RESUMEN
Background. Provisional side branch (SB) stenting strategy is the default approach for the majority of bifurcation lesions, but outcomes of SB is suboptimal. Though drug coated balloon (DCB) improving SB outcomes attracts an increasing attention, sequence of DCB hasn't yet been determined. We presented a novel hybrid strategy of DCB and stent for bifurcation lesions. Methods. With lesion preparation, DCB was persistently inflated in SB kissing with main branch (MB) stent deployment and balloon post-dilation of the bifurcation core. Proximal optimization technique was performed strictly not exceeding the bifurcation. Procedural and clinical adverse events were evaluated. Canadian Cardiovascular Society (CCS) angina classification was assessed at baseline and clinical follow-up. Results. Fourteen patients undergoing the hybrid technique from August 2020 to July 2021 were enrolled. The technique was successfully performed in all patients without rewiring or SB compromise. Minimal lumen diameter of SB increased from 0.60 ± 0.40 mm to 2.1 ± 0.2 mm while the percent stenosis decreased from 72.4 ± 17.9% to 19.6 ± 4.7%. In addition, intravascular ultrasound indicated comparable stent symmetry index and incomplete stent apposition between proximal and distal segments of stent. No further intervention was performed, and mean fractional flow reserve of SB (n = 12) was 0.88 ± 0.05. No major adverse cardiac events was noted in hospital and 12-month follow up. The mean CCS angina score was reduced by 84% (2.2 vs 0.4, p < .001). Conclusion. The hybrid strategy facilitates treatment of DCB and stent for bifurcation lesions, which appears to be feasible and acceptable in a short-term follow-up.
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Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Reserva del Flujo Fraccional Miocárdico , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/métodos , Angiografía Coronaria/métodos , Resultado del Tratamiento , Factores de Tiempo , Canadá , Stents , Angina de PechoRESUMEN
Acute myocardial infarction (MI) induces a sterile inflammatory response that may result in poor cardiac remodeling and dysfunction. Despite the progress in anti-cytokine biologics, anti-inflammation therapy of MI remains unsatisfactory, due largely to the lack of targeting and the complexity of cytokine interactions. Based on the nature of inflammatory chemotaxis and the cytokine-binding properties of neutrophils, we fabricated biomimetic nanoparticles for targeted and broad-spectrum anti-inflammation therapy of MI. By fusing neutrophil membranes with conventional liposomes, we fabricated biomimetic liposomes (Neu-LPs) that inherited the surface antigens of the source cells, making them ideal decoys of neutrophil-targeted biological molecules. Based on their abundant chemokine and cytokine membrane receptors, Neu-LPs targeted infarcted hearts, neutralized proinflammatory cytokines, and thus suppressed intense inflammation and regulated the immune microenvironment. Consequently, Neu-LPs showed significant therapeutic efficacy by providing cardiac protection and promoting angiogenesis in a mouse model of myocardial ischemia-reperfusion. Therefore, Neu-LPs have high clinical translation potential and could be developed as an anti-inflammatory agent to remove broad-spectrum inflammatory cytokines during MI and other neutrophil-involved diseases.
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Citocinas , Neutrófilos , Animales , Antiinflamatorios , Biomimética , Modelos Animales de Enfermedad , Lipopolisacáridos , Liposomas , RatonesRESUMEN
Resolvin D1 (RvD1) has been shown to provide effective protection against ischemia-reperfusion injury in multiple vital organs such as the heart, brain, kidney. However, the clinical translational potential of systemic administration of RvD1 in the treatment of ischemia-reperfusion injury is greatly limited due to biological instability and lack of targeting ability. Combining the natural inflammatory response and reactive oxygen species (ROS) overproduction after reperfusion injury, we developed a platelet-bionic, ROS-responsive RvD1 delivery platform. The resulting formulation enables targeted delivery of RvD1 to the injury site by hijacking circulating chemotactic monocytes, while achieving locally controlled release. In a mouse model of myocardial ischemia repefusuin (MI/R) injury, intravenous injection of our formula resulted in the enrichment of RvD1 in the injured area, which in turn promotes clearance of dead cells, production of specialized proresolving mediators (SPMs), and angiogenesis during injury repair, effectively improving cardiac function. This delivery system integrates drug bio-protection, targeted delivery and controlled release, which endow it with great clinical translational value.
