RESUMEN
Drug-coated balloon (DCB) is a therapeutic method that can effectively deliver antiproliferative drugs such as paclitaxel and rapamycin (RAPA) with no permanent implants left behind. However, delayed reendothelialization due to the toxicity of the delivered drugs leads to poor therapeutic effects. Here, we propose a new design of DCB coating, which incorporates both vascular endothelial growth factor (VEGF)-encoding plasmid DNA (pDNA) that can promote endothelial repair and RAPA into protamine sulfate (PrS). We demonstrate that the PrS/pDNA/RAPA coating had stability and good anticoagulation properties in vitro. We further show that the coating exhibited excellent transfer capacity from balloon substrates to vessel walls both in vitro and in vivo. Furthermore, the PrS/pDNA/RAPA coating effectively inhibited neointimal hyperplasia after balloon-induced vascular injuries through the down-regulation of the mammalian target of Rapamycin (mTOR) and promoted endothelium regeneration through increased expression of VEGF in vivo. These data indicate that our nanocomposite coating has great potential for use as a novel coating of DCB to treat neointimal hyperplasia after vascular injuries.
Asunto(s)
Factor A de Crecimiento Endotelial Vascular , Lesiones del Sistema Vascular , Humanos , Sirolimus/farmacología , Hiperplasia/tratamiento farmacológico , Plásmidos , ADN , Factores de Crecimiento Endotelial VascularRESUMEN
Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1α (HIF-1α) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1α and ABCG2 was tested using quantitative PCR, western blotting, and immuno-fluorescence under different culture conditions and treated with UA. Knockdown of HIF-1α by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1α under different culture conditions. HIF-1α inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1α and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1α and ABCG2.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Triterpenos/farmacología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/genética , Línea Celular Tumoral , Cisplatino/farmacología , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Ováricas/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ácido UrsólicoRESUMEN
Natural killer cells are a unique type of lymphocytes with cytotoxic capacity, and play important roles against tumors and infections. Recently, natural killer cells have been increasingly valued in their effects in hepatitis B virus infection. Since hepatitis B virus is not cytopathic, the subsequent antiviral immune responses of the host are responsible for sustaining the liver injury, which may result in cirrhosis and even hepatocellular carcinoma. Many studies have confirmed that natural killer cells participate in anti-hepatitis B virus responses both in the early phase after infection and in the chronic phase viacytolysis, degranulation, and cytokine secretion. However, natural killer cells play dichotomic roles: they exert antiviral and immunoregulatory functions whilst contribute to the pathogenesis of liver injury. Here, we review the roles of natural killer cells in hepatitis B virus infection, introducing novel therapeutic strategies for controlling hepatitis B virus infection viathe modulation of natural killer cells.
Asunto(s)
Humanos , Hepatitis B/inmunología , Células Asesinas Naturales/inmunología , Ilustración MédicaRESUMEN
Natural killer cells are a unique type of lymphocytes with cytotoxic capacity, and play important roles against tumors and infections. Recently, natural killer cells have been increasingly valued in their effects in hepatitis B virus infection. Since hepatitis B virus is not cytopathic, the subsequent antiviral immune responses of the host are responsible for sustaining the liver injury, which may result in cirrhosis and even hepatocellular carcinoma. Many studies have confirmed that natural killer cells participate in anti-hepatitis B virus responses both in the early phase after infection and in the chronic phase via cytolysis, degranulation, and cytokine secretion. However, natural killer cells play dichotomic roles: they exert antiviral and immunoregulatory functions whilst contribute to the pathogenesis of liver injury. Here, we review the roles of natural killer cells in hepatitis B virus infection, introducing novel therapeutic strategies for controlling hepatitis B virus infection via the modulation of natural killer cells.
Asunto(s)
Hepatitis B/inmunología , Células Asesinas Naturales/inmunología , Humanos , Ilustración MédicaRESUMEN
Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties. The purpose of this study is to investigate the HBV DNA replication inhibition in the mouse model with betulinic acid. Hydrodynamic injection method via the tail vein with the Paywl. 3 plasmid was used to establish the animal mode (n = 15), and the mice were randomly divided into the PBS control group (n = 5), Betulinic acid treatment group (n = 5) and lamivudine control group (n = 5). The day after successful modeling , the mice would have taken Betulinic acid (100 mg x kg(-1)), lamivudine (50 mg x kg(-1)), PBS drugs orally, once daily for 7 days, blood samples were acquired from the orbital venous blood at 3, 5, 7 days after the administering, HBsAg and HBeAg in serum concentration were measured by ELISA and the mice were sacrificed after 7 days, HBV DNA southern detections were used with part of mice livers. The results showed that betulinic acid significantly inhibited the expression of HbsAg in the mice model at the fifth day compared with the control group, and there was no significant differences between the effects of lamivudine and the PBS control group; both the betulinic acid and lamivudine groups had no significant inhibition for the HBeAg expression; the HBV DNA expressions of the liver tissue from the betulinic acid and lamivudine groups were inhibited compared with the control group. Taken together, these results reveal betulinic acid can inhibit the HBsAg expression and replication of the liver HBV DNA in the mouse model.