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1.
Int J Nanomedicine ; 16: 2173-2186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33758505

RESUMEN

Background: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth. Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo. Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by ß-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP. Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth. Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.


Asunto(s)
Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Imidazoles/uso terapéutico , Nanopartículas/química , Paclitaxel/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Recuento de Células , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Neoplasias del Colon/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Emulsiones/química , Femenino , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Int J Nanomedicine ; 16: 2219-2236, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33762822

RESUMEN

Introduction: In this paper, we have designed and formulated, a novel synthesis of doxorubicin (DOX) loaded bimetallic gold nanorods in which gold salt (HAuCl4) is chelated with anthracycline (DOX), diacid polyethylene-glycol (PEG-COOH) and gadolinium salt (GdCl3 * 6 H2O) to form DOX IN-Gd-AuNRs compared with DOX ON-Gd-AuNRs in which the drug was grafted onto the bimetallic pegylated nanoparticle surface by electrostatic adsorption. Material and Method: The physical and chemical evaluation was performed by spectroscopic analytical techniques (Raman spectroscopy, UV-Visible and transmission electron microscopy (TEM)). Magnetic features at 7T were also measured. Photothermal abilities were assessed. Cytotoxicity studies on MIA PaCa-2, human pancreatic carcinoma and TIB-75 hepatocytes cell lines were carried out to evaluate their biocompatibility and showed a 320 fold higher efficiency for DOX after encapsulation. Results: Exhaustive physicochemical characterization studies were conducted showing a mid size of 20 to 40 nm diameters obtained with low polydispersity, efficient synthesis using seed mediated synthesis with chelation reaction with high scale-up, long duration stability, specific doxorubicin release with acidic pH, strong photothermal abilities at 808 nm in the NIR transparency window, strong magnetic r1 relaxivities for positive MRI, well adapted for image guided therapy and therapeutical purpose in biological tissues. Conclusion: In this paper, we have developed a novel theranostic nanoparticle composed of gadolinium complexes to gold ions, with a PEG biopolymer matrix conjugated with antitumoral doxorubicin, providing multifunctional therapeutic features. Particularly, these nano conjugates enhanced the cytotoxicity toward tumoral MIAPaCa-2 cells by a factor of 320 compared to doxorubicin alone. Moreover, MRI T1 features at 7T enables interesting positive contrast for bioimaging and their adapted size for potential passive targeting to tumors by Enhanced Permeability Retention. Given these encouraging antitumoral and imaging properties, this bimetallic theranostic nanomaterial system represents a veritable promise as a therapeutic entity in the field of medicinal applications.


Asunto(s)
Doxorrubicina/uso terapéutico , Gadolinio/química , Oro/química , Nanotubos/química , Nanomedicina Teranóstica , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/farmacología , Liberación de Fármacos , Endocitosis , Humanos , Concentración 50 Inhibidora , Imagen por Resonancia Magnética , Ratones , Nanotubos/ultraestructura , Neoplasias/tratamiento farmacológico , Espectrofotometría Ultravioleta
3.
Biomed Res Int ; 2021: 6694572, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33521129