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Liposomas , Daño por Reperfusión Miocárdica , Ratones , Animales , Especies Reactivas de Oxígeno , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Preparaciones de Acción RetardadaRESUMEN
BACKGROUND: Due to the technical limitations of coronary artery angiography (CAG), ramus intermedius (RI) is sometimes difficult to distinguish from a high-origin obtuse marginal branch or a high-origin diagonal branch. This study sought to investigate the role of intravascular ultrasonography (IVUS) in the rectification of angiographically judged RI. METHODS: This study retrospectively analyzed 165 patients who were reported to have an RI based on CAG and underwent IVUS implementation from 02/01/2009 to 31/12/2019 in Zhongshan Hospital, Fudan University. Taking IVUS as the gold standard, we calculated the accuracy of RI identification by CAG and evaluated the impact of RI on revascularization strategy. RESULTS: Among the 165 patients, 89 patients (54%) were demonstrated to have an RI on IVUS (IVUS-RI), 32 patients (19%) were identified to have a high-origin diagonal branch on IVUS (IVUS-h-D), and 44 patients (27%) had an actual high-origin obtuse marginal artery on IVUS (IVUS-h-OM). Among 84 patients who underwent one-stent crossover stenting because of left main furcation lesions (48 patients in the IVUS-RI group, 12 patients in the IVUS-h-D group, and 24 in the IVUS-h-OM group), 14.6% of patients in the IVUS-RI group, 33.3% in the IVUS-h-D group and 0% in the IVUS-h-OM group had CAG-RI compromise (P = 0.02), which was defined as severe stenosis of the RI ostium (> 75%) or significant RI flow impairment (TIMI < 3). CONCLUSIONS: Only 54% of CAG-RIs were confirmed by IVUS, which indicates the necessity of preintervention IVUS to distinguish real RIs from other branches in LM furcation lesions.
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Angiografía Coronaria , Estenosis Coronaria/diagnóstico por imagen , Anomalías de los Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Ultrasonografía Intervencional , Anciano , Angioplastia Coronaria con Balón/instrumentación , Toma de Decisiones Clínicas , Estenosis Coronaria/terapia , Anomalías de los Vasos Coronarios/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , StentsRESUMEN
BACKGROUND: The jailed balloon technique is widely used for coronary bifurcation lesions, but a residual risk of SB occlusion remains, necessitating SB rewiring and further interventions, including balloon inflation or stenting, which may result in failure and SB loss. This study introduced a novel modified technique of small side branch (SB) protection, namely, double kissing inflation outside the stent (DKo) technique, for coronary bifurcations without the need for SB rewiring. METHODS: We performed the DKo technique in consecutive patients in our center from 1/2019 to 12/2019. The procedure was as follows. We inserted a guide wire into both branches followed by proper preparation. The SB balloon was simultaneously inflated with main vessel (MV) stenting. The SB balloon remained in situ until it was kissing inflated with postdilation of the bifurcation core, which is different from traditional strategies. The proximal optimization technique was performed with a short noncompliant balloon strictly not exceeding the bifurcation. Rates of SB loss and in-hospital outcomes were evaluated. RESULTS: The technique was successfully performed in all 117 enrolled patients without any rewiring or SB loss. The mean lesion lengths of the MV and SB were 38.3 ± 19.9 mm and 11.7 ± 7.1 mm, respectively. On average, 1.5 ± 0.6 stents were used per patient, while the mean pressure of the SB balloon was 7.4 ± 3.1 atm. DKo achieved excellent procedural success in the proximal and distal MVs: increased minimal lumen diameter (0.64 ± 0.58 mm to 3.05 ± 0.38 mm, p < 0.001; 0.57 ± 0.63 mm to 2.67 ± 0.35 mm, p < 0.001) and low residual stenosis (11.4 ± 3.4%; 7.2 ± 4.6%). DKo secured the patency of the SB without any rewiring and improved the SB stenosis with minimal lumen diameter (0.59 ± 0.48 mm to 1.20 ± 0.42 mm, p < 0.001) and stenosis (71.9 ± 19.4% to 42.2 ± 14.0%, p < 0.001). No MACE was noted in the hospital. CONCLUSIONS: DKo for bifurcation lesions was shown to be acceptable with high procedural success and excellent SB protection.
