RESUMEN
The identification of metastasis "seeds," isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for noninvasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T2-decaying effects under UHF conditions, which compromises T1 MRI capability and further impedes the precise imaging of small lesions. Herein, this study reports a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost nonmagnetic. This unique characteristic effectively mitigates T2-decaying effect while concurrently enhancing UHF T1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r2/r1 value (≈1.06), enabling noninvasive visualization of ITCs with an exceptional detection threshold of ≈0.16 mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research.
Asunto(s)
Medios de Contraste , Imagen por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Humanos , Animales , Ratones , Línea Celular Tumoral , Medios de Contraste/química , Neoplasias/diagnóstico por imagen , Neoplasias/patologíaRESUMEN
Oxidative stress-based antitumor modalities derived from reactive oxygen species (ROS) storms have attracted increasing attention. Nevertheless, low delivery efficiency, poor selectivity, hypoxia and overexpressed glutathione (GSH) have severely restricted the sustainable generation of the ROS storm in tumor cells. Herein, we design a bioengineered nanogenerator by coordination-driven co-assembly of sonosensitizer indocyanine green (ICG), Fenton-like agent copper ion (Cuâ ¡) and mitochondrial respiratory inhibitor metformin (MET), which is then camouflaged by a cancer cytomembrane to induce a sustainable intracellular ROS storm for on-demand self-reinforcing sono-chemodynamic oncotherapy. Such a nanogenerator with a core-shell structure, suitable diameter and outstanding stability can efficiently accumulate in tumor regions and then internalize into tumor cells through the camouflaging and homologous targeting strategy of the cancer cytomembrane. The nanogenerator shows an exceptional instability under the triple stimulations of acidic lysosomes, overexpressed GSH and ultrasound (US) radiation, thereby resulting in the rapid disassembly and burst drug release. Interestingly, the released MET significantly enhances the sonodynamic therapy (SDT) efficacy of the released ICG by inhibiting mitochondrial respiration and meanwhile the released Cuâ ¡ obviously reduces ROS elimination by downregulating overexpressed GSH for self-amplifying and self-protecting the intracellular ROS storm. Moreover, such a nanogenerator almost completely achieves the tumor ablation in vivo in a single therapy cycle. Taken together, our bioengineered nanogenerator with a sustainable ROS storm can provide a promising strategy for ROS storm-based oncotherapy.
Asunto(s)
Metformina , Neoplasias , Humanos , Especies Reactivas de Oxígeno , Estrés Oxidativo , Ingeniería Biomédica , Cobre/farmacología , Liberación de Fármacos , Glutatión , Verde de Indocianina , Metformina/farmacología , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Peróxido de HidrógenoRESUMEN
Twenty-six iridoids, including six undescribed ones (iridoidvols A-F) and an undescribed natural one, along with ten known sesquiterpenoids were isolated from the roots and rhizomes of Valeriana officinalis. Structurally, iridoidvol A is the first example of iridoid with sesquiterpenoid acid ester. In addition, all of the isolates were evaluated for anti-inflammatory and anti-influenza virus activities. Among them, isovaltrate isovaleroyloxyhydrin exhibited a significant inhibitory effect on NO production with an IC50 value of 19.00 µM.
Asunto(s)
Valeriana , Iridoides/farmacologíaRESUMEN
A new acylated iridoid, valejatadoid H (1), along with fourteen known compounds, were obtained from the n-BuOH extract of the roots and rhizomes of Valeriana jatamansi, and their structures were elucidated by various spectroscopic methods. Among them, compounds 8, 11 and 13 exhibited potent inhibition on NO production, with IC50 values of 4.21, 6.08 and 20.36 µM, respectively. In addition, compounds 14 and 15 showed anti-influenza virus activities, among which compound 14 exhibited significant effect with an IC50 value of 0.99 µM.
Asunto(s)
Valeriana , Valeriana/química , Iridoides/química , Raíces de Plantas/química , RizomaRESUMEN
Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aß-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aß clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aß). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aß clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aß-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.
