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1.
Adv Mater ; 34(1): e2106265, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34613627

RESUMO

Autoimmune diseases are the third most common disease influencing the quality of life of many patients. Here, a programmed cell death-ligand 1 + (PD-L1) mesenchymal stem cell (MSC) derived extracellular vesicles (MSC-sEVs-PD-L1) using lentivirus-mediated gene transfection technology is developed for reconfiguration of the local immune microenvironment of affected tissue in autoimmune diseases. MSC-sEVs-PD-L1 exhibits an impressive ability to regulate various activated immune cells to an immunosuppressed state in vitro. More importantly, in dextran sulfate sodium-induced ulcerative colitis (UC) and imiquimod-induced psoriasis mouse models, a significantly high accumulation of MSC-sEVs-PD-L1 is observed in the inflamed tissues compared to the PD-L1+ MSCs. Therapeutic efficiency in both UC and psoriasis mouse disease models is demonstrated using MSC-sEVs-PD-L1 to reshape the inflammatory ecosystem in the local immune context. A technology is developed using MSC-sEVs-PD-L1 as a natural delivery platform for autoimmune diseases treatment with high clinical potential.


Assuntos
Doenças Autoimunes , Vesículas Extracelulares , Células-Tronco Mesenquimais , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/terapia , Antígeno B7-H1/genética , Ecossistema , Vesículas Extracelulares/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Qualidade de Vida
2.
ACS Nano ; 15(5): 9111-9125, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-33988024

RESUMO

Immune checkpoint blockade (ICB) therapy has been considered as an effective way to boost immune cells to recognize and attack tumors. However, side effects known as immune-related adverse events (irAEs) should be carefully managed. Here, we engineer immunosuppressive nanoparticles by coating PD-L1 overexpressed mesenchymal stem cells (MSCs) plasma membrane on poly lactic-co-glycolic acid nanoparticles (MSC-PD-L1+ NPs) for managing and reducing irAEs induced by immune checkpoint inhibitors. The nanoparticles can enrich at liver site after intravenous administration. In the high dose of anti-PD-L1 mAb-induced irAEs clinically relevant mouse model, a low dose of MSC-PD-L1+ NPs (2 mg/kg) sufficiently rescues hepatitis by inactivating T cells and macrophages in the liver tissue. More intriguingly, due to the dose threshold for nanoparticles to the tumor site, we unexpectedly find that the injected NPs do not affect the efficiency of ICB therapy to inhibit solid tumor growth. Such a strategy shows potential for managing the various cancer immunotherapy associated irAEs in clinical applications.


Assuntos
Antineoplásicos Imunológicos , Nanopartículas , Neoplasias , Animais , Imunoterapia , Fígado , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/uso terapêutico
3.
Free Radic Biol Med ; 160: 319-333, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-32828953

RESUMO

Previous studies have shown that syntaxin 17 (STX17) is involved in mediating the fusion of autophagosomes and lysosomes. This study aimed to investigate the role and mechanism of STX17 in neuronal injury following cerebral ischemia/reperfusion. The ischemia/reperfusion (I/R) models were established by transient middle cerebral artery occlusion (tMCAO) in mice and oxygen glucose deprivation/reperfusion (O/R) in primary cultured cortical neurons and HT22 cells. Cerebral ischemia/reperfusion significantly up-regulated the expression of STX17 in neurons. Lentivirus mediated knockdown of STX17 in neurons reduced neuronal viability and increased LDH leakage. Injection of AAV9-shSTX17 into the brain of mice then subjected to tMCAO also significantly augmented the infarct area and exacerbated neurobehavioral deficits and mortality. Depletion of STX17 caused accumulation of autophagic marker/substrate LC3 II and p62, blockade of the autophagic flux, and the accumulation of dysfunctional lysosomes. Knockdown of STX17 also aggravated endoplasmic reticulum (ER) stress-dependent neuronal apoptosis induced by ischemia/reperfusion. Importantly, induction of autophagy-lysosomal pathway and alleviation of ER stress partially rescued STX17 knockdown-induced neuronal damage. These results suggest that STX17 may ameliorate ischemia/reperfusion-induced neuronal damage by enhancing autophagy flux and reducing ER stress-dependent neuronal apoptosis.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Apoptose , Autofagia , Estresse do Retículo Endoplasmático , Infarto da Artéria Cerebral Média , Camundongos , Neurônios , Proteínas Qa-SNARE , Traumatismo por Reperfusão/genética
4.
Methods Mol Biol ; 2126: 85-93, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32112381

RESUMO

Near-infrared (NIR)-to-visible upconversion nanomaterials (UCNPs) used as biomedical nanoprobes have considerable advantages over the traditional used "downconversion" fluorescent dyes. Functionalized upconversion nanoparticles (UCNPs) represent high sensitivity and great biocompatibility. Cells labeled with these UCNPs can be tracked for long term in vivo. Here we describe UCNP-PEG-ARG for highly sensitive in vivo cell tracking.


Assuntos
Rastreamento de Células/métodos , Corantes Fluorescentes/química , Células-Tronco Mesenquimais/citologia , Imagem Molecular/métodos , Nanopartículas/química , Animais , Sobrevivência Celular , Camundongos
5.
Sci Adv ; 5(10): eaaw6870, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31681841

RESUMO

Erythrocytes or red blood cells (RBCs) represent a promising cell-mediated drug delivery platform due to their inherent biocompatibility. Here, we developed an antigen delivery system based on the nanoerythrosomes derived from RBCs, inspired by the splenic antigen-presenting cell targeting capacity of senescent RBCs. Tumor antigens were loaded onto the nanoerythrosomes by fusing tumor cell membrane-associated antigens with nanoerythrosomes. This tumor antigen-loaded nanoerythrosomes (nano-Ag@erythrosome) elicited antigen responses in vivo and, in combination with the anti-programmed death ligand 1 (PD-L1) blockade, inhibited the tumor growth in B16F10 and 4T1 tumor models. We also generated a tumor model showing that "personalized nano-Ag@erythrosomes" could be achieved by fusing RBCs and surgically removed tumors, which effectively reduced tumor recurrence and metastasis after surgery.


Assuntos
Antígenos/imunologia , Eritrócitos/metabolismo , Imunoterapia , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/terapia , Proteolipídeos/química , Animais , Células Apresentadoras de Antígenos/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores/metabolismo , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/cirurgia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Baço/patologia , Resultado do Tratamento
6.
Molecules ; 18(3): 2458-68, 2013 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-23439562

RESUMO

Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+)-5,6-dehydrolycorine (1), (+)-3α,6ß-diacetyl-bulbispermine (2), (+)-3α-hydroxy-6ß-acetyl- bulbispermine (3), (+)-8,9-methylenedioxylhomolycorine-N-oxide (5), and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7), together with two known compounds, (+)-3α-methoxy- 6ß-acetylbulbispermine (4) and (+)-homolycorine- N-oxide (6). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251), as well as HL-60, SMMC-7721, and W480 cell lines with IC(50) values of 9.4-11.6 µM. Additonally, compound 1 exhibited antimalarial activity with IC(50) values of 2.3 µM for D-6 strain and 1.9 µM for W-2 strain of Plasmodium falciparum.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Antimaláricos/farmacologia , Lycoris/química , Raízes de Plantas/química , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/toxicidade , Antimaláricos/química , Antimaláricos/toxicidade , Linhagem Celular Tumoral , Células HL-60 , Humanos , Ressonância Magnética Nuclear Biomolecular , Testes de Sensibilidade Parasitária , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos
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