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1.
Theranostics ; 11(17): 8550-8569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373758

RESUMO

Heart failure is a serious clinical and public health problem. Currently there is an unmet demand for effective therapies for heart failure. Herein we reported noninvasive inhalation delivery of nanotherapies to prevent heart failure. Methods: A reactive oxygen species (ROS)-scavenging material (TPCD) was synthesized, which was processed into antioxidative and anti-inflammatory nanoparticles (i.e., TPCD NP). By decoration with a mitochondrial-targeting moiety, a multilevel targeting nanotherapy TTPCD NP was engineered. Pulmonary accumulation of inhaled TPCD NP and underlying mechanisms were examined in mice. In vivo efficacies of nanotherapies were evaluated in mice with doxorubicin (DOX)-induced cardiomyopathy. Further, an antioxidative, anti-inflammatory, and pro-resolving nanotherapy (i.e., ATTPCD NP) was developed, by packaging a peptide Ac2-26. In vitro and in vivo efficacies of ATTPCD NP were also evaluated. Results: TPCD NP alleviated DOX-induced oxidative stress and cell injury by internalization in cardiomyocytes and scavenging overproduced ROS. Inhaled TPCD NP can accumulate in the heart of mice by transport across the lung epithelial and endothelial barriers. Correspondingly, inhaled TPCD NP effectively inhibited DOX-induced heart failure in mice. TTPCD NP showed considerably enhanced heart targeting capability, cellular uptake efficiency, and mitochondrial localization capacity, thereby potentiating therapeutic effects. Notably, TPCD NP can serve as bioactive and ROS-responsive nanovehicles to achieve combination therapy with Ac2-26, affording further enhanced efficacies. Importantly, inhaled TPCD NP displayed good safety at a dose 5-fold higher than the efficacious dose. Conclusions: Inhalation delivery of nanoparticles is an effective, safe, and noninvasive strategy for targeted treatment of heart diseases. TPCD NP-based nanotherapies are promising drugs for heart failure and other acute/chronic heart diseases associated with oxidative stress.

2.
Int Heart J ; 62(4): 742-751, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34234075

RESUMO

Previous studies have indicated that low-dose new generation of P2Y12 receptor antagonists may be more suitable compared with clopidogrel at a standard dose for the dual antiplatelet therapy (DAPT) for East Asian patients receiving percutaneous coronary intervention (PCI). However, there remains no consensus in clinical practice. Thus, in this study, we aimed to determine the efficacy and safety of low-dose P2Y12 receptor antagonists, compared to clopidogrel at a standard dose, in DAPT in East Asian patients after PCI. We systematically searched literatures for randomized controlled trials (RCT) comparing low-dose P2Y12 receptor antagonists with standard-dose clopidogrel for the treatment of East Asian patients undergoing PCI. The endpoints of efficacy include major adverse cardiac events (MACEs), all-cause mortality, and the number of target vessel revascularization. The indicators of safety include major and minor bleeding events. Heterogeneity was evaluated by I2 statistic test. Begg's and Egger's tests were used to evaluate publication bias. In total, 2,747 subjects from 8 RCT studies were included. Low-dose new P2Y12 receptor antagonists, that is, ticagrelor or prasugrel, showed significantly lower incidence of MACEs, as compared with standard-dose clopidogrel, in the East Asian patients who are in DAPT after undergoing PCI. Further, no difference was noted for the risk of major and minor bleeding events. In East Asian patients undergoing PCI and receiving DAPT, the use of low-dose P2Y12 receptor antagonists, ticagrelor or prasugrel, has been determined to be superior than clopidogrel at standard dose; this has been evidenced by a lower incidence of MACEs without increasing the risk of bleeding.


Assuntos
Aspirina/administração & dosagem , Fibrinolíticos/administração & dosagem , Intervenção Coronária Percutânea/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Trombose/prevenção & controle , Aspirina/efeitos adversos , Extremo Oriente , Fibrinolíticos/efeitos adversos , Humanos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Trombose/etiologia
3.
Front Pharmacol ; 11: 510339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33364935

RESUMO

Over the past half-century, medical research on cardiovascular disease (CVD) has achieved a great deal; however, medication adherence is unsatisfactory. Nearly 50% of patients do not follow prescriptions when taking medications, which limits the ability to maximize their therapeutic effects and results in adverse clinical outcomes and high healthcare costs. Furthermore, the effects of medication adherence interventions are disappointing, and tailored interventions have been proposed as an appropriate way to improve medication adherence. To rethink and reconstruct methods of improving medication adherence for CVD, the literature on tailored interventions for medication adherence focusing on CVD within the last 5 years is retrieved and reviewed. Focusing on identifying nonadherent patients, detecting barriers to medication adherence, delivering clinical interventions, and constructing theories, this article reviews the present state of tailored interventions for medication adherence in CVD and also rethinks the present difficulties and suggests avenues for future development.

