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1.
Animals (Basel) ; 14(2)2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38254451

RESUMEN

Canine atopic dermatitis (CAD) is a genetically predisposed inflammatory pruritic skin disease. The available treatments for CAD have several adverse effects and vary in efficacy, indicating the need for the development of improved treatments. In this study, we aimed to elucidate the therapeutic effects of allogeneic and xenogeneic exosomes on CAD. Six laboratory beagle dogs with CAD were randomly assigned to three treatment groups: control, canine exosome (cExos), or human exosome (hExos) groups. Dogs in the cExos and hExos groups were intravenously administered 1.5 mL of cExos (5 × 1010) and hExos (7.5 × 1011) solutions, respectively, while those in the control group were administered 1.5 mL of normal saline three times per week for 4 weeks. Skin lesion score and transepidermal water loss decreased in cExos and hExos groups compared with those in the control group. The exosome treatments decreased the serum levels of inflammatory cytokines (interferon-γ, interleukin-2, interleukin-4, interleukin-12, interleukin-13, and interleukin-31) but increased those of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-ß), indicating the immunomodulatory effect of exosomes. Skin microbiome analysis revealed that the exosome treatments alleviated skin bacterial dysbiosis. These results suggest that allogeneic and xenogeneic exosome therapy may alleviate CAD in dogs.

2.
Arthritis Res Ther ; 26(1): 2, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-38167497

RESUMEN

BACKGROUND: This study aims to investigate the potential anti-inflammatory effects of exosomes engineered to carry super-repressor IκB (Exo-srIκB), an exosome-based NF-κB inhibitor, in the context of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from patients diagnosed with RA and treated with Exo-srIκB to test the therapeutic potential. Flow cytometry analysis was performed to assess the production of inflammatory cytokines (IL-17A and GM-CSF) by the cells. ELISA was utilized to measure the levels of TNF-α, IL-17A, IL-6, and GM-CSF. Arthritis was induced in SKG mice by intraperitoneal injection of curdlan. DBA/1 J mice were used in collagen-induced arthritis (CIA) experiments. After the development of arthritis, mice were injected with either Exo-Naïve (control exosome) or Exo-srIκB. Arthritis scores were recorded biweekly, and histological observations of the ankle joint were conducted using H&E and safranin-O staining. Additionally, bone erosion was evaluated using micro-CT imaging. RESULTS: In the ex vivo study involving human PBMCs and SFMCs, treatment with Exo-srIκB demonstrated a notable reduction in inflammatory cytokines. Furthermore, in both the SKG and CIA models, Exo-srIκB treatment exhibited significant reductions in inflammation, cartilage destruction, and bone erosion within the joint tissues when compared to the Exo-Naive control group. Additionally, the radiographic score assessed through microCT showed a significant decrease compared to the Exo-Naive control group. CONCLUSION: Overall, these findings suggest that Exo-srIκB possesses anti-inflammatory properties in human RA cells and animal models, making it a promising therapeutic candidate for the treatment of RA.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Exosomas , Humanos , Ratones , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Interleucina-17 , Inhibidor NF-kappaB alfa , Leucocitos Mononucleares/patología , Ratones Endogámicos DBA , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Inflamación/tratamiento farmacológico , Citocinas , Artritis Experimental/patología , Antiinflamatorios/uso terapéutico
3.
Membranes (Basel) ; 12(1)2022 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-35054611

RESUMEN

Among extracellular vesicles, exosomes have gained great attention for their role as therapeutic vehicles for delivering various active pharmaceutical ingredients (APIs). Exosomes "armed" with anti-cancer therapeutics possess great potential for an efficient intracellular delivery of anti-cancer APIs and enhanced targetability to tumor cells. Various technologies are being developed to efficiently incorporate anti-cancer APIs such as genetic materials (miRNA, siRNA, mRNA), chemotherapeutics, and proteins into exosomes and to induce targeted delivery to tumor burden by exosomal surface modification. Exosomes can incorporate the desired therapeutic molecules via direct exogenous methods (e.g., electroporation and sonication) or indirect methods by modifying cells to produce "armed" exosomes. The targeted delivery of "armed" exosomes to tumor burden could be accomplished either by "passive" targeting using the natural tropism of exosomes or by "active" targeting via the surface engineering of exosomal membranes. Although anti-cancer exosome therapeutics demonstrated promising results in preclinical studies, success in clinical trials requires thorough validation in terms of chemistry, manufacturing, and control techniques. While exosomes possess multiple advantages over synthetic nanoparticles, challenges remain in increasing the loading efficiency of anti-cancer agents into exosomes, as well as establishing quantitative and qualitative analytical methods for monitoring the delivery of in vivo administered exosomes and exosome-incorporated anti-cancer agents to the tumor parenchyma.