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Angioplastia Coronaria con Balón/instrumentación , Enfermedad de la Arteria Coronaria/terapia , Stents , Grado de Desobstrucción Vascular , Anciano , Angioplastia Coronaria con Balón/efectos adversos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Reperfusion may cause injuries to the myocardium in ischemia situation. Emerging studies suggest that exosomes may serve as key mediators in myocardial ischemia/reperfusion (MI/R) injury. OBJECTIVE: The study was conducted to figure out the mechanism of M2 macrophage-derived exosomes (M2-exos) in MI/R injury with the involvement of microRNA-148a (miR-148a). METHODS AND RESULTS: M2 macrophages were prepared and M2-exos were collected and identified. Neonatal rat cardiomyocytes (NCMs) were extracted for in vitro hypoxia/reoxygenation (H/R) model establishment, while rat cardiac tissues were separated for in vivo MI/R model establishment. Differentially expressed miRNAs in NCMs and H/R-treated NCMs after M2-exos treatment were evaluated using microarray analysis. The target relation between miR-148a and thioredoxin-interacting protein (TXNIP) was identified using dual luciferase reporter gene assay. Gain- and loss- of function studies of miR-148a and TXNIP were performed to figure out their roles in MI/R injury. Meanwhile, the activation of the TLR4/NF-κB/NLRP3 inflammasome signaling pathway and pyroptosis of NCMs were evaluated. M2 macrophages carried miR-148a into NCMs. Over-expression of miR-148a enhanced viability of H/R-treated NCMs, reduced infarct size in vivo, and alleviated dysregulation of cardiac enzymes and Ca2+ overload in both models. miR-148a directly bound to the 3'-untranslated region (3'UTR) of TXNIP. Over-expressed TXNIP triggered the TLR4/NF-κB/NLRP3 signaling pathway activation and induced cell pyroptosis of NCMs, and the results were reproduced in in vivo studies. CONCLUSION: This study demonstrated that M2-exos could carry miR-148a to mitigate MI/R injury via down-regulating TXNIP and inactivating the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. This study may offer new insights into MI/R injury treatment.
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Exosomas/metabolismo , Inflamasomas/metabolismo , Macrófagos/metabolismo , MicroARNs/genética , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Transducción de Señal , Animales , Biomarcadores , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunohistoquímica , Miocitos Cardíacos/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Receptor Toll-Like 4/metabolismoRESUMEN
Poor cell homing limits the efficacy of cardiac cellular therapy. The homing peptide, cysteine-arginine-glutamic acid-lysine-alanine (CREKA), targets fibrin effectively which is involved in the repair process of tissue injury. Here, we assessed if CREKA-modified stem cells had enhanced fibrin-mediated homing ability resulting in better functional recovery and structural preservation in a rat myocardial injury model. CREKA-modified mesenchymal stem cells (CREKA-MSCs) were obtained via membrane fusion with CREKA-modified liposomes. The fibrin targeting ability of CREKA-MSCs was examined both in vitro and in vivo. Under both static and flow conditions in vitro, CREKA significantly enhanced MSCs binding ability to fibrin clots (2.6- and 2.3-fold, respectively). CREKA-MSCs showed 6.5-fold higher accumulation than unmodified MSCs in injured rat myocardium one day after administration, resulting in better structural preservation and functional recovery. Fibrin is, therefore, a novel target for enhancing homing of transplanted cells to injured myocardium, and the delivery system of fibrin-targeting is on behalf of a universalizable platform technology for regenerative medicine. Stem Cells 2019;37:663-676.