4.
ACS Nano ; 14(9): 11083-11099, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32790342

RESUMO

Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is critical for the treatment of liver diseases. Herein we report luminescence imaging of neutrophil-mediated acute liver injury, including alcoholic liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chemical functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NPs). Luminescence of LaCD NPs was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NPs, and the luminescent signal was positively associated with the neutrophil count. In mouse models of ALI and ALF, LaCD NPs enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, the luminescence imaging capacity of LaCD NPs can be additionally improved by surface functionalization with a neutrophil-targeting peptide. In addition, preliminary in vitro and in vivo studies demonstrated good safety of LaCD NPs. Consequently, LaCD NPs can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-associated liver diseases.


Assuntos
Falência Hepática Aguda , Luminescência , Animais , Modelos Animais de Doenças , Fígado/diagnóstico por imagem , Falência Hepática Aguda/diagnóstico por imagem , Camundongos , Neutrófilos
5.
Med Hypotheses ; 144: 110008, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32590323

RESUMO

Atherosclerotic renal artery stenosis (ARAS) accounts for more than 90% of cases with renal artery stenosis, which is the recognized cause of secondary hypertension, renal dysfunction and acute pulmonary edema. It is estimated that about 15% of patients with hypertension also have different degrees of ARAS at the same time. Hypertension is known to be associated with the risk of atherosclerotic vascular disease; these two conditions usually co-exist and interact with each other. At present, many studies have focused on how to intervene ARAS correctly or just optimal medical therapy (OMT). For patients with severe ARAS, stent implantation seems to be able to receive better clinical benefits because it can avoid renal ischemic injury; however, it remains inconclusive whether stent implantation is suitable for the essential hypertension patients accompanied with mild to moderate ARAS. We speculate that renal artery revascularization may accelerate renal dysfunction in essential hypertensive patients accompanied with mild to moderate ARAS, especially when hypertension could not be controlled within the normal range after the revascularization.


Assuntos
Hipertensão , Obstrução da Artéria Renal , Constrição Patológica , Humanos , Hipertensão/complicações , Artéria Renal , Obstrução da Artéria Renal/complicações , Stents
6.
Med Hypotheses ; 144: 109938, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32570160

RESUMO

Left ventricular thrombus (LVT) after acute myocardial infarction (AMI) remains to be a common complication bearing adverse prognostic implication. Majority of LVT occurs within the first week after AMI. Over decades, the regional stasis of blood flow is regarded as the main reason for LVT formation. Here we hypothesize that LVT developed within the first week after AMI is the consequence of an incomplete wall rupture. Endocardial rupture with exposure of infarcted tissues triggers platelet thrombosis within the rupture site and then the thrombus grows towards the ventricular chamber forming LVT. This hypothesis is implicated by the comparable clinical features of patients with LVT or with cardiac rupture, and supported by experimental findings in murine model of AMI revealing the mechanistic link between rupture and LVT. This hypothesis, if confirmed, would improve our understanding on the pathophysiology of both rupture and LVT as two pivotal mechanical complications after AMI, and the role of platelets in the setting of AMI and hence the use of anti-platelet therapies. Future studies are warranted to test this hypothesis by serial cardiac imaging on AMI patients with high risk of LVT.


