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1.
ACS Nano ; 16(12): 20057-20074, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36373736

RESUMO

Although conventional topical approaches for treating psoriasis have been offered as an alternative, there are still unmet medical needs such as low skin-penetrating efficacy and off-target adverse effects. A hyaluronic acid nanoparticle (HA-NP) formed by self-assembly of HA-hydrophobic moiety conjugates has been broadly studied as a nanocarrier for long-term and target-specific delivery of drugs, owing to their excellent physicochemical and biological characteristics. Here, we identify HA-NPs as topical therapeutics for treating psoriasis using in vivo skin penetration studies and psoriasis animal models. Transcutaneously administered HA-NPs were found to be accumulated and associated with pro-inflammatory macrophages in the inflamed dermis of a psoriasis mouse model. Importantly, HA-NP exerted potent therapeutic efficacy against psoriasis-like skin dermatitis in a size-dependent manner by suppressing innate immune responses and restoring skin barrier function without overt toxicity signs. The therapeutic efficacy of HA-NPs on psoriasis-like skin dermatitis was due to the outermost hydrophilic HA shell layer of HA-NPs, independent of the molecular weight of HA and hydrophobic moiety, and comparable with that of other conventional psoriasis therapeutics widely used in the clinical settings. Overall, HA-NPs have the potential as a topical nanomedicine for treating psoriasis effectively and safely.


Assuntos
Dermatite , Nanopartículas , Psoríase , Camundongos , Animais , Ácido Hialurônico/química , Psoríase/tratamento farmacológico , Pele , Nanopartículas/química
2.
Biomaterials ; 275: 120967, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34153786

RESUMO

Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1ß treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders.


Assuntos
Cartilagem Articular , Nanopartículas , Osteoartrite , Animais , Condrócitos , Humanos , Ácido Hialurônico , Camundongos , Osteoartrite/tratamento farmacológico
4.
Pharmaceutics ; 12(10)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003609

RESUMO

Owing to their unique biological functions, hyaluronic acid (HA) and its derivatives have been explored extensively for biomedical applications such as tissue engineering, drug delivery, and molecular imaging. In particular, self-assembled HA nanoparticles (HA-NPs) have been used widely as target-specific and long-acting nanocarriers for the delivery of a wide range of therapeutic or diagnostic agents. Recently, it has been demonstrated that empty HA-NPs without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses. In this review, we aim to provide an overview of the significant achievements in this field and highlight the potential of HA-NPs for the treatment of inflammatory diseases.

5.
Carbohydr Polym ; 237: 116161, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32241446

RESUMO

Obesity, a major risk factor for type 2 diabetes and cardiovascular diseases, is characterized by an abnormal expansion of adipose tissue. Herein, we investigated the potential of hyaluronic acid nanoparticles (HA-NPs) as therapeutics to treat obesity-related diseases by assessing the in vitro and in vivo effects of HA-NPs on adipogenesis and lipogenesis. Treatment of 3T3-L1 preadipocytes with HA-NPs resulted in a dose-dependent suppression of adipogenesis and lipid accumulation, and decreased the expression of key adipogenic and lipogenic regulators. However, these HA-NPs mediated effects were not observed in 3T3-L1 cells transfected with siRNAs against CD44, a major HA receptor. Further, HA-NP treatment of diet-induced obese (DIO) mice reduced the epididymal fat mass and suppressed the induction of adipogenic and lipogenic regulators, while these effects were attenuated in the CD44-null mice. Thus, our study provides a better understanding of how HA-NP modulates fat accumulation and presents a potential anti-obesity strategy targeting CD44.


Assuntos
Adipogenia/efeitos dos fármacos , Receptores de Hialuronatos/genética , Ácido Hialurônico/administração & dosagem , Lipogênese/efeitos dos fármacos , Nanopartículas/administração & dosagem , Obesidade/tratamento farmacológico , Células 3T3-L1 , Animais , Dieta Hiperlipídica , Ácido Hialurônico/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/química , Obesidade/genética , Obesidade/metabolismo
6.
Bioconjug Chem ; 30(1): 210-217, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30562008

RESUMO

Herein, we developed a near-infrared (NIR) fluorescent probe for mitochondrial staining based on the NIR fluorochrome, silicon-rhodamine. The hydrophobicity of the fluorescent core was systematically modified by conjugation with 10 different commercial amines. The resulting fluorescent compounds exhibited similar photophysical properties but diverse hydrophobicity. We identified the optimal level of hydrophobicity associated with high mitochondrial targeting efficiency. In particular, the SiR-Mito 8 probe provided excellent mitochondrial staining and successfully differentiated the live Hep3B cancer cells from normal L02 cells in vitro.