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Sistemas de Liberación de Medicamentos , Trasplante de Células Madre Mesenquimatosas , Isquemia Miocárdica/terapia , Daño por Reperfusión/terapia , Animales , Modelos Animales de Enfermedad , Fibrina/antagonistas & inhibidores , Fibrina/genética , Fibrina/farmacología , Humanos , Células Madre Mesenquimatosas/citología , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Miocardio/patología , Nanopartículas/química , Oligopéptidos/farmacología , Ratas , Daño por Reperfusión/genética , Daño por Reperfusión/patologíaRESUMEN
BACKGROUND: Provisional 1-stent technique is currently regarded as the default approach for the majority of bifurcation lesions. Nonetheless, 2-stent techniques may be required for complex bifurcations with high compromise risk or fatal consequences of side branch (SB) occlusion. Limitations exist in current approaches, as stents gap, multiple metal layers and stent malapposition caused by imprecise placement with fluoroscopic guide and intrinsic technical defects. This study was designed to investigate the effectiveness of the novel Szabo 2-stent technique for coronary bifurcation lesions. METHODS: In the Szabo 2-stent technique, one stent is precisely implanted at the SB ostium with Szabo technique resulting in a single strut protruding into the main vessel (MV). After MV rewiring and SB guidewire withdrawal, another stent is implanted in MV followed by proximal optimization technique, SB rewiring, and final kissing inflation (FKI). RESULTS: The technique tested successfully in silicone tubes (n = 9) with: procedure duration, 31.2 ± 6.8 min; MV and SB rewiring time, 26.8 ± 11.2 s and 33.3 ± 15 s; easy FKI; and 2.3 ± 0.5 balloons/procedure. Bifurcation lesions (n = 22) were treated with angiographic success in MV and SB, respectively: increased minimal lumen diameter (0.63 ± 0.32 mm to 3.20 ± 0.35 mm; 0.49 ± 0.37 mm to 2.67 ± 0.25 mm); low residual stenosis (12.4 ± 2.4%; 12.4 ± 2.3%); and intravascular ultrasound confirmed (n = 19) full coverage; minimal overlap and malapposition; minimal lumen area (2.4 ± 1.2 mm2; 2.1 ± 1.0 mm2); plaque burden (78.1 ± 11.3%; 71.6 ± 15.5%); and minimal stent area (9.1 ± 1.6 mm2; 6.1 ± 1.3 mm2). Periprocedural cardiac troponin increased in 1 asymptomatic patient without electrocardiographic change. There was no target lesion failure (cardiac death, myocardial infarction, target lesion revascularization) at 6-month follow-up. CONCLUSIONS: The Szabo 2-stent technique for bifurcation lesions provided acceptable safety and efficacy at short-term follow-up.
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Angioplastia Coronaria con Balón/instrumentación , Enfermedad de la Arteria Coronaria/terapia , Stents , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/efectos adversos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Femenino , Humanos , Masculino , Ensayo de Materiales , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Heart failure is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT) with approximately one-third of non-response rate. Thus far, there is no specific biomarker to predict the response to CRT in patients with heart failure. In this study, we assessed the role of the blood metabolomic profile in predicting the response to CRT. METHODS: A total of 105 dilated cardiomyopathy patients with severe heart failure who received CRT were included in our two-stage study. Baseline blood samples were collected prior to CRT implantation. The response to CRT was defined according to echocardiographic criteria. Metabolomic profiling of serum samples was carried out using ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. RESULTS: Seventeen metabolites showed significant differences in their levels between responders and non-responders, and these metabolites were primarily involved in six pathways, including linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, citrate cycle, tryptophan metabolism, and sphingolipid metabolism. A combination of isoleucine, tryptophan, and linoleic acid was identified as an ideal metabolite panel to distinguish responders from non-responders in the discovery set (n = 51 with an AUC of 0.981), and it was confirmed in the validation set (n = 54 with an AUC of 0.929). CONCLUSIONS: Mass spectrometry based serum metabolomics approach provided larger coverage of metabolome which can help distinguish CRT responders from non-responders. A combination of isoleucine, tryptophan, and linoleic acid may associate with significant prognostic values for CRT.