Assuntos
Cardiopatias , Infarto do Miocárdio , Trombose , Animais , Ventrículos do Coração , Humanos , Camundongos , Infarto do Miocárdio/complicações , Estudos Retrospectivos
7.
Clin Exp Pharmacol Physiol ; 47(7): 1193-1202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32027390

RESUMO

Direct evidence is limited for the association between heart rate variability (HRV) indices and ventricular tachyarrhythmias (VTAs). While galectin-3 (Gal-3) is regarded as a causal factor for cardiac remodelling and a biomarker for arrhythmias, its regulation on VTAs and HVR is unknown. Using aged transgenic (TG) mice with cardiac overexpression of ß2 -adrenoceptors and spontaneous VTAs, we studied whether changes in HRV indices correlated with the severity of VTAs, and whether Gal-3 gene knockout (KO) in TG mice might limit VTA. Body-surface ECG was recorded (10-minute period) in 9- to 10-month-old mice of non-transgenic (nTG), TG and TG × Gal-3 knockout (TG/KO). Time-domain, frequency-domain and nonlinear-domain HRV indices were calculated using the R-R intervals extracted from ECG signals and compared with frequency of VTAs. TG and TG/KO mice developed frequent VTAs and showed significant changes in certain time-domain and nonlinear-domain HRV indices relative to nTG mice. The severity of VTAs in TG and TG/KO mice in combination, estimated by VTA counts and arrhythmia score, was significantly correlated with certain time-domain and nonlinear-domain HRV indices. In conclusion, significant changes in HRV indices were evident and correlated with the severity of spontaneous VTAs in TG mice. The frequency of VTA and HRV indices were largely comparable between TG and TG/KO mice. Deletion of Gal-3 in TG mice altered certain HRV indices implying influence by neuronally localized Gal-3 on autonomic nervous activity.

8.
Biomaterials ; 230: 119605, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31740099

RESUMO

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Vascular inflammation is closely related to the pathogenesis of a diverse group of CVDs. Currently, it remains a great challenge to achieve site-specific delivery and controlled release of therapeutics at vascular inflammatory sites. Herein we hypothesize that active targeting nanoparticles (NPs) simultaneously responsive to low pH and high levels of reactive oxygen species (ROS) can serve as an effective nanoplatform for precision delivery of therapeutic cargoes to the sites of vascular inflammation, in view of acidosis and oxidative stress at inflamed sites. The pH/ROS dual-responsive NPs were constructed by combination of a pH-sensitive material (ACD) and an oxidation-responsive material (OCD) that can be facilely synthesized by chemical functionalization of ß-cyclodextrin, a cyclic oligosaccharide. Simply by regulating the weight ratio of ACD and OCD, the pH/ROS responsive capacity can be easily modulated, affording NPs with varied hydrolysis profiles under inflammatory microenvironment. Using rapamycin (RAP) as a candidate drug, we first demonstrated in vitro therapeutic advantages of RAP-containing NPs with optimal dual-responsive capability, i.e. RAP/AOCD NP, and a non-responsive nanotherapy (RAP/PLGA NP) and two single-responsive nanotherapies (RAP/ACD NP and RAP/OCD NP) were used as controls. In an animal model of vascular inflammation in rats subjected to balloon injury in carotid arteries, AOCD NP could accumulate at the diseased site after intravenous (i.v.) injection. Consistently, i. v. treatment with RAP/AOCD NP more effectively inhibited neointimal hyperplasia in rats with induced arterial injuries, compared to RAP/PLGA NP, RAP/ACD NP, and RAP/OCD NP. By surface decoration of AOCD NP with a peptide (KLWVLPKGGGC) targeting type IV collagen (Col-IV), the obtained Col-IV targeting, dual-responsive nanocarrier TAOCD NP showed dramatically increased accumulation at injured carotid arteries. Furthermore, RAP/TAOCD NP exhibited significantly potentiated in vivo efficacy in comparison to the passive targeting nanotherapy RAP/AOCD NP. Importantly, in vitro cell culture experiments and in vivo animal studies in both mice and rats revealed good safety for AOCD NP and RAP/AOCD NP, even after long-term treatment via i. v. injection. Consequently, our results demonstrated that the newly developed Col-IV targeting, pH/ROS dual-responsive NPs may serve as an effective and safe nanovehicle for precision therapy of arterial restenosis and other vascular inflammatory diseases.


