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1.
Am J Physiol Endocrinol Metab ; 319(1): E217-E231, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32516026

RESUMEN

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.


Asunto(s)
Quimiotaxis de Leucocito/inmunología , Vesículas Extracelulares/inmunología , Enfermedades de las Válvulas Cardíacas/inmunología , Células Endoteliales de la Vena Umbilical Humana/inmunología , Riñón/inmunología , Neutrófilos/inmunología , Insuficiencia Renal/inmunología , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Adulto , Animales , Estudios de Casos y Controles , Quimiocina CCL5/efectos de los fármacos , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Quimiotaxis de Leucocito/efectos de los fármacos , Dexmedetomidina/farmacología , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Femenino , Proteína Forkhead Box O3/efectos de los fármacos , Proteína Forkhead Box O3/inmunología , Proteína Forkhead Box O3/metabolismo , Enfermedades de las Válvulas Cardíacas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Fosforilación , Factor Plaquetario 4/efectos de los fármacos , Factor Plaquetario 4/inmunología , Factor Plaquetario 4/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Insuficiencia Renal/metabolismo , Vasodilatación
2.
Int Immunopharmacol ; 51: 140-147, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28837866

RESUMEN

PURPOSE: Inflammatory responses play an important role in the tissue injury during liver ischemia/reperfusion (I/R). We previously reported that resolvin D1 (RvD1) administrated prior to hepatic I/R attenuates liver injury through inhibition of inflammatory response. In this study, we investigated the effects of the aspirin-triggered resolvin D1 (AT-RvD1) on hepatic I/R and the role of miR-146b in this process. METHODS: Partial warm ischemia was performed in the left and middle hepatic lobes of Sprague-Dawley rats for 1h, followed by 6h of reperfusion. Rats received either AT-RvD1 (5µg/kg), vehicle, or AT-RvD1+miR-146b antagomir by intravenous injection 30min before ischemia. Blood and tissue samples of the rats were collected after 6-h reperfusion. RESULTS: Pretreatment with AT-RvD1 significantly diminished I/R-induced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and significantly blunted the histological injury of the liver. Moreover, AT-RvD1 significantly inhibited inflammatory response, as indicated by attenuations of TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased survival rate were observed in the AT-RvD1 group compared with the control I/R group. AT-RvD1 pretreatment increased miR-146b expression in the liver of the rats with hepatic I/R. Administration of miR-146b antagomir impaired the effects of AT-RvD1 on hepatic I/R injury in rats. Downregulation of miR-146b inhibited TRAF6 and NF-κB expression in liver. CONCLUSIONS: Pre-administration of AT-RvD1 attenuates hepatic I/R injury partly through modulation of miR-146b.


Asunto(s)
Antiinflamatorios/uso terapéutico , Aspirina/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Hígado/patología , MicroARNs/genética , Daño por Reperfusión/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Apoptosis , Aspartato Aminotransferasas/sangre , Hígado/efectos de los fármacos , Masculino , Ratones , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/genética , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Chin J Cancer ; 35: 32, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-27013185

RESUMEN

The stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play pivotal roles in the modulation of Ca(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes. Increasing evidence has implicated the dysregulation of STIM-ORAI and IP3Rs in tumorigenesis and tumor progression. By controlling the activities, structure, and/or expression levels of these Ca(2+)-transporting proteins, malignant cancer cells can hijack them to drive essential biological functions for tumor development. However, the molecular mechanisms underlying the participation of STIM-ORAI and IP3Rs in the biological behavior of cancer remain elusive. In this review, we summarize recent advances regarding STIM-ORAI and IP3Rs and discuss how they promote cell proliferation, apoptosis evasion, and cell migration through temporal and spatial rearrangements in certain types of malignant cells. An understanding of the essential roles of STIM-ORAI and IP3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.


Asunto(s)
Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Invasividad Neoplásica , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos
5.
BMC Anesthesiol ; 15: 165, 2015 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-26577339

RESUMEN

BACKGROUND: Previous studies showed that cyclooxygenase(COX) was involved in ischemia/reperfusion (I/R) injuries. Parecoxib, a selective inhibitor for COX -2, has been shown to have protective properties in reducing I/R injury in the heart, kidney and brain. The aim of this study was to investigate the effects of parecoxib on hepatic I/R and to explore the underlying mechanisms. METHODS: Fifty-two Sprague-Dawley rats were randomly divided into three groups: the sham-operation (Sham) group, the hepatic ischemia/reperfusion (I/R) group, and the parecoxib pretreated I/R (I/R + Pare) group. Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6 h of reperfusion. Rats in the I/R + Pare group received parecoxib (10 mg/kg) intraperitoneally twice a day for three consecutive days prior to ischemia. Blood and tissue samples from the groups were collected 6 h after reperfusion, and a survival study was performed. RESULTS: Pretreatment with parecoxib prior to I/R insult significantly reduced I/R-induced elevations of aminotransferases, and significantly improved the histological status of the liver. Parecoxib significantly suppressed inflammatory cascades, as demonstrated by attenuations in TNF-α and IL-6. Parecoxib significantly inhibited iNOS and nitrotyrosine expression after I/R and significantly attenuated I/R-induced apoptosis. The 7-day survival rate was increased by pre-administration of parecoxib. CONCLUSIONS: Administration of parecoxib prior to hepatic I/R attenuates hepatic injury through inhibition of inflammatory response and nitrosative stress.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Isoxazoles/farmacología , Hepatopatías/prevención & control , Daño por Reperfusión/prevención & control , Animales , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley
6.
Oncol Rep ; 34(2): 755-62, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26062728

