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1.
Pestic Biochem Physiol ; 166: 104568, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32448422

RESUMEN

Thirty unreported indole derivatives containing dithioacetal moiety were synthesized and evaluated for anti-plant viral activity. Bioassay results displayed that some of the target compounds showed better activities against tobacco mosaic virus (TMV) than the commercial Ribavirin in vivo. In particular, anti-TMV curative, protective and inactivating activity of 4p were 55.1, 57.2, and 80.3%, respectively, and EC50 value for inactivating activity was 88.5 µg/mL. The observation of transmission electron microscope showed that 4p may have a certain destructive effect on TMV particles. To further study, microscale thermophoresis analysis result also demonstrated that 4p powerfully interacted with TMV coat protein in vitro. Hence, this study provides a strong evidence suporting that indole derivatives might be applied as new antiviral agents.


Asunto(s)
Antivirales , Virus del Mosaico del Tabaco , Indoles , Relación Estructura-Actividad
2.
Mutat Res ; 850-851: 503148, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32247557

RESUMEN

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of ß-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-ß-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to ß-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, ß-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-ß-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.


Asunto(s)
Carbolinas/química , Indoles/toxicidad , Mutagénesis/efectos de los fármacos , Piridinas/toxicidad , Toluidinas/química , Compuestos de Anilina/toxicidad , Animales , Carbolinas/toxicidad , Colon/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Ratones , Ratones Transgénicos , Mutación Puntual/efectos de los fármacos , Toluidinas/toxicidad
3.
Drug Discov Ther ; 14(2): 67-72, 2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-32336723

RESUMEN

The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Amidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , Cloroquina/uso terapéutico , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/tratamiento farmacológico , Darunavir/uso terapéutico , Combinación de Medicamentos , Humanos , Hidroxicloroquina/uso terapéutico , Inmunización Pasiva , Indoles/uso terapéutico , Interferón-alfa/uso terapéutico , Interferón beta/uso terapéutico , Lopinavir/uso terapéutico , Pandemias , Pirazinas/uso terapéutico , Ritonavir/uso terapéutico
4.
Life Sci ; 250: 117602, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32240677

RESUMEN

AIMS: Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability. MAIN METHODS: Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces. KEY FINDINGS: Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration. SIGNIFICANCE: Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.


Asunto(s)
Química Farmacéutica/métodos , Biología Computacional/métodos , Indoles/antagonistas & inhibidores , Monofenol Monooxigenasa/antagonistas & inhibidores , Piel/efectos de los fármacos , Agaricales/metabolismo , Dominio Catalítico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Electrones , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Relación Estructura-Actividad Cuantitativa , Pigmentación de la Piel/efectos de los fármacos , Tiosemicarbazonas/química , Rayos Ultravioleta
5.
Drug Discov Ther ; 14(1): 58-60, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32147628

RESUMEN

The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.


Asunto(s)
Antivirales/farmacología , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Descubrimiento de Drogas , Alanina/análogos & derivados , Alanina/farmacología , Amidas/farmacología , Antivirales/química , Betacoronavirus/efectos de los fármacos , Betacoronavirus/fisiología , Cloroquina/farmacología , Estudios Clínicos como Asunto , Humanos , Indoles/farmacología , Pandemias , Neumonía Viral , Pirazinas/farmacología , Ribonucleótidos/farmacología , Replicación Viral/efectos de los fármacos
6.
Artículo en Chino | MEDLINE | ID: mdl-32062902

RESUMEN

Pulmonary fibrosis is the terminal manifestation of a variety of interstitial lung diseases. Idiopathic pulmonary fibrosis (IPF) is one of the chronic, progressive, fibrotic lung disease with high incidence and poor prognosis. Nintedanib and pirfenidone are currently marketed anti-pulmonary fibrosis drugs, and their efficacy and safety are recognized in patients with IPF. This article reviews the targets and clinical trials of the two drugs, and provides a basis for the expansion of indications for anti-pulmonary fibrosis drugs.