Assuntos
Corantes Fluorescentes/farmacologia , Mitocôndrias/efeitos dos fármacos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Imagem Óptica , Células RAW 264.7 , Rodaminas/química
7.
FASEB J ; 33(3): 4314-4326, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30566396

RESUMO

The overactivity of cannabinoid 1 receptor (CB1R) is associated with obesity and type 2 diabetes. First-generation CB1R antagonists, such as rimonabant, offered therapeutic advantages for the control of obesity and related metabolic abnormalities, but their therapeutic potential was limited by undesirable neuropsychiatric side effects. Here, we evaluated AJ5012 as a novel potent peripheral CB1R antagonist and, using this antagonist, investigated the role of peripheral CB1R on adipose tissue inflammation in obese mouse models. AJ5012 had a high degree of CB1R and cannabinoid 2 receptor selectivity but a low brain:plasma concentration ratio without eliciting centrally mediated neurobehavioral effects. In diet-induced obese (DIO) mice, AJ5012 did not reduce food intake but did induce a significant weight loss, likely owing to an increased energy expenditure. It was as effective as rimonabant for the improvement of hormonal or metabolic abnormalities, glycemic control, and insulin sensitivity. The treatment of DIO and leptin receptor-deficient mice with AJ5012 also exhibited effects comparable to rimonabant for the prevention of macrophage infiltration, activation of the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome, and production of proinflammatory cytokines, which resulted in the suppression of adipose tissue inflammation. In addition to macrophage, activation of CB1R in 3T3-L1 adipocytes induced the expression of proinflammatory genes, which was fully inhibited by AJ5012. Our findings identified AJ5012 as a novel peripheral CB1R antagonist and suggest that peripheral CB1R blockade might break the links between insulin resistance and adipose tissue inflammation.-Han, J. H., Shin, H., Park, J.-Y., Rho, J. G., Son, D. H., Kim, K. W., Seong, J. K., Yoon, S.-H., Kim, W. A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Células 3T3 , Tecido Adiposo/metabolismo , Animais , Células CHO , Cricetulus , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Resistência à Insulina/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Células RAW 264.7 , Receptor CB2 de Canabinoide/metabolismo , Rimonabanto/metabolismo , Redução de Peso/efeitos dos fármacos
8.
Sci Transl Med ; 10(462)2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305454

RESUMO

Developing and mature chondrocytes constantly interact with and remodel the surrounding extracellular matrix (ECM). Recent research indicates that integrin-ECM interaction is differentially regulated during cartilage formation (chondrogenesis). Integrin signaling is also a key source of the catabolic reactions responsible for joint destruction in both rheumatoid arthritis and osteoarthritis. However, we do not understand how chondrocytes dynamically regulate integrin signaling in such an ECM-rich environment. Here, we found that developing chondrocytes express integrin-ß-like 1 (Itgbl1) at specific stages, inhibiting integrin signaling and promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 is secreted and physically interacts with integrins to down-regulate activity. We observed that Itgbl1 expression was strongly reduced in the damaged articular cartilage of patients with osteoarthritis (OA). Ectopic expression of Itgbl1 protected joint cartilage against OA development in the destabilization of the medial meniscus-induced OA mouse model. Our results reveal ITGBL1 signaling as an underlying mechanism of protection against destructive cartilage disorders and suggest the potential therapeutic utility of targeting ITGBL1 to modulate integrin signaling in human disease.