Assuntos
Nanopartículas , Estresse Oxidativo , Sirolimo , Doenças Vasculares , Animais , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Inflamação/terapia , Camundongos , Nanomedicina , Ratos , Espécies Reativas de Oxigênio , Doenças Vasculares/terapia
9.
Adv Mater ; 31(46): e1904607, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31583783

RESUMO

Inflammation is a common cause of many acute and chronic inflammatory diseases. A major limitation of existing anti-inflammatory therapeutics is that they cannot simultaneously regulate pro-inflammatory cytokine production, oxidative stress, and recruitment of neutrophils and macrophages. To overcome this limitation, nanoparticles (NPs) with multiple pharmacological activities are synthesized, using a chemically modified cyclic oligosaccharide. The manufacture of this type of bioactive, saccharide material-based NPs (defined as LCD NP) is straightforward, cost-effective, and scalable. Functionally, LCD NP effectively inhibits inflammatory response, oxidative stress, and cell migration for both neutrophils and macrophages, two major players of inflammation. Therapeutically, LCD NP shows desirable efficacies for the treatment of acute and chronic inflammatory diseases in mouse models of peritonitis, acute lung injury, and atherosclerosis. Mechanistically, the therapeutic benefits of LCD NP are achieved by inhibiting neutrophil-mediated inflammatory macrophage recruitment and by preventing subsequent pro-inflammatory events. In addition, LCD NP shows good safety profile in a mouse model. Thus, LCD NP can serve as an effective anti-inflammatory nanotherapy for the treatment of inflammatory diseases mainly associated with neutrophil and macrophage infiltration.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Nanopartículas/química , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Doença Aguda , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Transporte Biológico , Doença Crônica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , beta-Ciclodextrinas/metabolismo , beta-Ciclodextrinas/uso terapêutico
10.
Adv Sci (Weinh) ; 6(18): 1900610, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31559126

RESUMO

The incidence and prevalence of inflammatory bowel disease (IBD) increases steadily worldwide. There is an urgent need for effective and safe IBD therapies. Accelerated resolution of inflammation is a new strategy for the management of inflammatory diseases. For effective and safe IBD treatment, herein a smart nanotherapy (i.e. oxidation-responsive nanoparticles containing a proresolving annexin A1-mimetic peptide Ac2-26, defined as AON) is developed, which can release packaged Ac2-26, in response to highly expressed reactive oxygen species (ROS) at diseased sites. AON effectively protects Ac2-26 from degradation in the enzyme-rich environment of the gastrointestinal tract. By delivering this nanotherapy to the inflamed colons of mice with IBD, site-specific release and accumulation of Ac2-26 in response to high levels of ROS at the inflammatory sites are achieved. Mechanistically, the Ac2-26-containing, oxidation-labile nanotherapy AON effectively decreases the expression of proinflammatory mediators, attenuates trafficking and infiltration of inflammatory cells, promotes efferocytosis of apoptotic neutrophils, and increases phenotypic switching of macrophages. Therapeutically, AON reduces symptoms of inflammation, accelerates intestinal mucosal wound healing, reshapes the gut microbiota composition, and increases short-chain fatty acid production. Additionally, oral delivery of this nanomedicine shows excellent safety profile in a mouse model, conferring the confidence for further development of a targeted precision therapy for IBD and other inflammatory diseases.

11.
Br J Pharmacol ; 176(14): 2465-2481, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30932177

RESUMO

BACKGROUND AND PURPOSE: Expression of the pro-fibrotic galectin-3 and the pro-apoptotic BIM is elevated in diseased heart or after ß-adrenoceptor stimulation, but the underlying mechanisms are unclear. This question was addressed in the present study. EXPERIMENTAL APPROACH: Wild-type mice and mice with cardiac transgenic expression of ß2 -adrenoceptors, mammalian sterile-20 like kinase 1 (Mst1) or dominant-negative Mst1, and non-specific galectin-3 knockout mice were used. Effects of the ß-adrenoceptor agonist isoprenaline or ß-adrenoceptor antagonists were studied. Rat cardiomyoblasts (H9c2) were used for mechanistic exploration. Biochemical assays were performed. KEY RESULTS: Isoprenaline treatment up-regulated expression of galectin-3 and BIM, and this was inhibited by non-selective or selective ß-adrenoceptor antagonists (by 60-70%). Cardiac expression of galectin-3 and BIM was increased in ß2 -adrenoceptor transgenic mice. Isoprenaline-induced up-regulation of galectin-3 and BIM was attenuated by Mst1 inactivation, but isoprenaline-induced galectin-3 expression was exaggerated by transgenic Mst1 activation. Pharmacological or genetic activation of ß-adrenoceptors induced Mst1 expression and yes-associated protein (YAP) phosphorylation. YAP hyper-phosphorylation was also evident in Mst1 transgenic hearts with up-regulated expression of galectin-3 (40-fold) and BIM as well as up-regulation of many YAP-target genes by RNA sequencing. In H9c2 cells, isoprenaline induced YAP phosphorylation and expression of galectin-3 and BIM, effects simulated by forskolin but abolished by PKA inhibitors, and YAP knockdown induced expression of galectin-3 and BIM. CONCLUSIONS AND IMPLICATIONS: Stimulation of cardiac ß-adrenoceptors activated the Mst1/Hippo pathway leading to YAP hyper-phosphorylation with enhanced expression of galectin-3 and BIM. This signalling pathway would have therapeutic potential. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.