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Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/terapia , Isoleucina/sangre , Ácido Linoleico/sangre , Metabolómica , Triptófano/sangre , Anciano , Biomarcadores/sangre , Terapia de Resincronización Cardíaca/efectos adversos , Cromatografía Líquida de Alta Presión , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recuperación de la Función , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The poor survival of stem cells seriously limits their therapeutic efficacy for myocardial infarction (MI). Mineralocorticoid receptor (MR) activation plays an important role in the pathogenesis of multiple cardiovascular diseases. Here, we examined whether MR silencing in bone marrow derived mesenchymal stem cells (MSCs) could improve MSCs' survival and enhance their cardioprotective effects in MI. MSCs from male Sprague-Dawley rats were transfected with adenoviral small interfering RNA to silence MR (siRNA-MR). MR silencing decreased hypoxia-induced MSCs' apoptosis, as demonstrated by Annexin V/7-AAD staining. The mechanisms contributing to the beneficial effects of MR depletion were associated with inhibiting intracellular reactive oxygen species production and increased Bcl-2/Bax ratio. In vivo study, 1 × 106 of MSCs with or without siRNA-MR were injected into rat hearts immediately after MI. Depletion of MR could improve the MSCs' survival significantly in infarcted myocardium, associated with more cardiac function improvement and smaller infarct size. Capillary density were also significantly higher in siRNA group with increased expression of vascular endothelial growth factor. Our study demonstrated that silencing MR promoted MSCs' survival and repair efficacy in ischaemic hearts. MR might be a potential target for enhancing the efficacy of cell therapy in ischaemic heart disease.
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Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Infarto del Miocardio/terapia , Receptores de Mineralocorticoides/deficiencia , Adenoviridae , Animales , Apoptosis , Supervivencia Celular , Células Cultivadas , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Although certain success has been achieved in atherosclerosis treatment, tremendous challenges remain in developing more efficient strategies to treat atherosclerosis. Platelets have inherent affinity to plaques and naturally home to atherosclerotic sites. Rapamycin features potent anti-atherosclerosis effect, but its clinical utility is limited by its low concentration at the atherosclerotic site and severe systemic toxicity. In the present study, we used platelet membrane-coated nanoparticles (PNP) as a targeted drug delivery platform to treat atherosclerosis through mimicking platelets' inherent targeting to plaques. PNP displayed 4.98-fold greater radiant efficiency than control nanoparticles in atherosclerotic arterial trees, indicating its effective homing to atherosclerotic plaques in vivo. In an atherosclerosis model established in apolipoprotein E-deficient mice, PNP encapsulating rapamycin significantly attenuated the progression of atherosclerosis and stabilized atherosclerotic plaques. These results demonstrated the perfect efficacy and pro-resolving potential of PNP as a targeted drug delivery platform for atherosclerosis treatment.
