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1.
ACS Appl Mater Interfaces ; 13(14): 15959-15972, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33797220

RESUMO

Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/patologia , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Hipertermia Induzida , Nanopartículas de Magnetita/química , Células-Tronco Neoplásicas/patologia , Terapia Combinada , Humanos
2.
Pharmacol Res ; 160: 105064, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32634582

RESUMO

N-Acylethanolamine acid amidase (NAAA) deactivates the endogenous peroxisome proliferator-activated receptor-α (PPAR-α) agonist palmitoylethanolamide (PEA). NAAA-regulated PEA signaling participates in the control of peripheral inflammation, but evidence suggests also a role in the modulation of neuroinflammatory pathologies such as multiple sclerosis (MS). Here we show that disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS is accompanied by induction of NAAA expression in spinal cord, which in presymptomatic animals is confined to motor neurons and oligodendrocytes but, as EAE progresses, extends to microglia/macrophages and other cell types. As previously reported for NAAA inhibition, genetic NAAA deletion delayed disease onset and attenuated symptom intensity in female EAE mice, suggesting that accrued NAAA expression may contribute to pathology. To further delineate the role of NAAA in EAE, we generated a mouse line that selectively overexpresses the enzyme in macrophages, microglia and other monocyte-derived cells. Non-stimulated alveolar macrophages from these NaaaCD11b+ mice contain higher-than-normal levels of inducible nitric oxide synthase and display an activated morphology. Furthermore, intranasal lipopolysaccharide injections cause greater alveolar leukocyte accumulation in NaaaCD11b+ than in control mice. NaaaCD11b+ mice also display a more aggressive clinical response to EAE induction, compared to their wild-type littermates. The results identify NAAA as a critical control step in EAE pathogenesis, and point to this enzyme as a possible target for the treatment of MS.


Assuntos
Amidoidrolases/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/enzimologia , Esclerose Múltipla/patologia , Amidoidrolases/genética , Animais , Progressão da Doença , Feminino , Lipopolissacarídeos , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/enzimologia , Neurônios Motores/enzimologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Oligodendroglia/metabolismo , Medula Espinal/enzimologia
3.
Adv Funct Mater ; 30(28): 2002362, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32684910

RESUMO

Here, cation exchange (CE) reactions are exploited to radiolabel ZnSe, ZnS, and CuFeS2 metal chalcogenide nanocrystals (NCs) with 64Cu. The CE protocol requires one simple step, to mix the water-soluble NCs with a 64Cu solution, in the presence of vitamin C used to reduce Cu(II) to Cu(I). Given the quantitative cation replacement on the NCs, a high radiochemical yield, up to 99%, is reached. Also, provided that there is no free 64Cu, no purification step is needed, making the protocol easily translatable to the clinic. A unique aspect of the approach is the achievement of an unprecedentedly high specific activity: by exploiting a volumetric CE, the strategy enables to concentrate a large dose of 64Cu (18.5 MBq) in a small NC dose (0.18 µg), reaching a specific activity of 103 TBq g-1. Finally, the characteristic dielectric resonance peak, still present for the radiolabeled 64Cu:CuFeS2 NCs after the partial-CE reaction, enables the generation of heat under clinical laser exposure (1 W cm-2). The synergic toxicity of photo-ablation and 64Cu ionization is here proven on glioblastoma and epidermoid carcinoma tumor cells, while no intrinsic cytotoxicity is seen from the NC dose employed for these dual experiments.

4.
J Invest Dermatol ; 138(3): 562-569, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29054595

RESUMO

N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase highly expressed in macrophages and B lymphocytes, catalyzes the degradation of palmitoylethanolamide. Palmitoylethanolamide is an agonist of PPAR-α and an important regulator of pain and innate immunity. In this study, we investigated the properties of the NAAA inhibitor, ARN077, in a mouse model of allergic contact dermatitis. Acute topical applications of ARN077 attenuated key signs of DNFB-induced dermatitis in a dose-dependent manner. Moreover, ARN077 increased tissue palmitoylethanolamide content and normalized circulating levels of cytokines and immunoglobulin E. No such effect was seen in PPAR-α-deficient mice. Moreover, mice lacking NAAA failed to develop edema or scratching behavior after challenge with DNFB, confirming that this enzyme plays an important role in dermatitis. Consistent with this conclusion, subchronic applications of ARN077 suppressed DNFB-induced inflammation when administered either before or after the DNFB challenge. The effects of subchronic ARN077 were dose dependent and comparable in size to those produced by the steroids clobetasol and dexamethasone. Unlike the latter, however, ARN077 did not cause skin atrophy. The results identify NAAA as a promising target for the development of effective and safe treatments for atopic dermatitis and other inflammatory disorders of the skin.


