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In this article, we discuss the synthesis of eight novel zirconium and hafnium complexes containing amidoxime ligands as potential precursors for atomic layer deposition (ALD). Two amidoximes, viz., (E)-N'-hydroxy-N,N-dimethylacetimidamide (mdaoH) and (Z)-N'-hydroxy-N,N-dimethylpivalimidamide (tdaoH), along with their Zr and Hf homoleptic complexes, Zr(mdao)4 (1), Hf(mdao)4 (2), Zr(tdao)4 (3), and Hf(tdao)4 (4) were prepared. We further synthesized heteroleptic compounds with different physical properties by introducing cyclopentadienyl (Cp) ligand, namely, CpZr(mdao)3 (5), CpHf(mdao)3 (6), CpZr(tdao)3 (7), and CpHf(tdao)3 (8). Thermogravimetric analysis was used for the assessment of the evaporation characteristics of complexes 1, 2, 5, and 6, and it revealed multistep weight losses with high residues. On the other hand, the thermogravimetric analysis curves of complexes 3, 4, 7, and 8 comprising tdao ligands revealed single-step weight losses with moderate residues. Single-crystal X-ray diffraction studies of complexes 1, 3, and 7 showed that all of the complexes have monomeric molecular structures. Complex 7 exhibited a low melting point (75 °C), good volatility, and high thermal stability compared with other complexes. Therefore, an atomic layer deposition process for the growth of ZrO2 was developed by using ZrCp(tdao)3 (7) as a novel precursor.
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This paper reports the synthesis of three novel titanium complexes containing amidoxime ligands as potential precursors for titanium nitride (TiN) thin films fabricated using atomic layer deposition (ALD). A series of ligands, viz., N'-methoxy-N-methylacetimidamide (mnnoH), N'-ethoxy-N-methylacetimidamide (ennoH), and N'-methoxy-N-methylbenzimidamide (pnnoH), were successfully synthesized and used to produce Ti(mnno)(NMe2)3 (4), Ti(enno)(NMe2)3 (5), and Ti(pnno)(NMe2)3 (6). Thermogravimetric analysis curves of complexes 4-6 revealed a single-step weight loss up to 200 °C. Pyrolysis occurred beyond 200 °C. Among the three new complexes, 5 was liquid at room temperature. Therefore, TiN was synthesized by ALD using Ti(enno)(NMe2)3 (5) as a novel precursor. A TiN thin film was deposited from the Ti(enno)(NMe2)3 (5) precursor and NH3 plasma, and self-limiting growth was achieved by varying the injection/purge duration. TiN thin film growths were observed with a growth per cycle (GPC) of 0.05-0.13 nm·cy-1 at deposition temperatures between 150 and 300 °C, while the measured resistivity was as low as 420 µΩ·cm. The high reactivity of the precursor promotes nucleation, resulting in TiN thin films with smooth, good step coverage and preferentially orientated microstructure.
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Seomae mugwort, a Korean native variety of Artemisia argyi, exhibits physiological effects against various diseases. However, its effects on osteoarthritis (OA) are unclear. In this study, a Seomae mugwort extract prevented cartilage destruction in an OA mouse model. In vitro and ex vivo analyses revealed that the extract suppressed MMP3, MMP13, ADAMTS4 and ADAMTS5 expression induced by IL-1ß, IL-6 and TNF-α and inhibited the loss of extracellular sulphated proteoglycans. In vivo analysis revealed that oral administration of the extract suppressed DMM-induced cartilage destruction. We identified jaceosidin in Seomae mugwort and showed that this compound decreased MMP3, MMP13, ADAMTS4 and ADAMTS5 expression levels, similar to the action of the Seomae mugwort extract in cultured chondrocytes. Interestingly, jaceosidin and eupatilin combined had similar effects to Seomae mugwort in the DMM-induced OA model. Induction of IκB degradation by IL-1ß was blocked by the extract and jaceosidin, whereas JNK phosphorylation was only suppressed by the extract. These results suggest that the Seomae mugwort extract and jaceosidin can attenuate cartilage destruction by suppressing MMPs, ADAMTS4/5 and the nuclear factor-κB signalling pathway by blocking IκB degradation. Thus, the findings support the potential application of Seomae mugwort, and particularly jaceosidin, as natural therapeutics for OA.
Assuntos
Artemisia/química , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Flavonoides/farmacologia , Proteínas I-kappa B/metabolismo , Osteoartrite/metabolismo , Extratos Vegetais/farmacologia , Animais , Artrite Experimental , Biomarcadores , Cartilagem Articular/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Flavonoides/química , Expressão Gênica , Imuno-Histoquímica , Interleucina-1beta/farmacologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Osteoartrite/patologia , Extratos Vegetais/química , Proteoglicanas/metabolismo , Proteólise , Transdução de Sinais/efeitos dos fármacosRESUMO
Although Hif-2α is a master regulator of catabolic factor expression in osteoarthritis development, Hif-2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents, apigenin, could attenuate the Hif-2α-induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL-1ß-, IL-6, IL-17- and TNF-α-induced up-regulation of MMP3, MMP13, ADAMTS4, ADAMTS5 and COX-2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif-2α, which directly up-regulates MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression, is inhibited by CJM extract. Although cirsimarin, cirsimaritin and apigenin are components of CJM and can reduce inflammation, only apigenin effectively reduced Hif-2α expression and inhibited Hif-2α-induced MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression in articular chondrocytes. IL-1ß induction of JNK phosphorylation and IκB degradation, representing a critical pathway for Hif-2α expression, was completely blocked by apigenin in a concentration-dependent manner. Collectively, these effects indicate that CJM and one of its most potent constituents, apigenin, can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif-2α inhibitors.