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Aterosclerosis/tratamiento farmacológico , Plaquetas/fisiología , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Placa Aterosclerótica/tratamiento farmacológico , Sirolimus/farmacología , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/fisiología , Aterosclerosis/genética , Aterosclerosis/patología , Membrana Celular/química , Membrana Celular/metabolismo , Células Cultivadas , Inmunosupresores/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nanopartículas/química , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Adhesividad PlaquetariaRESUMEN
A new non-toxic ferromagnetic biological patch (MBP) was designed in this paper. The MBP consisted of two external layers that were made of transparent silicone, and an internal layer that was made of a mixture of pure iron powder and silicon rubber. Finite-element analysis showed that the local inhomogeneous magnetic field (MF) around the MBP was generated when MBP was placed in a uniform MF. The local MF near the MBP varied with the uniform MF and shape of the MBP. Therefore, not only could the accumulation of paramagnetic particles be adjusted by controlling the strength of the uniform MF, but also the distribution of the paramagnetic particles could be improved with the different shape of the MBP. The relationship of the accumulation of paramagnetic particles or cells, magnetic flux density, and fluid velocity were studied through in vitro experiments and theoretical considerations. The accumulation of paramagnetic particles first increased with increment in the magnetic flux density of the uniform MF. But when the magnetic flux density of the uniform MF exceeded a specific value, the magnetic flux density of the MBP reached saturation, causing the accumulation of paramagnetic particles to fall. In addition, the adsorption morphology of magnetic particles or cells could be improved and the uniform distribution of magnetic particles could be achieved by changing the shape of the MBP. Also, MBP may be used as a new implant to attract magnetic drug carrier particles in magnetic drug targeting. Bioelectromagnetics. 39:98-107, 2018. © 2017 Wiley Periodicals, Inc.
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Sistemas de Liberación de Medicamentos/métodos , Campos Magnéticos , Imanes , Adsorción , Animales , Imanes/química , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/químicaRESUMEN
BACKGROUND/AIMS: To investigate whether nucleosome assembly protein 1-like 1 (Nap1l1) regulates the proliferation of induced pluripotent stem cells (iPSC) and the potential mechanisms. METHODS: Nap1l1-knockdown-iPSC and Nap1l1-overexpression-iPSC were constructed by transfection of lentiviral particles. The proliferation of iPSC was detected by MTT analysis, and cell cycle was analyzed by flow cytometry. RESULTS: Nap1l1 overexpression promoted iPSC proliferation and induced G2/M transition compared to their control iPSC while Nap1l1-knockdown-iPSC dramatically displayed the reduced proliferation and accumulated G2/M phase cells. Further analysis showed that Nap1l1 overexpression in iPSC increased the expression of cyclin B1, downregulated the expression of p21 and p27, while knockdown of Nap1l1 showed the opposite effects. In addition, overexpression of Nap1l1 promoted the phosphorylation of AKT and ERK in iPSC, while knockdown of Nap1l1 inhibited the effects. However, these effects displayed in Nap1l1-overexpression-iPSC were greatly suppressed by the inhibition of AKT or ERK signaling. CONCLUSIONS: The results indicate that Nap1l1 promotes the proliferation of iPSC attributable to G2/M transition caused by downregulation of p27 and p21, and upregulation of cyclin B1, the activation of AKT or ERK is involved in the process. The present study has revealed a novel molecular mechanism involved in the proliferation of iPSC.
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Células Madre Pluripotentes Inducidas/citología , Proteína 1 de Ensamblaje de Nucleosomas/metabolismo , Animales , Proliferación Celular , Ciclina B1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Proteína 1 de Ensamblaje de Nucleosomas/antagonistas & inhibidores , Proteína 1 de Ensamblaje de Nucleosomas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
Magnetic targeting is a promising therapeutic strategy for localizing systemically delivered magnetic responsive drugs or cells to target tissue, but excessive aggregation of magnetic particles could result in vascular embolization. To analyze the reason for embolization, the attractive process of magnetic particles in magnetic field (MF) was studied in this paper by analyzing the form of the aggregated paramagnetic particles while the particle suspension flowed through a tube, which served as a model of blood vessels. The effects of magnetic flux density and fluid velocity on the formation of aggregated paramagnetic particles were investigated. The number of large aggregated clusters dramatically increased with increment in the magnetic flux density and decreased with increment in the fluid velocity. The analysis of accumulative process demonstrates the MF around initially attracted particles was focused, which induced the formation of clusters and increased the possibility of embolism. Bioelectromagnetics. 37:323-330, 2016. © 2016 Wiley Periodicals, Inc.