Assuntos
Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrogênese , Integrina beta1/metabolismo , Osteoartrite/metabolismo , Osteoartrite/prevenção & controle , Idoso , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Condrócitos/metabolismo , Modelos Animais de Doenças , Embrião não Mamífero/metabolismo , Matriz Extracelular/metabolismo , Face/embriologia , Regulação da Expressão Gênica , Humanos , Articulações/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/patologia , Xenopus/embriologia
9.
J Pathol ; 246(2): 231-243, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30014466

RESUMO

For the majority of patients diagnosed with pancreatic neuroendocrine tumors (NETs), there is significant malignant potential with a poor prognosis; however, the molecular abnormalities and pathogenesis of pancreatic NETs have not been firmly established. Here, we report that loss of expression of the RNA-binding protein HuD correlates with low p27Kip1 (p27) levels and poor prognosis in pancreatic NETs. HuD expression was frequently lost in many human pancreatic NETs, and these pancreatic NETs showed aggressive clinicopathological phenotypes with low p27 levels, increased tumor size, higher World Health Organization grade and pT stage of the tumor, and the presence of angioinvasion. Furthermore, loss of HuD was an independent, progression-free prognostic factor in multivariate survival analysis. However, the level of HuR, a member of the same Hu protein family as HuD, was not significantly correlated with pancreatic NET size and progression. Mechanistically, HuD enhanced p27 mRNA translation by interacting with both the 5'-untranslated region (UTR) and the 3'-UTR of p27 mRNA, and consequently suppressed cell cycle progression and tumor growth. In addition, HuD competed with miR-30a-3p for binding to the 3'-UTR of p27 mRNA, suggesting an interplay between HuD and miR-30a-3p in controlling p27 translation. Our results identify HuD as a pivotal suppressor of pancreatic NET growth, and suggest that HuD has potential value as a prognostic factor of pancreatic NETs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteína Semelhante a ELAV 4/metabolismo , Neoplasias Pancreáticas/metabolismo , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Adulto , Idoso , Animais , Sítios de Ligação , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação para Baixo , Proteína Semelhante a ELAV 4/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fenótipo , Intervalo Livre de Progressão , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais , Fatores de Tempo , Carga Tumoral
10.
J Control Release ; 279: 89-98, 2018 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-29649530

RESUMO

Self-assembled hyaluronic acid nanoparticles (HA-NPs) have been extensively investigated for biomedical and pharmaceutical applications owing to their biocompatibility and receptor-binding properties. Here, we report that an empty HA-NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibited not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild-type mice, but not in CD44-null (CD44-/-) BMDMs. An in vivo biodistribution study showed the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissues (eWATs), but these were rarely observed in the eWATs of CD44-/- mice. In addition, CD44 expression and HA-NP accumulation in the eWATs were increased in mice with diet-induced obesity (DIO) compared to lean mice. Interestingly, treatment with HA-NPs in DIO mice suppressed adipose tissue inflammation as indicated by reduced macrophage content, the production of proinflammatory cytokines and NLRP3 inflammasome activity in eWATs, leading to improved insulin sensitivity and normalized blood glucose levels. Collectively, these results suggest that an empty HA-NP itself can be a therapeutic agent for the treatment of type 2 diabetes.


Assuntos
Ácido Hialurônico/administração & dosagem , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Nanopartículas/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Glicemia/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Receptores de Hialuronatos/genética , Ácido Hialurônico/farmacocinética , Inflamação/patologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Nanomedicina/métodos , Obesidade/metabolismo , Distribuição Tecidual
11.
Sci Rep ; 7: 44847, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28337997

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by suppressing translation or facilitating mRNA decay. Differential expression of miRNAs is involved in the pathogenesis of several diseases including cancer. Here, we investigated the role of-miR-24-3p as a downregulated miRNA in metastatic cancer. miR-24-3p was decreased in metastatic cancer and lower expression of miR-24-3p was related to poor survival of cancer patients. Consistently, ectopic expression of miR-24-3p suppressed the cell migration, invasion, and proliferation of MCF7, Hep3B, B16F10, SK-Hep1, and PC-3 cells by directly targeting p130Cas. Stable expression of p130Cas restored miR-24-3p-mediated inhibition of cell migration and invasion. These results suggest that miR-24-3p functions as a tumor suppressor and the miR-24-3p/p130Cas axis is a novel factor of cancer progression by regulating cell migration and invasion.


Assuntos
Proteína Substrato Associada a Crk/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/mortalidade , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
12.
PLoS One ; 11(3): e0150981, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26967640

RESUMO

Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic ß cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic ß cells. Treatment of MIN6 and ßTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic ß cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of ß-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance ß-cell function and growth in diabetes.


Assuntos
Canabinoides/farmacologia , Ciclina D2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptor CB1 de Canabinoide/fisiologia , Animais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/genética , Ciclina D2/metabolismo , Citometria de Fluxo , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor CB1 de Canabinoide/metabolismo
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