Asunto(s)
Indoles/farmacología , Piridonas/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos
7.
J Photochem Photobiol B ; 204: 111811, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32028187

RESUMEN

The development of multidrug resistance is often associated with the over-expression of P-glycoprotein (P-gp). This protein prevents drug accumulation and extrudes them out of the cell before they reach the intended target. The aim of this study was to develop an in vitro MCF-7 cell line with increased expression of P-gp and test the phototoxicity of a novel photoactivated zinc phthalocyanine tetrasulfonic acid (ZnPcS4) on these cells. The over-expressed P-gp MCF-7 cells (MCF-7/DOX) were developed from wildtype (WT) MCF-7 cells by a stepwise continuous exposure of the WT cells to different concentrations of Doxorubicin (DOX) (0.1 - 1 µM) over a period of 4 months. The P-gp expression was measured using flow cytometry, immunofluorescence and enzyme immunoassay. To verify whether zinc phthalocyanine-mediated photodynamic therapy (ZnPcS4 - PDT) is effective in MCF-7/DOX, we studied the subcellular localization, phototoxicity and nuclear damage. The flow cytometry result showed two distinct peaks of P-gp positive and negative expression in MCF-7/DOX cell population, which correlates with the ELISA-based assay (p˂0.001). The ME16C (Normal breast cells) was used as control. The localization studies showed that ZnPcS4 have greater affinity for lysosome than mitochondria. Phototoxicity results indicated that photoactivated zinc phthalocyanine decreased the cell proliferation and viability as the drug and laser light dosages increased to 16 µM and 20 J/cm2 respectively. PDT-induced cytotoxicity using lactose dehydrogenase (LDH) enzyme leakage as measure did not increase likewise. The ZnPcS4-induced PDT was less effective for MCF-7/DOX cells which could be attributed to decreased retention of ZnPcS4 in major cellular organelles due to the presence of increased drug efflux P-gp. The current findings suggest that, increased P-gp expression, a characteristic of multidrug resistance together with other related intrinsic mechanisms might contribute to render MCF-7/DOX cells less sensitive to ZnPcS4-induced phototoxicity.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Proliferación Celular/efectos de los fármacos , Indoles/farmacología , Láseres de Semiconductores , Compuestos Organometálicos/farmacología , Adenosina Trifosfato/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de la radiación , Femenino , Humanos , Indoles/química , Células MCF-7 , Compuestos Organometálicos/química , Fotoquimioterapia , Rodamina 123/química , Rodamina 123/metabolismo
8.
Biosci Trends ; 14(1): 64-68, 2020 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-32037389

RESUMEN

Pneumonia associated with the 2019 novel coronavirus (2019-nCoV) is continuously and rapidly circulating at present. No effective antiviral treatment has been verified thus far. We report here the clinical characteristics and therapeutic procedure for four patients with mild or severe 2019-nCoV pneumonia admitted to Shanghai Public Health Clinical Center. All the patients were given antiviral treatment including lopinavir/ritonavir (Kaletra®), arbidol, and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine) and other necessary support care. After treatment, three patients gained significant improvement in pneumonia associated symptoms, two of whom were confirmed 2019-nCoV negative and discharged, and one of whom was virus negative at the first test. The remaining patient with severe pneumonia had shown signs of improvement by the cutoff date for data collection. Results obtained in the current study may provide clues for treatment of 2019-nCoV pneumonia. The efficacy of antiviral treatment including lopinavir/ritonavir, arbidol, and SFJDC warrants further verification in future study.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Indoles/uso terapéutico , Lopinavir/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ritonavir/uso terapéutico , Adulto , China , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
9.
Ann Rheum Dis ; 79(4): 507-517, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32041748

RESUMEN

BACKGROUND: Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). METHODS: Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. RESULTS: SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. CONCLUSIONS: Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.


Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Fibroblastos/metabolismo , MicroARNs/metabolismo , Miofibroblastos/metabolismo , ARN Largo no Codificante/metabolismo , Receptores Notch/metabolismo , Esclerodermia Sistémica/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Epigénesis Genética , Fibrosis , Código de Histonas , Humanos , Indoles/farmacología , Fenotipo , Piridonas/farmacología , Receptores Notch/antagonistas & inhibidores , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Transducción de Señal , Piel/citología , Piel/metabolismo , Piel/patología
10.
Chemosphere ; 248: 125956, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32028156

RESUMEN

Biofouling and organic fouling are major obstacles for polymeric membranes during application. In this work, zeolitic imidazolate framework-8@polydopamine (ZIF-8@PDA) nanoparticles were prepared by an aqueous synthesis strategy and incorporated into the polyamide (PA) selective layer to synthesize thin film nanocomposite membrane (TFN) during interfacial polymerization. The permeability and selectivity of the composite membrane were simultaneously improved with the introduction of ZIF-8@PDA. The water permeability of the TFN membrane increased to 3.74 ± 0.19 L/(m2·h·bar), which is 43.8% higher than that of the control membrane. Besides, the rejection of TFN membrane to sodium chloride is 98.68 ± 0.13%, which shows 0.99% increment than the unmodified membrane. Moreover, organic fouling and biofouling of the TFN membrane were also alleviated thanks to the introduction of the hydrophilic ZIF-8@PDA. The short-term filtration results indicate the performance of the TFN membrane is stable during operation.


Asunto(s)
Incrustaciones Biológicas , Membranas Artificiales , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Filtración/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Indoles , Nanocompuestos , Nanopartículas , Nylons , Permeabilidad , Polímeros , Agua , Zeolitas
11.
J Photochem Photobiol B ; 204: 111808, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32006892

RESUMEN

Photodynamic therapy (PDT) is effective in the treatment of different types of cancer, such as basal cell carcinoma and other superficial cancers. However, improvements in photosensitizer delivery are still needed, and the use of PDT against more deeply located tumors has been the subject of many studies. Thus, the goal of this study was to evaluate the efficacy of a nanoemulsion containing aluminium-phthalocyanine (AlPc-NE) as a mediator of photodynamic therapy (PDT-AlPc-NE) against grafted 4T1 breast adenocarcinoma tumors in mice (BALB/c). Short after the appearance of the tumor, the animals were divided into groups (n = 5) as follows: untreated; only AlPc-NE and treated with PDT-AlPc-NE. The tumor volume was measured with a digital calliper at specific times. The presence of metastasis in the lungs was evaluated by microtomography and histopathological analyses. The results show that the application of PDT-AlPc-NE eradicated the transplanted tumors in all the treated animals, while the animals from control groups presented a robust increase in the tumor volume. Still more significantly, microtomography showed the animals submitted the PDT-AlPc-NE to be free of detectable metastasis in the lungs. The histological analysis of the lungs further confirmed the results verified by the microtomography. Therefore, this study suggests that PDT-AlPc-NE is effective in the elimination of experimentally grafted breast tumors in mice and also in preventing the formation of metastasis in the lungs.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Aluminio/química , Neoplasias de la Mama/tratamiento farmacológico , Indoles/química , Neoplasias Pulmonares/tratamiento farmacológico , Nanoestructuras/química , Fármacos Fotosensibilizantes/uso terapéutico , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Nanoestructuras/uso terapéutico , Nanoestructuras/toxicidad , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Trasplante Homólogo , Microtomografía por Rayos X
12.
Chem Commun (Camb) ; 56(20): 3089-3092, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-32052805

RESUMEN

Reaction of FeIII(O2˙-)(TPP) with 2,3-dimethylindole at -40 °C gives the ring-opened, dioxygenated N-(2-acetyl-phenyl)-acetamide product. The reaction was monitored in situ by low-temperature UV-vis and 1H NMR spectroscopies. This work demonstrates that a discrete iron(iii)(superoxo) porphyrin is competent to carry out indole oxidation, as proposed for the tryptophan and indoleamine 2,3-dioxygenases.