Asunto(s)
Enfermedad de Alzheimer , Metformina , Nanopartículas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Humanos , Metformina/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Microglía , Nanopartículas/uso terapéuticoRESUMEN
Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Estructuras Metalorgánicas/farmacología , Neovascularización Patológica/tratamiento farmacológico , Nanomedicina Teranóstica , Inhibidores de la Angiogénesis/química , Antineoplásicos/química , Materiales Biocompatibles/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos/química , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ensayo de Materiales , Estructuras Metalorgánicas/química , Neovascularización Patológica/patología , Tamaño de la Partícula , Pemetrexed/química , Pemetrexed/farmacología , Propiedades de SuperficieRESUMEN
The synergistic nanotheranostics of reactive oxygen species (ROS) augment or phototherapy has been a promising method within synergistic oncotherapy. However, it is still hindered by sophisticated design and fabrication, lack of a multimodal synergistic effect, and hypoxia-associated poor photodynamic therapy (PDT) efficacy. Herein, a kind of porous shuttle-shape platinum (IV) methylene blue (Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) is fabricated to address the abovementioned limitations. Our nanoreactors possess spatiotemporally controlled O2 self-supply, self-sufficient singlet oxygen (1O2), and outstanding photothermal effect. Once they are taken up by tumor cells, nanoreactors as a cascade catalyst can efficiently catalyze degradation of the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia. The production of O2 can ensure enhanced PDT. Subsequently, under both stimuli of external red light irradiation and internal lysosomal acidity, nanoreactors can achieve the on-demand release of CPT to augment in situ mitochondrial ROS and highly efficient tumor ablation via phototherapy. Moreover, under the guidance of near-infrared (NIR) fluorescent imaging, our nanoreactors exhibit strongly synergistic potency for treatment of hypoxic tumors while reducing damages against normal tissues and organs. Collectively, shuttle-shape platinum-coordinated nanoreactors with augmented ROS capacity and enhanced phototherapy efficiency can be regarded as a novel tumor theranostic agent and further promote the research of synergistic oncotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Portadores de Fármacos/química , Nanoestructuras/química , Neoplasias/tratamiento farmacológico , Hipoxia Tumoral/efectos de los fármacos , Animales , Antineoplásicos/química , Camptotecina/química , Camptotecina/uso terapéutico , Catálisis/efectos de la radiación , Línea Celular Tumoral , Portadores de Fármacos/efectos de la radiación , Liberación de Fármacos , Femenino , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Luz , Azul de Metileno/análogos & derivados , Azul de Metileno/efectos de la radiación , Ratones Endogámicos BALB C , Nanoestructuras/efectos de la radiación , Neoplasias/metabolismo , Oxígeno/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Terapia Fototérmica , Platino (Metal)/química , Platino (Metal)/efectos de la radiación , Polímeros/síntesis química , Polímeros/química , Polímeros/efectos de la radiación , Porosidad , Oxígeno Singlete/metabolismo , Nanomedicina TeranósticaRESUMEN
Sonodynamic therapy has attracted wide attention as a noninvasive therapy due to deep tissue penetration. However, majority sonosensitizers often suffer from poor physiological stability, rapid blood clearance and nonspecific targeting, which seriously hinders their further practical applications. Inspired by the concept of active targeting drug delivery, both dual-functional chemo-drug pemetrexed (PEM, emerges an innate affinity toward the folate receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected to be covalently linked by an esterase-responsive ester linkage. The synthesized self-targeting TPGS-PEM prodrug and indocyanine green (ICG) as functional motifs can be self-assembled into a TPGS-PEM-ICG nanoplatform within an aqueous medium. The TPGS-PEM-ICG nanoplatform with outstanding structural and physiological stability not only protects the sonosensitizer from reticular endothelial system clearance but also achieves active targeting drug delivery and efficient tumor enrichment. Moreover, TPGS-PEM-ICG nanoplatform can selectively recognize tumor cells and then realize on-demand drug burst release by multiple stimuli of internal lysosomal acidity, esterase and external ultrasound, which guarantee low side effects toward normal tissues and organs. It is also worth noting that our nanoplatform exhibits protruding tumor enrichment under the precise guidance of photoacoustic/fluorescence imaging. Further in vitro and in vivo experimental results well confirmed that the TPGS-PEM-ICG nanoplatform possesses enhanced chemo-sonodynamic effects. Interestingly, the highly toxic reactive oxygen species can remarkably reduce the blood oxygen saturation signal of the tumor microenvironment via precise, multifunctional and high-resolution photoacoustic imaging. Taken together, the TPGS-PEM-ICG nanoplatform can be expected to hold enormous potential for diagnosis, prognosis and targeted therapy for tumor.
Asunto(s)
Antineoplásicos/farmacología , Verde de Indocianina/química , Nanopartículas/química , Técnicas Fotoacústicas , Profármacos/farmacología , Terapia por Ultrasonido , Vitamina E/farmacología , Animales , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Imagen Óptica , Tamaño de la Partícula , Profármacos/química , Vitamina E/químicaRESUMEN
Recently, smart nanomaterials from peptide self-assembly have received extensive attention in the field of biological and medical applications. Through rationally designing the molecular structure, we constructed a borono-peptide that self-assembled into well-defined nanofibers. Relying on the specific recognition between the vicinal diol compound and boronic acid, a novel alizarin red S (ARS)-borono-peptide (BP) spherical nanoindicator was fabricated, accompanying with the emission of strong fluorescent signal. The fluorescent nanoindicator displayed an intense response to copper(II) ions and underwent the fluorescent "turn-off" due to the strong binding-induced displacement. Originating from the high selectivity toward copper(II) ions, good biocompatibility and cancer cell targeting, the nanoindicator offered the opportunity to image copper(II) ions in cancer cells via fluorescent change.