Assuntos
Amidoidrolases/antagonistas & inibidores , Carbamatos/uso terapêutico , Dermatite Alérgica de Contato/tratamento farmacológico , Éteres Cíclicos/uso terapêutico , Inflamação/tratamento farmacológico , Prurido/tratamento farmacológico , Amidas , Amidoidrolases/fisiologia , Animais , Dermatite Alérgica de Contato/etiologia , Dinitrofluorbenzeno , Modelos Animais de Doenças , Etanolaminas/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Palmíticos/análise
5.
Theranostics ; 7(15): 3653-3666, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29109767

RESUMO

Corticosteroids, such as dexamethasone (DEX), are the mainstays for the treatment of moderate to severe inflammatory bowel disease (IBD). However, their relatively poor bioavailability and lack of specificity is often the origin of short and long-term adverse effects. Here, spherical polymeric nanoconstructs (SPNs) encapsulating dexamethasone are proposed for the systemic treatment of IBD. In a mouse model of colitis, the accumulation of SPNs within the inflamed intestine is firstly assessed using near infra-red fluorescent (NIRF) imaging at different stages of the disease - 5, 7 and 10 days of Dextran Sulfate Sodium (DSS) administration. Then, the efficacy of DEX-SPNs is tested in vitro over macrophages and in vivo by monitoring the animal weight, food and water intake; expression of inflammatory cytokines (TNF-α, IL-1ß, IL-6); intestinal density of macrophages; rectal bleeding and histological scoring. 150 nm DEX-SPNs are shown to deposit within the hyper-permeable inflamed intestine in a disease severity-dependent fashion. DEX-SPNs exposed to LPS-stimulated RAW 264.7 cells reduce the expression of inflammatory cytokines as rapidly as free DEX. In DSS-administered mice, DEX-SPNs treatments improve weight loss, reduce the macrophage infiltration, expression of inflammatory cytokines, rectal bleeding and histological scoring, as compared to free DEX. Moreover, DEX-SPNs exert a strong systemic anti-inflammatory effect and facilitate animal recovery. This work confirms the benefits of using sufficiently small nanoconstructs for targeting inflamed, hyper-permeable tissues and efficiently delivering high doses of corticosteroids for the treatment of intestinal and systemic inflammation.


Assuntos
Dexametasona/química , Nanoestruturas/química , Polímeros/química , Animais , Sulfato de Dextrana/química , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Camundongos , Nanopartículas/química , Células RAW 264.7
6.
Pharmacol Res ; 100: 288-95, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26319800

RESUMO

Disruption of the circadian clock is associated with a variety of human pathologies, including cancer. Rather than being a mere consequence of a global changes associated with the cancer cell transcriptome, the aberrant clock gene expression observed in many tumors may serve for cancer cell survival. This scenario suggests the provocative hypothesis that pharmacological modulation of clock-related proteins may be suitable as an effective anticancer strategy. In this review, we focus on the functions of the druggable circadian nuclear receptors, REV-ERBα and REV-ERBß, in cancer cell survival and describe the potential development of small molecule compounds that modulate REV-ERB activity as novel anticancer therapeutics. In addition, we debate the use of circadian rhythm-based synthetic lethal approaches to identify yet unexplored anticancer strategies.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Humanos , Neoplasias/genética , Receptores Citoplasmáticos e Nucleares/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
7.
J Med Chem ; 58(15): 5900-15, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26135471

RESUMO

Autophagy inhibition is emerging as a promising anticancer strategy. We recently reported that the circadian nuclear receptor REV-ERBß plays an unexpected role in sustaining cancer cell survival when the autophagy flux is compromised. We also identified 4-[[[1-(2-fluorophenyl)cyclopentyl]amino]methyl]-2-[(4-methylpiperazin-1-yl)methyl]phenol, 1 (ARN5187), as a novel dual inhibitor of REV-ERBß and autophagy. 1 had improved cytotoxicity against BT-474 breast cancer cells compared to chloroquine, a clinically relevant autophagy inhibitor. Here, we present the results of structure-activity studies, based around 1, that disclose the first class of dual inhibitors of REV-ERBß and autophagy. This study led to identification of 18 and 28, which were more effective REV-ERBß antagonists than 1 and were more cytotoxic to BT-474. The combination of optimal chemical and structural moieties of these analogs generated 30, which elicited 15-fold greater REV-ERBß inhibitory and cytotoxic activities compared to 1. Furthermore, 30 induced death in a panel of tumor cell lines at doses 5-50 times lower than an equitoxic amount of chloroquine but did not affect the viability of normal mammary epithelial cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Técnicas In Vitro , Relação Estrutura-Atividade
8.
Mol Endocrinol ; 27(6): 953-65, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23608643