Asunto(s)
Compuestos Férricos/química , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indoles/química , Metaloporfirinas/química , Superóxidos/química , Triptófano Oxigenasa/química , Compuestos Férricos/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indoles/metabolismo , Metaloporfirinas/metabolismo , Estructura Molecular , Oxidación-Reducción , Superóxidos/metabolismo , Triptófano Oxigenasa/metabolismo
13.
Toxicol Lett ; 324: 104-110, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32092453

RESUMEN

Dietary and microbial indoles can act as ligands and activators of pregnane X receptor (PXR), with implications in human intestinal health. In the current study, we examined the effects of simple mono-methylated indoles (MMIs) on the activity and function of PXR, using a series of human hepatic and intestinal cell models. Indoles 1-MMI and 2-MMI strongly induced CYP3A4 and MDR1 mRNAs in human intestinal adenocarcinoma cells LS180, but not in primary human hepatocytes. The levels of CYP3A4 mRNA were increased by 1-MMI and 2-MMI in wild type, but not in PXR-knock-out human hepatic progenitor HepaRG cells, implying the involvement of PXR in CYP3A4 induction by MMIs. Utilizing reporter gene assay, we observed dose-dependent activation of PXR by all MMIs, and their efficacies and potencies were comparable. Tested MMIs also displayed moderate antagonist effects on PXR, revealing about partial agonist effects of these compounds. As demonstrated using the Chromatin immunoprecipitation assay (ChIP),1-MMI increased PXR occupancy of the CYP3A4 promoter. Time-Resolved Fluorescence Resonance Energy Transfer revealed that MMIs are weak ligands of human PXR. Collectively, we show that MMIs are ligands and partial agonists of human PXR, which induce PXR-regulated genes in human intestinal cells.


Asunto(s)
Hepatocitos/efectos de los fármacos , Indoles/farmacología , Mucosa Intestinal/efectos de los fármacos , Receptor X de Pregnano/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Línea Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/fisiología , Hepatocitos/metabolismo , Humanos , Indoles/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , Regiones Promotoras Genéticas , Transducción de Señal/efectos de los fármacos
14.
J Agric Food Chem ; 68(9): 2795-2802, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32031786

RESUMEN

Polydopamine (PDA) possesses high aqueous dispersibility, strong optical absorption, and a zwitterionic property, which give it multitudes of advantages to coat light-sensitive hydrophobic curcumin (Cur) for pH-responsive release. However, PDA is formed in alkaline conditions, which hinders its potential application for alkali-sensitive curcumin coating. Here, we developed a method to prepare PDA-coated Cur nanoparticles (NPs), which reduced chemical degradation of Cur in alkaline conditions. Encapsulation efficiency and loading capacity decreased to 73.69% and 51.80%, as the time for dopamine polymerization went on. PDA could protect Cur from light-induced degradation in powder and solution forms. Controlled release and pH-responsive delivery of PDA-coated Cur were observed under stomach and intestinal conditions compared to free Cur, which resulted from the coverage and thickness of the PDA shell and the electrostatic attraction between PDA and Cur. PDA-coated Cur NPs could be a promising way for the application of Cur in the beverage and food industry.


Asunto(s)
Curcumina/química , Indoles/química , Nanopartículas/química , Polímeros/química , Portadores de Fármacos/química , Composición de Medicamentos , Concentración de Iones de Hidrógeno , Cinética , Tamaño de la Partícula
15.
Int J Nanomedicine ; 15: 137-149, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32021170