Assuntos
Apigenina/farmacologia , Artrite Experimental/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Cirsium/química , Osteoartrite/tratamento farmacológico , Animais , Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Meniscos Tibiais/efeitos dos fármacos , Meniscos Tibiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
3'-Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3'-sialyllactose on osteoarthritic cartilage destruction. In vitro and ex vivo, biochemical and histological analysis demonstrated that 3'-sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL-1ß, IL-6, IL-17 and TNF-α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3'-sialyllactose, whereas the direct binding of NF-κB to the Mmp3, Mmp13 and Cox2 promoters was reduced by 3'-sialyllactose in IL-1ß-treated chondrocytes. Additionally, IL-1ß induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3'-sialyllactose in a dose-dependent manner. In vivo, 3'-sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3'-sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration via promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3'-sialyllactose could be attributed in part to its regulation of Sox9 or NF-κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3'-sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.
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Cartilagem Articular/patologia , Homeostase , Oligossacarídeos/uso terapêutico , Osteoartrite/tratamento farmacológico , Administração Oral , Animais , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/enzimologia , Condrócitos/patologia , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Meniscos Tibiais/patologia , Camundongos , NF-kappa B/metabolismo , Oligossacarídeos/administração & dosagem , Oligossacarídeos/farmacologia , Osteoartrite/patologia , Proteoglicanas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Sulfatos/metabolismoRESUMO
Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.
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Cartilagem Articular , Osteoartrite , Camundongos , Animais , Fosforilação , Poloxâmero/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/uso terapêutico , Osteoartrite/patologia , Cartilagem Articular/metabolismo , Injeções Intra-ArticularesRESUMO
Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Osteoartrite , Estados Unidos , Animais , Camundongos , Fosforilação , Poloxâmero , Osteoartrite/tratamento farmacológicoRESUMO
Chondrocytes secrete massive extracellular matrix (ECM) molecules that are produced, folded, and modified in the endoplasmic reticulum (ER). Thus, the ER-associated degradation (ERAD) complex-which removes misfolded and unfolded proteins to maintain proteostasis in the ER- plays an indispensable role in building and maintaining cartilage. Here, we examined the necessity of the ERAD complex in chondrocytes for cartilage formation and maintenance. We show that ERAD gene expression is exponentially increased during chondrogenesis, and disruption of ERAD function causes severe chondrodysplasia in developing embryos and loss of adult articular cartilage. ERAD complex malfunction also causes abnormal accumulation of cartilage ECM molecules and subsequent chondrodysplasia. ERAD gene expression is decreased in damaged cartilage from patients with osteoarthritis (OA), and disruption of ERAD function in articular cartilage leads to cartilage destruction in a mouse OA model.
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3'-Sialyllactose (3'-SL), a natural prebiotic, maintains immune homeostasis and exerts anti-inflammatory and anti-arthritic effects. Although regulatory T cells (Tregs) prevent excessive inflammation and maintain immune tolerance, the effect of 3'-SL on Treg regulation is unclear. This study aimed to investigate the effect of 3'-SL on Treg responses in atopic dermatitis (AD) pathogenesis. Oral administration of 3'-SL reduced AD-like symptoms such as ear, epidermal, and dermal thickness in repeated topical application of house dust mites (HDM) and 2,4-dinitrochlorobenzene (DNCB). 3'-SL inhibited IgE, IL-1ß, IL-6, and TNF-α secretion and markedly downregulated AD-related cytokines including IL-4, IL-5, IL-6, IL-13, IL-17, IFN-γ, TNF-α, and Tslp through regulation of NF-κB in ear tissue. Additionally, in vitro assessment of Treg differentiation revealed that 3'-SL directly induced TGF-ß-mediated Treg differentiation. Furthermore, 3'-SL administration also ameliorated sensitization and elicitation of AD pathogenesis by suppressing mast cell infiltration and production of IgE and pro-inflammatory cytokines in mouse serum by mediating the Treg response. Furthermore, Bifidobacterium population was also increased by 3'-SL administration as prebiotics. Our data collectively show that 3'-SL has therapeutic effects against AD progression by inducing Treg differentiation, downregulating AD-related cytokines, and increasing the Bifidobacterium population.
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Dermatite Atópica/prevenção & controle , Oligossacarídeos/uso terapêutico , Prebióticos , Pele/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND PURPOSE: 3'-Sialyllactose (3'-SL) is a safe compound that is present in high levels in human milk. Although it has anti-inflammatory properties and supports immune homeostasis, its effect on collagen-induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3'-SL on the progression of rheumatoid arthritis (RA) in in vitro and in vivo models. EXPERIMENTAL APPROACH: The anti-arthritic effect of 3'-SL was analysed with fibroblast-like synoviocytes in vitro and an in vivo mouse model of CIA. RT-PCR, Western blotting and ELISA were performed to evaluate its effects in vitro. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin-O and haematoxylin staining. KEY RESULTS: 3'-SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3'-SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro-inflammatory cytokines, matrix metalloproteinases and osteoclastogenesis via NF-κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF-κB signalling pathway, was totally blocked by 3'-SL in the RA models. CONCLUSIONS AND IMPLICATIONS: 3'-SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated via blockade of the NF-κB signalling pathway. Therefore, 3'-SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.