Asunto(s)
Cobre , Colorantes Fluorescentes , Antraquinonas , Humanos , Iones , PéptidosRESUMEN
Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109â¯nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808â¯nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas , Línea Celular Tumoral , Supervivencia Celular , Grafito , MetotrexatoRESUMEN
D-a-tocopheryl polyethylene glycol succinate (TPGS) as a FDA-approved safe adjuvant has shown an excellent application in the targeting delivery of antitumor drugs and overcoming multidrug resistance. Beside, TPGS can result in apoptogenic activity toward many tumor types because it can induce mitochondrial dysfunction. Therefore, TPGS can serve as an antineoplastic agent. However, the current research on the selective antitumor activity of TPGS is ignored. To reveal the issue, herein we develop a mitochondria-targeting drug-free TPGS nanomicelles with the hydrodynamic diameter of about 100 nm and outstanding serum stability by weak interaction-driven self-assembly of the amphiphilic TPGS polymer. Moreover, such drug-free TPGS nanomicelles intravenously injected into tumor-bearing mice exhibit long blood circulation time, superior tumor enrichment, and inhibit the tumor growth via inducing excessive reactive oxygen species (ROS) generation within tumor cells. Further in vitro and in vivo researches jointly demonstrate that drug-free TPGS nanomicelles have more significant antitumor effect on HeLa cells compared with that of other tumor cells. On the contrary, drug-free TPGS nanomicelles display the low toxicity toward normal cells and tissues. Taken together, these new findings confirm that TPGS drug-free nanomicelles represent simple, multifunctional, safe, and efficient antineoplastic agents, which can be expected to bring new light on the development of drug-free polymers for tumor therapy.
Asunto(s)
Antineoplásicos , Polietilenglicoles , Animales , Antineoplásicos/farmacología , Muerte Celular , Línea Celular Tumoral , Células HeLa , Humanos , Ratones , Micelas , Mitocondrias , Especies Reactivas de Oxígeno , Vitamina ERESUMEN
Distinct circularly polarized luminescence (CPL) activity was observed in chiral (Câ§Nâ§N)Pt(II) [(Câ§Nâ§N) = 4,5-pinene-6'-phenyl-2,2'-bipyridine] complexes with bis- or triphenylphosphine ligands. Compared to the pseudo-square-planar geometry of chiral (Câ§Nâ§N)Pt(II) complexes with chloride, phenylacetylene (PPV) and 2,6-dimethylphenyl isocyanide (Dmpi) ligands, the coordination configuration around the Pt(II) nucleus of chiral (Câ§Nâ§N)Pt(II) complexes with bulk phosphine ligands is far more distorted. The geometry is straightforwardly confirmed by X-ray crystallography. The phosphines' participation enhanced the CPL signal of Pt(II) complexes profoundly, with the dissymmetry factor (g lum) up to 10-3. The distorted structures and enhanced chiroptical signals were further confirmed by time-dependent density functional theory (TD-DFT) calculations.
RESUMEN
BACKGROUND: Methotrexate (MTX) is the prior drug in ectopic pregnancy (EP). However, approximately 10% of patients suffer from failure by MTX therapy. Reduced folate carrier 1 (RFC1), methylene tetrahydrofolate reductase (MTHFR), and dihydrofolate reductase (DHFR) are involved in the transport and effects of MTX in vivo. In the present study, we aim to investigate the relationship between the genetic polymorphisms of RFC1, MTHFR, and DHFR and the clinical efficacy of MTX in tubal pregnancies. METHODS: 100 patients of EP were enrolled in this study. Polymorphisms of RFC1 G80A, MTHFR C677T, and DHFR A-317G were genotyped. ß-hCG level was detected in day 0, 4, and 7 after MTX injection. Association of MTX efficacy and genetic polymorphisms was analyzed. RESULTS: Methylene tetrahydrofolate reductase C677T was associated with MTX treatment (P = .017). The success rate of first MTX injection was superior in patients with harboring mutation allele of MTHFR gene than that in patients with wild-type gene (P = .001). However, there was no significant association between the polymorphisms of RFC1 G80A, DHFR A-317G, and surgical treatment (P = .709 and .476, respectively). In addition, ß-hCG level decrement was not significantly changed by MTX injection with different polymorphisms of RFC1, MTHFR, and DHFR on either day 4 (P = .214, 0.197 and 0.270, respectively) or day 7 (P = .172, .554, and .726, respectively). CONCLUSION: Our results suggested that the reliable indicator was polymorphism of MTHFR C677T in failure by MTX injection.