Assuntos
Proteína 11 Semelhante a Bcl-2/metabolismo , Doenças Cardiovasculares/metabolismo , Galectina 3/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais , Regulação para Cima , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Proteína 11 Semelhante a Bcl-2/antagonistas & inibidores , Doenças Cardiovasculares/tratamento farmacológico , Carvedilol/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Galectina 3/antagonistas & inibidores , Galectina 3/deficiência , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Propanolaminas/farmacologia , Propranolol/farmacologia , Ratos , Receptores Adrenérgicos beta 3/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
12.
J Cell Physiol ; 234(11): 19640-19654, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30950039

RESUMO

Angiotensin II (AngII) facilitates angiogenesis that is associated with the continuous progression of atherosclerotic plaques, but the underlying mechanisms are still not fully understood. Several microRNAs (miRNAs) have been shown to promote angiogenesis; however, whether miRNAs play a crucial role in AngII-induced angiogenesis remains unclear. This study evaluated the functional involvement of miRNA-21 (miR-21) in the AngII-mediated proangiogenic response in human microvascular endothelial cells (HMECs). We found that AngII exerted a proangiogenic role, indicated by the promotion of proliferation, migration, and tube formation in HMECs. Next, miR-21 was found to be upregulated in AngII-treated HMECs, and its specific inhibitor potently blocked the proangiogenic effects of AngII. Subsequently, we focused on the constitutive activation of STAT3 in the AngII-mediated proangiogenic process. Bioinformatic analysis indicated that STAT3 acted as a transcription factor initiating miR-21 expression, which was verified by ChIP-PCR. A reporter assay further identified three functional binding sites of STAT3 in the miR-21 promoter region. Moreover, phosphatase and tensin homolog (PTEN) was recognized as a target of miR-21, and STAT3 inhibition restored AngII-induced reduction in PTEN. Similarly, the STAT3/miR-21 axis was shown to mediate AngII-provoked angiogenesis in vivo, which was demonstrated by using the appropriate inhibitors. Our data suggest that AngII was involved in proangiogenic responses through miR-21 upregulation and reduced PTEN expression, which was, at least in part, linked to STAT3 signaling. The present study provides novel insights into AngII-induced angiogenesis and suggests potential treatment strategies for attenuating the progression of atherosclerotic lesions and preventing atherosclerosis complications.


Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , PTEN Fosfo-Hidrolase/genética , Placa Aterosclerótica/genética , Fator de Transcrição STAT3/genética , Indutores da Angiogênese/farmacologia , Angiotensina II/genética , Angiotensina II/farmacologia , Animais , Movimento Celular/genética , Proliferação de Células/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Neovascularização Patológica/patologia , Placa Aterosclerótica/patologia , Transdução de Sinais/genética
13.
J Am Coll Cardiol ; 72(21): 2591-2605, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30466517

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a leading cause of mortality and morbidity in the elderly. Currently, there remain no effective drugs that can prevent the growth of aneurysms and delay aneurysm rupture in the clinical setting. OBJECTIVES: The aim of this study was to develop a nanotherapy that can target aneurysms and release drug molecules in response to the inflammatory microenvironment. METHODS: Using a reactive oxygen species (ROS)-responsive nanoparticle and a candidate drug rapamycin, in combination with a peptide ligand for integrin and biomimetic cloaking with macrophage cell membrane, a nanotherapy was developed. Its effectiveness was demonstrated by in vitro and in vivo studies. RESULTS: Based on a facile and translational method, a rapamycin-loaded responsive nanotherapy was successfully prepared, which could release drug molecules upon triggering by the high level of ROS. In cells associated with the development of AAAs, the nanotherapy significantly inhibited calcification and attenuated ROS-mediated oxidative stress and apoptosis. By passively targeting aneurysms and releasing drug molecules in response to the inflammatory microenvironment, the intravenously injected ROS-responsive nanotherapy more effectively prevented aneurysm expansion in AAA rats than a nonresponsive control nanotherapy. After decoration with a peptide ligand cRGDfK and macrophage cell membrane, the aneurysmal targeting capability and therapeutic effects of a ROS-responsive nanotherapy with a mean diameter of 190 nm were further enhanced. Moreover, the nanotherapy showed a good safety profile in a preliminary safety test. CONCLUSIONS: The multifunctional nanotherapy can be further studied as a promising targeted drug for treatment of aneurysms. The underlying design principles enable the development of a broad range of nanomedicines for targeted therapy of other vascular diseases.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Imunossupressores/administração & dosagem , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , Animais , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Células RAW 264.7 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
14.
Adv Sci (Weinh) ; 5(10): 1800781, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30356945