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Campos Magnéticos , Imanes/química , Tamaño de la PartículaRESUMEN
A rapid pacing-induced heart failure model is commonly used in developing dilated cardiomyopathy (DCM). Traditionally, the right ventricular lead was connected with a single chamber pacemaker specific for animals that had a high frequency. However, the pacemaker used in this model is commercially unavailable. We developed a "pacing bigeminal" method using a commercially available dual-chamber (DDD) pacemaker to achieve high-frequency pacing. Twenty beagles were assigned to group A (n = 10) (pacing bigeminal method) and group B (n = 10) (traditional method). Echocardiographic measurements and electrocardiograms were obtained at baseline, at two weeks of pacing, and at 4 weeks of end pacing. LV anterior wall cardiac samples were obtained at 2 weeks of pacing and 4 weeks of end pacing for myocardial microscopic evaluation. Clinical manifestation and exposure time were also observed. After pacing for 10.5 ± 2.3 (714) days, the beagles in group B experienced heart failure, whereas in group A, only 7.9 ± 2.5 (5-12) days (P < 0.05) were needed to reach heart failure. Both methods could induce wide QRS duration, heart rate elevation, and myocardial microscopic changes (P > 0.05). In conclusion, this pacing bigeminal-induced heart failure method is feasible and can induce heart failure faster than the traditional method, which makes it a promising alternative method.
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Estimulación Cardíaca Artificial/métodos , Cardiomiopatía Dilatada/etiología , Modelos Animales de Enfermedad , Animales , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/fisiopatología , Perros , Electrocardiografía , Femenino , Masculino , Marcapaso ArtificialRESUMEN
OBJECTIVE: Mesenchymal stem cell (MSC) therapy is a promising treatment for ischemic injury. However, the environmental regulatory mechanism is essentially unclear and thus greatly limits its application in clinical setting. Accumulating evidence suggests a vital role of aldehyde dehydrogenase-2 (ALDH2) in microenvironment homeostasis after ischemia. About 540 million people or 8% of population worldwide carry a loss-of-function allele of ALDH2. It is unknown whether ALDH2 functions as a host factor regulating the therapeutic potential of donor MSCs. Therefore, this study was designed to determine whether and how host ALDH2 regulates MSC retention and therapeutic efficacy after transplantation into ischemic tissues. APPROACH AND RESULTS: Mice limb ischemia was performed by femoral artery ligation. A total of 10(6) MSCs were injected into the ischemic thigh muscles. One, 2, and 4 weeks after transplantation, MSC retention, blood perfusion recovery, limb necrosis, and fibrosis were analyzed. Compared with wild-type tissue, ALDH2 deficiency tissue significantly limited MSC retention and its perfusion recovery and limb salvage effects after ischemia. Importantly, local overexpression of ALDH2 optimized tissue microenvironment and significantly magnified all these MSC-induced improvement. Further study indicated that host ALDH2 regulated transplanted MSC survival and therapy as a microenvironment homeostasis mediator via local capillary density, energy supply, and oxidative stress regulating after ischemia. CONCLUSIONS: Our study establishes ALDH2 as a key mediator of host stem cell niche for optimal MSC therapy and suggests that ALDH2 deficiency present in the general population is a limiting host factor to be considered for MSC therapy.