RESUMEN

Allanblackia floribunda has been used to treat an upset stomach in African traditional medicine, but its efficacy and safety have not been scientifically studied. The present research is aimed at assessing the antiulcer property of the seed extract of the plant to validate its traditional claim. Rats were pretreated with three doses of aqueous extract of A. floribunda (AFE) at 30, 100, and 300 mg/kg or omeprazole 10 mg/kg for 1 hr before the acute gastric ulcer was induced by oral administration of 5 mL/kg of 98% ethanol. The animals were sacrificed under anesthesia, and the stomach and blood were collected. The gross histology of the stomach, percentage protection conferred by the treatment, gastric pH, and serum TNF-α and INF-γ were assessed as well as the expression of Ki67 antigens. The antioxidant properties as well as the acute toxicity profile of the plant extract were also assessed. The results show that A. floribunda conferred significant protection on the rats against gastric ulceration with % protection of 46.15, 57.69, and 65.38 for AFE 30, 100, and 300 mg/kg, respectively, as well as 69.23% for omeprazole 10 mg/kg. The plant extract caused marked reductions in gastric pH, TNF-α, and INF-γ with statistical significance (p < 0.001) for AFE 300 mg/kg and omeprazole 10 mg/kg. Also, the plant showed good antioxidant activity comparable to gallic acid. Furthermore, the plant extract modulated the expression of Ki67 antigens. All animals survived the 14-day delayed toxicity test with no significant differences in physical, hematological, and biochemical parameters between rats orally administered with supratherapeutic doses of AFE (5000 mg/kg) or normal saline. The study established that the gastroprotective effect of the seed extract of A. floribunda is attributable to its antisecretory, antioxidant, and anti-inflammatory properties. Additionally, the plant was found to promote ulcer healing via the modulation of the expression Ki67 and was safe at supratherapeutic doses.


Asunto(s)
Clusiaceae/química , Etanol/toxicidad , Interferón gamma/metabolismo , Antígeno Ki-67/metabolismo , Semillas/química , Úlcera Gástrica/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Compuestos de Bifenilo/química , Quelantes/farmacología , Modelos Animales de Enfermedad , Depuradores de Radicales Libres , Concentración 50 Inhibidora , Masculino , Óxido Nítrico/metabolismo , Fitoterapia , Picratos/química , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamente
4.
Chem Biol Interact ; 338: 109371, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33582112

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most deadly malignancies worldwide. However, current therapeutic drugs for HCC are far from satisfactory. Thus, the development of new drugs is urgently needed. In this study, we identified a novel quinazoline derivative, 04NB-03, with potent anti-HCC activities both in vitro and in vivo. 04NB-03 effectively suppressed the viability and proliferation of HCC cells. It induced both cell cycle arrest at the G2/M phase and apoptosis in concentration- and time-dependent manners. Moreover, 04NB-03 treatment significantly reduced xenograft tumor growth without notable toxic effects. Mechanistically, 04NB-03 induced endogenous reactive oxygen species (ROS) accumulation in concentration- and time-dependent manners. Scavenging the ROS reversed 04NB-03-induced cell cycle arrest and apoptosis. Taken together, these results indicate that the quinazoline derivative, 04NB-03, inhibits the growth of HCC cells through the induction of cell cycle arrest and apoptosis in an ROS-dependent manner. 04NB-03 is, therefore, a potential small molecule candidate for the development of antitumor drugs targeting HCC.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Quinazolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Quinazolinas/química
5.
Nat Commun ; 12(1): 1052, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594070

RESUMEN

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.


Asunto(s)
Glucólisis/efectos de los fármacos , Fosfofructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Trypanosoma/enzimología , Tripanosomiasis Africana/metabolismo , Tripanosomiasis Africana/parasitología , Enfermedad Aguda , Regulación Alostérica/efectos de los fármacos , Animales , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Parásitos/efectos de los fármacos , Fosfofructoquinasas/química , Fosfofructoquinasas/metabolismo , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína , Relación Estructura-Actividad , Trypanosoma/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico
6.
Int J Nanomedicine ; 16: 1189-1206, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33623382

RESUMEN

Introduction: Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies. Methods: Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay. Results: All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro. Conclusions: This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lectinas/uso terapéutico , Fármacos Anti-VIH/farmacología , Antirretrovirales/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular , Composición de Medicamentos , Liberación de Fármacos , Sinergismo Farmacológico , Femenino , VIH-1/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Lectinas/farmacología , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Pirimidinas/farmacología , Raltegravir Potásico/farmacología , Tenofovir/farmacología
7.
Int J Nanomedicine ; 16: 951-976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603362

RESUMEN

Purpose: Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers. Methods: For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice. Results and Conclusion: The mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from -12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.