RESUMO

Despite the great potential of numerous antioxidants for pharmacotherapy of diseases associated with inflammation and oxidative stress, many challenges remain for their clinical translation. Herein, a superoxidase dismutase/catalase-mimetic material based on Tempol and phenylboronic acid pinacol ester simultaneously conjugated ß-cyclodextrin (abbreviated as TPCD), which is capable of eliminating a broad spectrum of reactive oxygen species (ROS), is reported. TPCD can be easily synthesized by sequentially conjugating two functional moieties onto a ß-cyclodextrin scaffold. The thus developed pharmacologically active material may be easily produced into antioxidant and anti-inflammatory nanoparticles, with tunable size. TPCD nanoparticles (TPCD NP) effectively protect macrophages from oxidative stress-induced apoptosis in vitro. Consistently, TPCD NP shows superior efficacies in three murine models of inflammatory diseases, with respect to attenuating inflammatory responses and mitigating oxidative stress. TPCD NP can also protect mice from drug-induced organ toxicity. Besides the passive targeting effect, the broad spectrum ROS-scavenging capability contributes to the therapeutic benefits of TPCD NP. Importantly, in vitro and in vivo preliminary experiments demonstrate the good safety profile of TPCD NP. Consequently, TPCD in its native and nanoparticle forms can be further developed as efficacious and safe therapies for treatment of inflammation and oxidative stress-associated diseases.

15.
ACS Nano ; 12(9): 8943-8960, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30114351

RESUMO

Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide ß-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE-/-) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE-/- mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aterosclerose/tratamento farmacológico , Nanopartículas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Marcadores de Spin , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia
16.
Nanoscale ; 10(26): 12364-12377, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29682667

RESUMO

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.


Assuntos
Ciclodextrinas/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Óxidos N-Cíclicos/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Polietilenoglicóis/química , Células RAW 264.7 , Marcadores de Spin
17.
Mol Med Rep ; 16(5): 7657-7664, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944849

RESUMO

Reactive oxygen species (ROS) production has been implicated in the promotion of cellular senescence. Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exerts antioxidant effects and enhances autophagy in various cell types. Since autophagy serves an important role in regulating ROS, it was hypothesized that the antioxidant effect of celastrol is via enhanced autophagy, thus inhibiting cell senescence. Therefore, the present study used a Senescence ß­Galactosidase Staining kit, western blot analysis and cell cycle analysis to investigate whether celastrol alleviates angiotensin (Ang) II­induced cellular senescence by upregulating autophagy in vascular smooth muscle cells (VSMCs). The results demonstrated that celastrol reduced Ang II­induced senescence of VSMCs. Ang II­induced generation of ROS and the subsequent VSMC senescence were counteracted by pretreatment with celastrol, determined by a ROS assay kit. Celastrol significantly upregulated VSMC autophagy, which reduced intracellular ROS and the subsequent cellular senescence induced by Ang II. Furthermore, celastrol markedly suppressed activity of the mechanistic target of rapamycin signaling pathway in VSMCs. In conclusion, the present study demonstrated that celastrol counteracts VSMC senescence probably by reducing ROS production via activation of autophagy, which may hold promise for the prevention and treatment of aging­associated cardiovascular disorders such as atherosclerosis.


