUSIONS This study suggests that HIF-1alpha promotes ovarian cancer cell invasion through a MMP13 mechanism. It might be an effective strategy targeting HIF-1alpha - MMP13 to inhibit invasion and metastasis of ovarian cancer.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Ovarianas/patologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo
20.
Nutrients ; 11(10)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581754

RESUMO

Our previous study showed that hydrangenol isolated from Hydrangea serrata leaves exerts antiphotoaging activity in vitro. In this study, we determined its antiphotoaging effect in UVB-irradiated HR-1 hairless mice. We evaluated wrinkle formation, skin thickness, histological characteristics, and mRNA and protein expression using qRT-PCR and Western blot analysis in dorsal skins. Hydrangenol mitigated wrinkle formation, dorsal thickness, dehydration, and collagen degradation. Hydrangenol increased the expression of involucrin, filaggrin, and aquaporin-3 (AQP3) as well as hyaluronic acid (HA) production via hyaluronidase (HYAL)-1/-2 downregulation. Consistent with the recovery of collagen composition, the expression of Pro-COL1A1 was increased by hydrangenol. Matrix metalloproteinase (MMP)-1/-3, cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) expression was reduced by hydrangenol. Hydrangenol attenuated the phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK and p38, activator protein 1 (AP-1) subunit, and signal transduction and activation of transcription 1 (STAT1). Hydrangenol upregulated the expression of nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), glutamate cysteine ligase modifier subunit (GCLM), and glutamate cysteine ligase catalysis subunit (GCLC). Taken together, our data suggest that hydrangenol can prevent wrinkle formation by reducing MMP and inflammatory cytokine levels and increasing the expression of moisturizing factors and antioxidant genes.


Assuntos
Fármacos Dermatológicos/farmacologia , Hydrangea/química , Isocumarinas/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Água/metabolismo , Animais , Antioxidantes/metabolismo , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Fármacos Dermatológicos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Isocumarinas/isolamento & purificação , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Camundongos Pelados , Extratos Vegetais/isolamento & purificação , Proteólise , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação , Envelhecimento da Pele/efeitos da radiação
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