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Aldehído Deshidrogenasa/metabolismo , Isquemia/cirugía , Trasplante de Células Madre Mesenquimatosas , Músculo Esquelético/irrigación sanguínea , Aldehído Deshidrogenasa/deficiencia , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Metabolismo Energético , Miembro Posterior , Isquemia/enzimología , Isquemia/genética , Isquemia/fisiopatología , Recuperación del Miembro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Fisiológica , Estrés Oxidativo , Recuperación de la Función , Flujo Sanguíneo Regional , Nicho de Células Madre , Factores de Tiempo , TransfecciónRESUMEN
Detection of the optimal cell transplantation strategy for myocardial infarction (MI) has attracted a great deal of attention. Commitment of engrafted cells to angiogenesis within damaged myocardium is regarded as one of the major targets in cell-based cardiac repair. Bone marrow-derived CD34-positive cells, a well-characterized population of stem cells, might represent highly functional endothelial progenitor cells and result in the formation of new blood vessels. Recently, physical microenvironment (extracellular matrix stiffness) around the engrafted cells was found to exert an essential impact on their fate. Stem cells are able to feel and respond to the tissue-like matrix stiffness to commit to a relevant lineage. Notably, the infarct area after MI experiences a time-dependent stiffness change from flexible to rigid. Our previous observations demonstrated myocardial stiffness-dependent differentiation of the unselected bone marrow-derived mononuclear cells (BMMNCs) along endothelial lineage cells. Myocardial stiffness (~42 kPa) within the optimal time domain of cell engraftment (at week 1 to 2) after MI provided a more favourable physical microenvironment for cell specification and cell-based cardiac repair. However, the difference in tissue stiffness-dependent cell differentiation between the specific cell subsets expressing and no expressing CD34 phenotype remains uncertain. We presumed that CD34-positive cell subsets facilitated angiogenesis and subsequently resulted in cardiac repair under induction of infarcted myocardium-like matrix stiffness compared with CD34-negative cells. If the hypothesis were true, it would contribute greatly to detect the optimal cell subsets for cell therapy and to establish an optimized therapy strategy for cell-based cardiac repair.
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Antígenos CD34/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos , Infarto del Miocardio/terapia , Miocardio/patología , Neovascularización Fisiológica , Cicatrización de Heridas/fisiología , Humanos , Infarto del Miocardio/fisiopatologíaRESUMEN
CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.
Asunto(s)
Antígeno CD47 , Macrófagos , Receptores Inmunológicos , Antígeno CD47/inmunología , Antígeno CD47/metabolismo , Animales , Receptores Inmunológicos/metabolismo , Ratones , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Infarto del Miocardio/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Antígenos de Diferenciación/inmunología , Fagocitosis/efectos de los fármacos , Biomimética/métodos , Humanos , EferocitosisRESUMEN
Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK ï¼main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.
Asunto(s)
Antígeno CD47 , Macrófagos , Daño por Reperfusión Miocárdica , Tirosina Quinasa c-Mer , Animales , Antígeno CD47/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Ratones Endogámicos C57BL , Remodelación Ventricular/efectos de los fármacos , Receptores CCR2/metabolismo , Ingeniería Genética/métodos , Masculino , Liposomas/química , Fagocitosis/efectos de los fármacos , EferocitosisRESUMEN
Side branch (SB) occlusion remains challenging in bifurcation percutaneous coronary intervention. We have introduced a novel method to protect SB named double kissing inflation outside the stent (DKo), which features twice inflation of protective balloon kissing with stent and postdilation balloon. This study compared protective effects of DKo vs jailed balloon technique (JBT) for bifurcation. This retrospective, single-center study enrolled 875 consecutive bifurcation lesions receiving either DKo (n = 209) or JBT (n = 666). At the 12-month follow-up, major adverse cardiac event occurred less in DKo (6.7% vs 12.0%; P = 0.042), even in 1:2 propensity score matching analysis (6.4% vs 12.3%; P = 0.034). Rewiring and transient SB loss occurred also less in DKo (0.5% vs 13.8% [P < 0.001]; 0.5% vs 4.8% [P = 0.003]). Similar results were observed in matching analysis. This study demonstrated DKo protected SB better than JBT in bifurcation percutaneous coronary intervention.