Assuntos
Angiotensina II/farmacologia , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Autofagia/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Senescência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
18.
Cell Physiol Biochem ; 42(2): 427-440, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28571029

RESUMO

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Complicações do Diabetes/genética , Proteína HMGB1/genética , Esclerose Calcificante da Média de Monckeberg/genética , Animais , Valva Aórtica/metabolismo , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Remodelação Óssea/genética , Calcinose/metabolismo , Calcinose/fisiopatologia , Diferenciação Celular/genética , Cromatina/genética , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Proteína HMGB1/metabolismo , Humanos , Esclerose Calcificante da Média de Monckeberg/metabolismo , Esclerose Calcificante da Média de Monckeberg/fisiopatologia , Ligação Proteica , Transdução de Sinais
19.
Cell Physiol Biochem ; 41(6): 2319-2332, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28463834

RESUMO

BACKGROUND/AIMS: Platelet microvesicles (PMVs) contribute to angiogenesis and vasculogenesis, but the mechanisms underlying these contributions have not been fully elucidated. In the present study, we investigated whether PMVs regulate the angiogenic properties of endothelial cells (ECs) via mechanisms extending beyond the transport of angiogenic regulators from platelets. METHODS: In vitro Matrigel tube formation assay and in vivo Matrigel plug assay were used to evaluate the pro-angiogenic activity of PMVs. The effects of PMVs on the migration of human umbilical vein endothelial cells (HUVECs) were detected by transwell assay and wound-healing assay. Real-time PCR and western blot were conducted to examine mRNA and protein expression of pro-angiogenic factors in HUVECs. Matrix metalloproteinase (MMP) activity was assayed by gelatin zymography. Moreover, the effects of specific MMP inhibitors were tested. RESULTS: PMVs promoted HUVEC capillary-like network formation in a dose-dependent manner. Meanwhile, PMVs dose-dependently facilitated HUVEC migration. Levels of MMP-2 and MMP-9 expression and activity were up-regulated in HUVECs stimulated with PMVs. Inhibition of MMPs decreased their pro-angiogenic and pro-migratory effects on HUVECs. Moreover, we confirmed the pro-angiogenic activity of PMVs in vivo in mice with subcutaneous implantation of Matrigel, and demonstrated that blockade of MMPs attenuated PMV-induced angiogenesis. CONCLUSION: The findings of our study indicate that PMVs promote angiogenesis by up-regulating MMP expression in ECs via mechanism extending beyond the direct delivery of angiogenic factors.


Assuntos
Células Endoteliais da Veia Umbilical Humana/enzimologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/fisiologia , Regulação para Cima/fisiologia , Inibidores da Angiogênese/farmacologia , Plaquetas/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Dipeptídeos/farmacologia , Humanos , Metaloproteinase 2 da Matriz/química , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
ACS Nano ; 10(11): 9957-9973, 2016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27736084

RESUMO

Currently, there is still unmet demand for effective and safe hemostats to control abnormal bleeding in different conditions. With the aim to develop affordable, safe, effective, easily stored, and low-cost hemostats, we developed a series of positively charged nanoparticles by a facile one-pot assembly approach. In this strategy, nanoparticles were formed by cholic-acid-mediated self-assembly of polyethylenimine (PEI). Regardless of different structures of cholic acids and PEIs, well-defined nanoparticles could be successfully formed. The assembly process was dominated by multiple interactions between cholic acid and PEI, including electrostatic, hydrogen bonding, and hydrophobic forces. In vitro studies showed that assembled nanoparticles effectively induced aggregation and activation of platelets. Local application of aqueous solution containing nanoparticles assembled by different cholic acids and PEIs significantly reduced bleeding times in different rodent models including tail transection in mice as well as liver bleeding and femoral artery bleeding in rats or rabbits. Moreover, intravenous (i.v.) injection of this type of positively charged nanoparticles notably prevented bleeding in the femoral artery in rats by targeting the injured site via opsonization of nanoparticles with fibrinogen. By contrast, a control negatively charged nanoparticle showed no hemostatic activity after i.v. delivery. Also, preliminary evaluations in rats revealed a good safety profile after i.v. administration of assembled nanoparticles at a dose 4-fold higher than that used for hemostasis. These results demonstrated that cholic acid/PEI-assembled positive nanoparticles may function as cost-effective and locally applicable or injectable nanohemostats for hemorrhage control in the civilian setting and on the battlefield.


Assuntos
Hemorragia/tratamento farmacológico , Hemostáticos/química , Nanopartículas , Polietilenoimina , Animais , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Coelhos , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
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