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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.
ACS Chem Neurosci ; 13(6): 818-833, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35196855

RESUMO

Aberrant activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays an essential role in multiple diseases, including Alzheimer's disease (AD) and psoriasis. We report a novel small-molecule inhibitor, NLRP3-inhibitory compound 7 (NIC7), and its derivative, which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1ß, IL-18, and lactate dehydrogenase. We examined the therapeutic potential of NIC7 in a disease model of AD by analyzing its effect on cognitive impairment as well as the expression of dopamine receptors and neuronal markers. NIC7 significantly reversed the associated disease symptoms in the mice model. On the other hand, NIC7 did not reverse the disease symptoms in the imiquimod (IMQ)-induced disease model of psoriasis. This indicates that IMQ-based psoriasis is independent of NLRP3. Overall, NIC7 and its derivative have therapeutic prospects to treat AD or NLRP3-mediated diseases.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Psoríase , Doença de Alzheimer/tratamento farmacológico , Animais , Disfunção Cognitiva/tratamento farmacológico , Inflamassomos , Interleucina-1beta , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Psoríase/induzido quimicamente
3.
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.
Sci Rep ; 8(1): 11122, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042406

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of human brain cancer. Surgery is a current gold standard for GBM treatment but the complete surgical resection of GBM is almost impossible due to their diffusive characteristics into surrounded normal brain tissues. There is an urgent need to develop a sensitive imaging tool for accurate delineation of GBM in the operating room to guide surgeons. Here we illustrate the feasibility of using near-infrared fluorescent silica coated iron oxide nanoparticles (NF-SIONs) with high water dispersion capacity and strong fluorescence stability for intraoperative imaging of GBM by targeting tumor-associated macrophages. Abundant macrophage infiltration is a key feature of GBM margins and it is well associated with poor prognosis. We synthesized NF-SIONs of about 37 nm to maximize endocytosis activity for macrophage uptake. The NF-SIONs selectively visualized tumor-associated macrophage populations by in vitro live-cell imaging and in vivo fluorescence imaging. In the orthotopic GBM xenograft models, the NF-SIONs could successfully penetrate blood-brain barrier and delineated tumor burden specifically. Taken together, this study showcased the potential applications in GBM treatment for improved intraoperative staging and more radical surgery as well as dual modality benefit in order to circumvent previous clinical failure.


Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Imagem de Difusão por Ressonância Magnética , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Nanopartículas Metálicas/química , Camundongos , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Diabetes Obes Metab ; 20(9): 2179-2189, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29740969

RESUMO

AIM: To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. MATERIALS AND METHODS: The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice. RESULTS: AJ5018 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance, as reflected by the lower brain/plasma concentration ratio and the attenuated centrally mediated neurobehavioural effects, compared with its brain-penetrant parent compound rimonabant. In DIO and db/db mice, AJ5018 exhibited comparable effects to rimonabant in improving metabolic abnormalities and suppressing macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines. CONCLUSIONS: These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.


Assuntos
Tecido Adiposo/metabolismo , Antagonistas de Receptores de Canabinoides/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamassomos/metabolismo , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/tratamento farmacológico , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Resistência à Insulina/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Rimonabanto/farmacologia
6.
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
7.
J Cell Mol Med ; 22(4): 2337-2345, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29431265

RESUMO

Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse ß-cell lines, human islets and CB1R-null (CB1R-/- ) mice, we have now investigated the role of CB1Rs in modulating ß-cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP-1-mediated cAMP accumulation and insulin secretion as well as glucose-stimulated insulin secretion in mouse ß-cell lines and human islets. In addition, silencing CB1R in mouse ß cells resulted in an increased expression of pro-insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in ß cells lacking insulin receptor. Furthermore, CB1R-/- mice had increased pro-insulin, GCK and GLUT2 expression in ß cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve ß-cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to ß-cell function in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Receptor CB1 de Canabinoide/genética , Animais , Antígenos CD/genética , AMP Cíclico/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica/genética , Glucoquinase/genética , Glucose/metabolismo , Transportador de Glucose Tipo 2/genética , Humanos , Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Receptor CB1 de Canabinoide/metabolismo , Receptor de Insulina/genética
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