RESUMEN

Purpose: Traditional chemotherapy is accompanied by significant side effects, which, in many aspects, limits its treatment efficacy and clinical applications. Herein, we report an oxidative responsive polymersome nanosystem mediated by near infrared (NIR) light which exhibited the combination effect of photodynamic therapy (PDT) and chemotherapy. Methods: In our study, poly (propylene sulfide)20-bl-poly (ethylene glycol)12 (PPS20-b-PEG12) block copolymer was synthesized and employed to prepare the polymersome. The hydrophobic photosensitizer zinc phthalocyanine (ZnPc) was loaded in the shell and the hydrophilic doxorubicin hydrochloride (DOX·HCl) in the inner aqueous space of the polymersome. Results: Under the irradiation of 660 nm NIR light, singlet oxygen 1O2 molecules were generated from ZnPc to oxidize the neighbouring sulfur atoms on the PPS block which eventually ruptured the intact structure of polymersomes, leading to the release of encapsulated DOX·HCl. The released DOX and the 1O2 could achieve a combination effect for cancer therapy if the laser activation and drug release occur at the tumoral sites. In vitro studies confirmed the generation of singlet oxygen and DOX release by NIR irradiation. In vivo studies showed that such a combined PDT-chemotherapy nanosystem could accumulate in A375 tumors efficiently, thus leading to significant inhibition on tumor growth as compared to PDT (PZ group) or chemotherapy alone (DOX group). Conclusion: In summary, this oxidation-sensitive nanosystem showed excellent anti-tumor effects by synergistic chemophotodynamic therapy, indicating that this novel drug delivery strategy could potentially provide a new means for cancer treatments in clinic.


Asunto(s)
Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Melanoma Experimental/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Liberación de Fármacos , Humanos , Indoles/administración & dosificación , Indoles/química , Rayos Láser , Masculino , Ratones Endogámicos BALB C , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Polietilenglicoles/química , Polímeros/química , Oxígeno Singlete/farmacocinética , Sulfuros/química
16.
Int J Nanomedicine ; 15: 301-313, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32021181

RESUMEN

Purpose: Multifunctional drug delivery systems (DDS) are emerging as a new strategy to highly treat malignant tumors. The aim of this study is to develop a drug dual-carriers delivery system (DDDS) using the natural protein ferritin (FRT) and a nanoscale graphene oxide (NGO) as dual-carriers. Methods: The FRT is a pH-sensitive hollow cage protein with disassembly and reassembly properties and the NGO has a large surface area and a photothermal effect by which it can load and release drugs under near-infrared irradiation (NIR). Due to these unique features, the NGO loaded the anticancer drug resveratrol (RSV) and the conjugated mitochondrion targeted molecule IR780 as IR780-NGO-RSV (INR), the first drug delivery platform. Next, the INR was capsulated by FRT to form the DDDS INR@FRT which was applied for synergistic photothermal-chemotherapy of ovarian cancer. Results: Through a series of characterizations, INR@FRT showed a uniform nanosphere structure and remarkable stability in physiological condition. Heat/pH 5.0 was confirmed to trigger RSV release from the INR@FRT. After taken up by cells, INR@FRT located to the lysosomes where the acidic environment triggered INR release. INR targeted the mitochondrion and released RSV to directly react with organelles, which in turn decreased the mitochondrion membrane potential and caused cell apoptosis. In-vivo experiments showed that INR@FRT combined with NIR irradiation displayed remarkable tumor suppression with a high survival rate after 60 days of treatment. Finally, the biocompatibility of INR@FRT was demonstrated in vitro and in vivo. Conclusion: These results highlight the immense potential of INR@FRT as a type of DDDS for the treatment of tumors.


Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Indoles/farmacología , Mitocondrias/efectos de los fármacos , Nanoestructuras/química , Neoplasias Ováricas/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Femenino , Ferritinas/química , Grafito/química , Calor , Humanos , Concentración de Iones de Hidrógeno , Indoles/administración & dosificación , Indoles/química , Rayos Infrarrojos , Ratones Desnudos , Nanoestructuras/administración & dosificación , Resveratrol/administración & dosificación , Resveratrol/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Nat Commun ; 11(1): 855, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32071312

RESUMEN

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.


Asunto(s)
Disfunción Cognitiva/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ayuno , Microbioma Gastrointestinal/fisiología , Animales , Encéfalo/metabolismo , Cognición , Biología Computacional , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicaciones , Metabolismo Energético/genética , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal/genética , Regulación de la Expresión Génica , Hipocampo/metabolismo , Indoles/metabolismo , Resistencia a la Insulina , Masculino , Metaboloma , Ratones , Propionatos/metabolismo , ARN Ribosómico 16S , Serotonina/metabolismo , Sinapsis/ultraestructura , Ácido Tauroquenodesoxicólico/metabolismo
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