RESUMEN
The occurrence of multidrug-resistant bacteria necessitates the development of new antibacterial agents. This study synthesized artemisinin-zinc nanoparticles (AZ NPs) using a simple green method and investigated their physicochemical properties, antibacterial activity, and oral biological activity. A spherical shape morphology of AZ NPs was observed by scanning and transmission electron microscopy, with a particle size of 73 ± 2.604 nm. Energy dispersive spectrometry analysis showed that the AZ NPs consisted mainly of Zn, C, N, and O elements. According to differential scanning calorimeter analysis, the AZ NPs were stable up to 450 °C. Fourier-transform infrared spectroscopy revealed that artemisinin successfully bound to zinc acetate. The AZ NPs showed antibacterial activity against Salmonella and Escherichia coli, with a minimum inhibitory concentration of 0.056 mg/mL for both and minimum bactericidal concentrations of 0.21 and 0.11 mg/mL, respectively. The mechanisms by which AZ NPs mediate membrane damage were revealed by the downregulation of gene expression, and potassium ion and protein leakage. In vivo safety trials of these drugs revealed low toxicity. After AZ NPs were administered to infected mice, the intestinal bacteria decreased significantly, liver and kidney function were restored, histopathological damage to the liver and spleen were reduced, and the expression of inflammatory cytokines decreased. Therefore, AZ NPs have the potential as an oral antibacterial agent and can be used in antibiotic development and in the pharmaceutical industry.
Asunto(s)
Artemisininas , Nanopartículas del Metal , Animales , Ratones , Zinc , Nanopartículas del Metal/química , Antibacterianos/farmacología , Antibacterianos/química , Espectroscopía Infrarroja por Transformada de Fourier , Extractos Vegetales/química , Artemisininas/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Prenatal food restriction (PFR) induces dysfunction of the hypothalamicpituitaryadrenal (HPA) axis in the adult offspring. The aim of the present study was to identify the underlying mechanism of this process. Pregnant rats were placed on a restricted diet between gestational day 11 and 21. The offspring were fed with a highfat diet and were subjected to unpredictable chronic stress (UCS) from postnatal week 17 to 20. A higher serum corticosterone (CORT) level was observed in the PFR fetuses. Although lower arginine vasopressin (AVP), hippocampal vesicular glutamate transporter 2 (vGLUT2) and glutamic acid decarboxylase 65 (GAD65) mRNA expression levels were detected in the hippocampi of PFR fetuses, the ratio of the mRNA expression levels of vGLUT2 and GAD65 was higher compared with that of the controls, which was accompanied by histopathological and ultrastructural abnormalities of both the hypothalamus and hippocampus. However, there were no marked changes in the hippocampal expression levels of glucocorticoids receptor (GR) and mineralocorticoids receptor (MR) or the ratio of MR/GR ratio. After the fetuses had matured, lower serum CORT and adrenocorticotropic hormone (ACTH) levels were observed in PFR rats without UCS when compared with the control. A higher rise rate of serum ACTH was also observed after UCS when compared with that in rats without UCS. Furthermore, the hypothalamic mRNA expression level of corticotrophinreleasing hormone (CRH) was lower in PFR rats without UCS, while expression levels of CRH, AVP, GAD65 and vGLUT2 were enhanced after UCS when compared with the control, accompanied by an increased vGLUT2/GAD65 expression ratio. MR mRNA expression was lower, and GR mRNA expression was higher in the hippocampus of the PFR rats without UCS when compared with the control. However, the mRNA expression levels of both MR and GR in the PFR rats were higher compared with those of the control after UCS, which was accompanied histopathological changes in the dentate gyrus, cornu ammonis (CA1) and CA3 areas. In summary, it was suggested that PFR induced fetal alterations of the HPA axis manifesting as hypothalamic hyperexcitability and poor hippocampal feedback, which persisted to adulthood and affected the behavior of the rat offspring.
Asunto(s)
Desarrollo Fetal , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Animales , Corticosterona , Hormona Liberadora de Corticotropina/metabolismo , Dieta Alta en Grasa , Femenino , Masculino , Neurofisinas , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Precursores de Proteínas , Ratas , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , VasopresinasRESUMEN
Accumulating evidence has suggested that the tumor microenvironment of nonsmall-cell lung cancer (NSCLC) may be impacted by chemotherapy, radiotherapy, or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). PD-L1 is an important biomarker in the tumor microenvironment that can predict patient response to immunotherapies. Therefore, it is highly desirable to achieve a real-time, noninvasive assessment of PD-L1 expression, which can provide critical information for recruiting patients as well as monitoring therapeutic efficacy. We herein studied the EGFR-TKI-induced effects on PD-L1 levels in NSCLC tumor models using immuno-PET imaging with 89Zr-Df-KN035, an imaging tracer previously established by our group. A549 human NSCLC xenografts were established in BALB/c nude mice and treated with different doses of an EGFR-TKI gefitinib. PET imaging with 89Zr-Df-KN035 was performed before and after the treatment to evaluate PD-L1 expression, which was further verified by immunohistochemical staining. Our results demonstrate that 89Zr-Df-KN035 can specifically evaluate PD-L1 levels in NSCLC tumor models. Compared to the untreated control, the high dose of gefitinib inhibited tumor growth and lowered the tumor uptake of 89Zr-Df-KN035. In comparison, the low dose of gefitinib did not affect tumor growth, although the extensive tumor necrosis also led to the lower uptake of 89Zr-Df-KN035. In conclusion, our results demonstrate that immuno-PET imaging with 89Zr-Df-KN035 is a promising tool to noninvasively monitor PD-L1 expression in NSCLC treated with EGFR-TKIs and can be used to optimize treatment plans for immunotherapy.
Asunto(s)
Antígeno B7-H1/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Monitoreo de Drogas/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Células A549 , Animales , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Gefitinib/farmacología , Gefitinib/uso terapéutico , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Imagen Molecular/métodos , Tomografía de Emisión de Positrones/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Trazadores Radiactivos , Radioisótopos/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Circonio/administración & dosificaciónRESUMEN
Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.