Asunto(s)
Lípidos/química , Nanopartículas/química , Neoplasias Ováricas/tratamiento farmacológico , Fotoquimioterapia , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Cinética , Liposomas , Pruebas de Función Hepática , Mesoporfirinas/farmacología , Mesoporfirinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Neoplasias Ováricas/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Especies Reactivas de Oxígeno/metabolismo , Pruebas de Toxicidad Aguda
8.
Int J Nanomedicine ; 16: 977-987, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603363

RESUMEN

Background: The dragon tongue beans are a legume belonging to the Fabaceae family, are rich in protein, starch, fiber, and other micronutrients that have numerous health-promoting benefits. Its peel commonly the waste parts also contains lots of bioactive compounds. Materials and Methods: In the current research, dragon tongue bean peels (DtbP) extract is tested for the existence of phytochemicals. Ag nanoparticles are biosynthesized using DtbP extract. The generated DtbP silver nanoparticle characterization was accomplished using UV-Vis spectral analysis, FTIR spectral analysis, SEM analysis, EDX analysis, XRD analysis, zeta potential, and DLS study. Furthermore, comparative assessment on multi-biological activities of the biosynthesized Ag nanoparticles was accomplished by employing cytotoxicity (inhibition against HepG2 cancer cells), antidiabetic (α-glucosidase inhibition assay), and antioxidant (free-radical scavenging) analysis. Results: The characterization result of the DtbP-AgNPs demonstrated that the AgNPs synthesized within 24 h. The AgNPs are nearly spherical. The biological effect assay of AgNPs displayed that DtbP-AgNPs is having significant cytotoxicity, antidiabetic, and moderate antioxidant effect. This study results as a whole report the biosynthesis of DtbP-AgNPs utilizing the legume dragon tongue bean waste peel and assessment of their multiple biological activities. The synthesized DtbP-AgNPs could serve as a potential candidate in the pharmaceutical industries in the formulation of drugs for the treatment of several medical ailments concerning cancer, diabetes, etc.


Asunto(s)
Fabaceae/química , Nanopartículas del Metal/química , Extractos Vegetales/química , Plata/química , Antioxidantes/farmacología , Compuestos de Bifenilo/química , Muerte Celular , Tecnología Química Verde , Células Hep G2 , Humanos , Hipoglucemiantes/farmacología , Concentración 50 Inhibidora , Tamaño de la Partícula , Picratos/química , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Difracción de Rayos X
9.
Int J Nanomedicine ; 16: 1005-1019, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603365

RESUMEN

Purpose: Development of hyaluronic acid conjugated metformin-phospholipid sonocomplexes (HA-MPS), a biphasic complexation product compiled for enhancing both the lipophilicity and targeting potential of Metformin (MET) to CD44 receptors on pancreatic cancer. Methods: MET was chemically conjugated to hyaluronic acid (HA) via amide coupling reaction. Then, the HA conjugated MET was physically conjugated to Lipoid™S100 via ultrasound irradiation. A combined D-optimal design was implemented to statistically optimize formulation variables. The HA-MPS were characterized through solubility studies, partition coefficient, drug content uniformity, particle size and zeta potential. The optimized HA-MPS was tested via proton nuclear magnetic resonance, infrared spectroscopy to elucidate the nature of physicochemical interactions in the complex which was further scrutinized on molecular level via molecular docking and dynamic simulation. Results: The solubility and partition studies showed a lipophilicity enhancement up to 67 folds as they adopted inverted micelles configuration based on the packing parameter hypothesis. The optimized HA-MPS showed 11.5 folds lower IC50, extra 25% reduction in oxygen consumption rate, better reduction in hypoxia-inducible factor and reactive oxygen species in MiaPaCa-2 cells. Conclusion: These results proved better internalization of MET which was reflected by abolishing hypoxic tumour microenvironment, a mainstay toward a normoxic and less resistant pancreatic cancer.