RESUMO

Dopamine acting through D2 receptors (D2Rs) controls lactotroph proliferation and prolactin (PRL) levels. Ablation of this receptor in mice results in lactotroph hyperplasia and prolactinomas in aged females. Alternative splicing of the Drd2 gene generates 2 independent isoforms, a long (D2L) and a short (D2S) isoform, which are present in all D2R-expressing cells. Here, we addressed the role of D2L and D2S on lactotroph physiology through the generation and analysis of D2S-null mice and their comparison with D2L-null animals. These mice represent a valuable tool with which to investigate dopamine-dependent isoform-specific signaling in the pituitary gland. We sought to assess the existence of a more prominent role of D2L or D2S in controlling PRL expression and lactotroph hyperplasia. Importantly, we found that D2L and D2S are specifically linked to independent transduction pathways in the pituitary. D2L-mediated signaling inhibits the AKT/protein kinase B kinase activity whereas D2S, in contrast, is required for the activation of the ERK 1/2 pathway. Under normal conditions, presence of only 1 of the 2 D2R isoforms in vivo prevents hyperprolactinemia, formation of lactotroph's hyperplasia, and tumorigenesis that is observed when both isoforms are deleted as in D2R-/- mice. However, the protective function of the single D2R isoforms is overridden when single isoform-knockout mice are challenged by chronic estrogen treatments as they show increased PRL production and lactotroph hyperplasia. Our study indicates that signaling from each of the D2R isoforms is sufficient to maintain lactotroph homeostasis in physiologic conditions; however, signaling from both is necessary in conditions simulating pathologic states.


Assuntos
Lactotrofos/fisiologia , Receptores de Dopamina D2/metabolismo , Animais , Carcinogênese/metabolismo , Linhagem Celular , Estradiol/fisiologia , Estrogênios/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Hiperplasia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Hipófise/metabolismo , Hipófise/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt , Receptores de Dopamina D2/genética , Transdução de Sinais
9.
J Neurosci ; 32(26): 9023-34, 2012 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-22745501

RESUMO

Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic- versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.


Assuntos
Dopamina/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Terminações Pré-Sinápticas/metabolismo , Receptores de Dopamina D2/metabolismo , Sinapses/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Análise de Variância , Animais , Biofísica , Cromatografia Líquida de Alta Pressão/métodos , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica/métodos , Técnicas Eletroquímicas , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Ácido Homovanílico/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Mutação/genética , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Terminações Pré-Sinápticas/efeitos dos fármacos , Quimpirol/farmacologia , RNA Mensageiro/metabolismo , Tempo de Reação/genética , Receptores de Dopamina D2/genética , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos
10.
PLoS One ; 6(5): e19849, 2011 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-21589880

RESUMO

Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.


Assuntos
Rede Nervosa , Oligodendroglia/fisiologia , Animais , Camundongos , Camundongos Transgênicos
11.
Curr Opin Pharmacol ; 9(1): 53-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19138563

RESUMO

Dopamine (DA) signaling controls many physiological functions ranging from locomotion to hormone secretion, and plays a critical role in addiction. DA elevation, for instance in response to drugs of abuse, simultaneously activates neurons expressing different DA receptors; how responses from diverse neurons/receptors are orchestrated in the generation of behavioral and cellular outcomes, is still not completely defined. Signaling from D2 receptors (D2Rs) is a good example to illustrate this complexity. D2Rs have presynaptic and postsynaptic localization and functions, which are shared by two isoforms in vivo. Recent results from knockout mice are clarifying the role of site and D2 isoform-specific effects thereby increasing our understanding of how DA modulates neuronal physiology.


Assuntos
Dopamina/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores Pré-Sinápticos/fisiologia , Sinapses/fisiologia , Animais , Cocaína/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Mutação , Neurônios/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/genética , Receptores Pré-Sinápticos/agonistas , Receptores Pré-Sinápticos/antagonistas & inibidores , Reforço Psicológico , Recompensa , Transmissão Sináptica
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