Asunto(s)
Metotrexato/uso terapéutico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Embarazo Ectópico/tratamiento farmacológico , Embarazo Ectópico/genética , Adulto , Gonadotropina Coriónica/sangre , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Embarazo , Embarazo Ectópico/sangre , Embarazo Ectópico/enzimologíaRESUMEN
The mammalian target of rapamycin is critical in hypoxia-triggered angiogenesis. Cardamonin inhibits proliferation of various cancer cells through suppressing the mammalian target of rapamycin. In this study, the antiangiogenic effect of cardamonin on CoCl2-mimicked hypoxic SKOV3 cells was investigated. Cardamonin exhibited an antiproliferative effect on normal and CoCl2-mimicked hypoxic SKOV3 cells. Messenger RNA expression of vascular endothelial growth factor was inhibited with cardamonin and rapamycin in SKOV3 cells under both conditions. However, cardamonin had little effect on the messenger RNA expression of hypoxia-inducible factor-α. Cardamonin inhibited the protein expression of hypoxia-inducible factor-1α, hypoxia inducible factor-2α, vascular endothelial growth factor, and the phosphorylation of mammalian target of rapamycin and ribosomal S6 kinase 1. Furthermore, angiogenesis induced by a medium of SKOV3 cells was reduced by cardamonin in a chicken embryo allantois membrane model. These findings suggest that cardamonin inhibits protein expression of hypoxia-inducible factor-α, and vascular endothelial growth factor, which was induced by CoCl2-mimicked hypoxia and this effect partially correlates with the mammalian target of rapamycin inhibition. Cardamonin might be a potential angiogenesis inhibitor for ovarian cancer therapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Chalconas/química , Neovascularización Patológica/prevención & control , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Embrión de Pollo , Regulación hacia Abajo/efectos de los fármacos , HumanosRESUMEN
The mammalian target of rapamycin (mTOR) regulates the motility and invasion of cancer cells. Cardamonin is a chalcone that exhibits anti-tumor activity. The previous study had proved that the anti-tumor effect of cardamonin was associated with mTOR inhibition. In the present study, the anti-metastatic effect of cardamonin and its underlying molecule mechanisms were investigated on the highly metastatic Lewis lung carcinoma (LLC) cells. The proliferation, invasion and migration of LLC cells were measured by MTT, transwell and wound healing assays, respectively. The expression and activation of mTOR- and adhesion-related proteins were assessed by Western blotting. The in vivo effect of cardamonin on the metastasis of the LLC cells was investigated by a mouse model. Treated with cardamonin, the proliferation, invasion and migration of LLC cells were significantly inhibited. The expression of Snail was decreased by cardamonin, while that of E-cadherin was increased. In addition, cardamonin inhibited the activation of mTOR and its downstream target ribosomal S6 kinase 1 (S6K1). Furthermore, the tumor growth and its lung metastasis were inhibited by cardamonin in C57BL/6 mice. It indicated that cardamonin inhibited the invasion and metastasis of LLC cells through inhibiting mTOR. The metastasis inhibitory effect of cardamonin was correlated with down-regulation of Snail and up-regulation of E-cadherin.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Chalconas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Antineoplásicos/administración & dosificación , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chalconas/administración & dosificación , Modelos Animales de Enfermedad , Activación Enzimática , Expresión Génica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Metástasis de la Neoplasia , FosforilaciónRESUMEN
The objective of this study was to determine possible effects and potential mechanisms of cardamonin on improving insulin resistance and vascular proliferative lesions in the rat's model system. Fed with 60% fructose-enriched diet for 12 weeks, male Sprague-Dawley (SD) rats developed insulin resistance and hyperinsulinemia. They also showed excessive proliferation of the vascular smooth muscle cells (VSMCs) and activation of the mammalian target of rapamycin (mTOR)/translation control proteins p70 ribosomal S6 kinase (P70S6K1)/eukaryotic initiation factor 4E binding protein 1 (4E-BP1) signaling in the rat thoracic aorta. From weeks 9-12, cardamonin was injected into the peritoneal cavity once daily. Under the detection of microscopy and electron microscopy, cardamonin improved hyperinsulinemia and inhibited proliferation of VSMCs in the thoracic aorta of rats in a dose-dependent manner. By the Real-Time RT-PCR, mRNA expression of mTOR, P70S6K1 and 4E-BP1 was significantly reduced in cardamonin treated rats. Similarly, protein over-expression of mTOR and p-P70S6K1 was obviously inhibited by immunohistochemical analyses. These findings suggest that cardamonin may play a role in ameliorating insulin resistance and smooth muscle hyperplasia of major vessels in fructose-induced rats, possibly via a mechanism that involves the modulation of insulin/mTOR signaling.