RESUMEN

Multidrug resistance (MDR) remains a formidable challenge in the use of chemotherapy and represents a powerful obstacle to the treatment of leukemia. ATP-binding cassette subfamily B member 1 (ABCB1) is a recognized factor which causes MDR and is closely related to poor outcome and relapse in leukemia. Ongoing research concerning the strategy for inhibiting the abnormally high activity of the ABCB1 transporter is critically needed. In the present study, we sought to elucidate the interaction between ABCB1 transporter and butorphanol. Our results showed that butorphanol significantly antagonized ABCB1-mediated drug efflux and increased the intracellular drug concentration by inhibiting the transport activity of ABCB1 in leukemia cells. Mechanistic investigations demonstrated that butorphanol did not alter the protein expression or localization of ABCB1 in HL60/VCR and K562/ADR cells. Furthermore, homology modeling indicated that butorphanol could fit into the large drug-binding cavity of ABCB1 and form a binding conformation. In conclusion, butorphanol reversed the ABCB1-mediated MDR in leukemia cells by directly suppressing the efflux activity of ABCB1.


Asunto(s)
Butorfanol/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos/genética , Humanos , Leucemia/genética , Leucemia/patología , Proteínas de Neoplasias/biosíntesis , Paclitaxel/administración & dosificación
7.
Int Immunopharmacol ; 28(1): 322-7, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26118631

RESUMEN

OBJECTIVE: Inflammatory responses play an important role in the tissue damage during hepatic ischemia/reperfusion (I/R). Some resolvins have been shown to have protective properties in reducing I/R injury in the heart and kidney. The aim of the study was to investigate the effects of resolvin D1 (RvD1) on hepatic I/R. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6h of reperfusion. Rats received either RvD1 (5 µg/kg) or vehicle by intravenous injection prior to ischemia. On the basis of treatment with RvD1, some rats further received the PI3K inhibitor LY294002. Blood and tissue samples from the groups were collected after 6-h reperfusion. RESULTS: Our results indicate that the RvD1 receptor ALX/FPR2 is present in liver, and that pretreatment with RvD1 prior to I/R insult significantly blunted I/R-induced elevations of alanine aminotransferase (AST) and aspartate aminotransferase (ALT), and significantly improved the histological status of the liver. Moreover, RvD1 significantly inhibited inflammatory cascades, as demonstrated by attenuations of IL-6, TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased phosphorylation of Akt, were observed in the RvD1 group compared with the control I/R group. These effects of RvD1 on hepatic I/R injury were diminished by the PI3K inhibitor. CONCLUSIONS: Administration of RvD1 prior to hepatic I/R attenuates hepatic injury, at least in part through inhibition of inflammatory response and enhancement of phosphorylation of Akt.


Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Hepatopatías/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Ácidos Docosahexaenoicos/farmacología , Interleucina-6/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/sangre , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Peroxidasa/metabolismo , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Lipoxina/metabolismo , Daño por Reperfusión/sangre , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factor de Necrosis Tumoral alfa/genética
8.
Am J Chin Med ; 39(5): 879-87, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21905279

RESUMEN

Astragalus membranaceus, also known as huang qi, a traditional Chinese medicine, is often used in formulas for deficiency of vital energy characterized by limb weakness, pale face, and dizziness. Previous studies have shown that Astragalus membranaceus could attenuate intestinal ischemia-reperfusion injury induced by hemorrhagic shock in rats; however, the underlying mechanism still remains unclear. Using a hemorrhagic shock rat model to examine the effect of Astragalus membranaceus on intestinal mucosa injury induced by ischemia-reperfusion, we found that treatment (20 g crude drugs/kg, i.v.) produced antioxidative effects in the intestinal mucosa of rats after ischemia-reperfusion (p < 0.05). We also found that Astragalus membranaceus could partly attenuate intestinal mucosa ischemia-reperfusion injury (chiu's score, apoptosis index p < 0.05). These results suggest that Astragalus membranaceus reduces intestinal mucosa injury induced by ischemia-reperfusion in rats, at least in part, through its anti-oxidative effects.


Asunto(s)
Antioxidantes/uso terapéutico , Astragalus propinquus/química , Mucosa Intestinal/metabolismo , Extractos Vegetales/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/lesiones , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo
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