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1.
Arterioscler Thromb Vasc Biol ; 42(5): 580-596, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35387478

RESUMEN

BACKGROUND: Macrophages are implicated in atherosclerotic plaque instability by inflammation and degradation of extracellular matrix. However, the regulatory mechanisms driving these macrophage-associated processes are not well understood. Here, we aimed to identify the plaque destabilization-associated cytokines and signaling pathways in macrophages. METHODS: The atherosclerotic models of myeloid-specific MVP (major vault protein) knockout mice and control mice were generated. Atherosclerotic instability, macrophage inflammatory signaling, and active cytokines released by macrophages were examined in vivo and in vitro by using cellular and molecular biological approaches. RESULTS: MVP deficiency in myeloid cells exacerbated murine plaque instability by increasing production of both MMP (matrix metallopeptidase)-9 and proinflammatory cytokines in artery wall. Mechanistically, expression of MMP-9 was mediated via ASK1 (apoptosis signal-regulating kinase 1)-MKK-4 (mitogen-activated protein kinase kinase 4)-JNK (c-Jun N-terminal kinase) signaling in macrophages. MVP and its α-helical domain could bind with ASK1 and inhibit its dimerization and phosphorylation. A 62 amino acid peptide (MVP-[686-747]) in the α-helical domain of MVP showed a crucial role in preventing macrophage MMP-9 production and plaque instability. CONCLUSIONS: MVP may act as an inhibitor for ASK1-JNK signaling-mediated MMP-9 production in macrophages and, thereby, attenuate unstable plaque formation. Our findings suggest that suppression of macrophage ASK1-JNK signaling may be a useful strategy antagonizing atherosclerotic diseases.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Citocinas/metabolismo , Macrófagos/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Placa Aterosclerótica/metabolismo , Partículas Ribonucleoproteicas en Bóveda
2.
IET Nanobiotechnol ; 15(1): 107-116, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34694723

RESUMEN

Ischemic stroke is often involved in the excessive production of reactive oxygen species (ROS), which aggravate ischemic injury. Edaravone (EDV) as an efficient free radical scavenger has demonstrated the effective neuroprotective effects in the therapy of ischemic stroke. Although EDV promotes ischemic recovery by inhibiting the generation of ROS, its poor safety and bioavailability limit its clinical applications. Herein, we developed plasma exosomes (EXO) containing EDV (EXO + EDV) for improving short-term functional and histological outcomes for stroke treatment. The results showed that EXO + EDV improved brain targeting based on the transferrin-transferrin receptor interaction, and the safety and bioavailability of EDV were also significantly increased. Furthermore, compared with EDV, EXO + EDV significantly rescued ischemic damage in brain tissue by reducing infarct area and improving neurological performance in the acute stage of stroke (first 7 days).


Asunto(s)
Isquemia Encefálica , Exosomas , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Encéfalo , Isquemia Encefálica/tratamiento farmacológico , Edaravona , Depuradores de Radicales Libres , Humanos , Accidente Cerebrovascular/tratamiento farmacológico
3.
Neurochem Res ; 45(9): 2161-2172, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32583212

RESUMEN

Accumulation of amyloid-ß (Aß) peptides in the brain is regarded as a major contributor to the pathogenesis and progression of Alzheimer's disease (AD). P-glycoprotein (P-gp) as a member of ABC transporter family situated in blood brain barrier (BBB) plays a role on cleaning of Aß via its efflux transport effect in the treatment of AD. However, the expression of P-gp in pathological BBB was lower than that in normal BBB, thus impeding the clearance of Aß. Here, we used human brain microvascular endothelial cells (HBMVECs) derived exosomes (HBMVECs-Ex) inheriting P-gp as an extracorporeal Aß cleansing system to remove Aß peptides from the brain by specific capture between P-gp and Aß. The results showed that HBMVECs-Ex inheriting P-gp greatly facilitated the cerebral clearance of Aß by effectively transporting Aß out of brain and potently ameliorated cognitive dysfunction in AD mice. Taken together, HBMVECs-Ex provided a new strategy on the treatment of AD.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/terapia , Exosomas , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/citología , Células Endoteliales/citología , Humanos , Masculino , Ratones Endogámicos C57BL , Prueba del Laberinto Acuático de Morris/efectos de los fármacos
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