4.
Pharmaceutics ; 14(6)2022 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-35745690

RESUMEN

For the successful clinical advancement of exosome therapeutics, the biodistribution and pharmacokinetic profile of exogenous exosomes in various animal models must be determined. Compared with fluorescence or bioluminescence imaging, radionuclide imaging confers multiple advantages for the in vivo tracking of biomolecular therapeutics because of its excellent sensitivity for deep tissue imaging and potential for quantitative measurement. Herein, we assessed the quantitative biodistribution and pharmacokinetics of good manufacturing practice-grade therapeutic exosomes labeled with zirconium-89 (89Zr) after systemic intravenous administration in mice and rats. Quantitative biodistribution analysis by positron emission tomography/computed tomography and gamma counting in mice and rats revealed that the total 89Zr signals in the organs were lower in rats than in mice, suggesting a higher excretion rate of exosomes in rats. A prolonged 89Zr signal for up to 7 days in most organs indicated that substantial amounts of exosomes were taken up by the parenchymal cells in those organs, highlighting the therapeutic potential of exosomes for the intracellular delivery of therapeutics. Exosomes were mainly distributed in the liver and to a lesser extent in the spleen, while a moderately distributed in the kidney, lung, stomach, intestine, urinary bladder, brain, and heart. Exosomes were rapidly cleared from the blood circulation, with a rate greater than that of free 89Zr, indicating that exosomes might be rapidly taken up by cells and tissues.

5.
J Neurochem ; 109(5): 1483-96, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19457162

RESUMEN

Although there is known to be a marked concentration of reactive microglia in the substantia nigra pars compacta (SNpc) of patients with Parkinson's disease (PD), a disorder in which alpha-synuclein plays a key pathogenic role, the specific roles of alpha-synuclein and microglia remains poorly understood. In this study, we investigated the effects of alpha-synuclein and the mechanisms of invasive microglial migration into the SNpc. We show that alpha-synuclein up-regulates the expressions of the cell adhesion molecule CD44 and the cell surface protease membrane-type 1 matrix metalloproteinase through the extracellular regulated kinases 1/2 pathway. These concurrent inductions increased the generation of soluble CD44 to liberate microglia from the surrounding extracellular matrix for migration. The effects of alpha-synuclein were identical in BV-2 murine microglial cells subjected to cDNA transfection and extracellular treatment. These inductions in primary microglial cultures of C57Bl/6 mice were identical to those in BV-2 cells. alpha-Synuclein-induced microglial migration into the SNpc was confirmed in vivo using a 6-hydroxydopamine mouse model of PD. Our data demonstrate a correlation between alpha-synuclein-induced phenotypic changes and microglial migration. With the recruitment of the microglial population into the SNpc during dopaminergic neurodegeneration, alpha-synuclein may play a role in accelerating the pathogenesis of PD.


Asunto(s)
Movimiento Celular/fisiología , Receptores de Hialuranos/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Microglía/fisiología , Regulación hacia Arriba/fisiología , alfa-Sinucleína/fisiología , Animales , Encéfalo/citología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Trasplante de Células/métodos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Modelos Animales de Enfermedad , Receptores de Hialuranos/genética , Metaloproteinasa 14 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/cirugía , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/cirugía , Transfección , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , alfa-Sinucleína/genética
6.
Mol Cell Biol ; 26(11): 4327-38, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16705182

RESUMEN

Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3beta and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.


Asunto(s)
Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Núcleo Celular/metabolismo , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Treonina/metabolismo , Transporte Activo de Núcleo Celular , Enfermedad de Alzheimer/patología , Animales , Encéfalo/citología , Encéfalo/patología , Muerte Celular , Células Cultivadas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Ratones Transgénicos , Mutación/genética , Factor de Crecimiento Nervioso/farmacología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Proteínas Nucleares/metabolismo , Células PC12 , Fosforilación , Estructura Terciaria de Proteína , Transporte de Proteínas , Ratas , Proteínas tau/metabolismo
7.
Int J Dev Neurosci ; 24(1): 81-5, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16289942

RESUMEN

Huntington's disease (HD) is a dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the gene encoding huntingtin. Moreover, the nuclear targeting of mutant huntingtin increases cellular toxicity, whereas normal huntingtin resides mainly in the cytoplasm, and is associated with membranes or microtubules. Huntingtin is enriched in neurons and its expression is increased during neural development. The inactivation of the HD gene results in embryonic lethality before nervous system development. Thus, huntingtin is critical during early embryonic development. Nevertheless, the function of huntingtin at this stage is unknown, even the distribution of the protein has not been described. The present study was undertaken to elucidate the distribution of huntingtin during the early developmental period in the mouse embryo. At the preimplantation stage, huntingtin was detected in nuclei up to 2.5 days post coitum (dpc), but disappeared from nuclei during the blastocyst stage (3.5 dpc). Following this stage, huntingtin was mainly localized in the cytoplasm and co-localized with mitotic spindles. These data suggest that the nuclear targeting of normal huntingtin is required during early embryo development in mice.


Asunto(s)
Blastocisto/metabolismo , Núcleo Celular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Animales , Blastocisto/citología , Humanos , Proteína Huntingtina , Enfermedad de Huntington , Inmunohistoquímica , Ratones , Oocitos/citología , Oocitos/metabolismo
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