Asunto(s)
Ácido Hialurónico/química , Metformina/farmacología , Fosfolípidos/química , Sonicación , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , 1-Octanol/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glucosa/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Concentración 50 Inhibidora , Micelas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Consumo de Oxígeno/efectos de los fármacos , Neoplasias Pancreáticas/patología , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Agua/química
10.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557278

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. The virus still spreads globally through human-to-human transmission. Nevertheless, there are no specific treatments clinically approved. This study aimed to compare antiviral activity of gemcitabine and its analogue 2'-fluoro-2'-deoxycytidine (2FdC) against SARS-CoV-2 as well as cytotoxicity in vitro. Fluorescent image-based antiviral assays revealed that gemcitabine was highly potent, with a 50% effective concentration (EC50) of 1.2 µM, more active than the well-known nucleoside monophosphate remdesivir (EC50 = 35.4 µM). In contrast, 2FdC was marginally active (EC50 = 175.2 µM). For all three compounds, the 50% cytotoxic concentration (CC50) values were over 300 µM toward Vero CCL-81 cells. Western blot and quantitative reverse-transcription polymerase chain reaction analyses verified that gemcitabine blocked viral protein expression in virus-infected cells, not only Vero CCL-81 cells but also Calu-3 human lung epithelial cells in a dose-dependent manner. It was found that gemcitabine has a synergistic effect when combined with remdesivir. This report suggests that the difluoro group of gemcitabine is critical for the antiviral activity and that its combination with other evaluated antiviral drugs, such as remdesivir, could be a desirable option to treat SARS-CoV-2 infection.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Desoxicitidina/análogos & derivados , /efectos de los fármacos , Adenosina Monofosfato/farmacología , Alanina/farmacología , Animales , Antivirales/farmacología , /virología , Línea Celular , Chlorocebus aethiops , Desoxicitidina/farmacología , Quimioterapia Combinada , Humanos , Concentración 50 Inhibidora , Células Vero , Replicación Viral/efectos de los fármacos
11.
Int J Nanomedicine ; 16: 579-589, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531802

RESUMEN

Purpose: Breast cancer is one of the most lethal types of cancer in women. Curcumin showed therapeutic potential against breast cancer, but applying that by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Moreover, poor water solubility of curcumin causes accumulation of a high concentration of curcumin and so decrease its permeability to the cell. Many strategies are employed to reduce curcumin metabolism such as adjuvants and designing novel delivery systems. Therefore, in this study sodium alginate and chitosan were used to synthesize the hydrogels that are known as biocompatible, hydrophilic and low toxic drug delivery systems. Also, folic acid was used to link to chitosan in order to actively targetfolate receptors on the cells. Methods: Chitosan-ß-cyclodextrin-TPP-Folic acid/alginate nanoparticles were synthesized and then curcumin was loaded on them. Interaction between the constituents of the particles was characterized by FTIR spectroscopy. Morphological structures of samples were studied by FE-SEM. Release profile of curcumin was determined by dialysis membrane. The cytotoxic test was done on the Kerman male breast cancer (KMBC-10) cell line by using MTT assay. The viability of cells was detected by fluorescent staining. Gene expression was investigated by real-time PCR. Results: The encapsulation of curcumin into nano-particles showed an almost spherical shape and an average particle size of 155 nm. In vitro cytotoxicity investigation was indicated as dose-respond reaction against cancer breast cells after 24 h incubation. On the other hand, in vitro cell uptake study revealed active targeting of CUR-NPs into spheroids. Besides, CXCR 4 expression was detected about 30-fold less than curcumin alone. The CUR-NPs inhibited proliferation and increased apoptosis in spheroid human breast cancer cells. Conclusion: Our results showed the potential of NPs as an effective candidate for curcumin delivery to the target tumor spheroids that confirmed the creatable role of folate receptors.


Asunto(s)
Alginatos/química , Quitosano/química , Curcumina/farmacología , Nanosferas/química , Esferoides Celulares/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Fluorescencia , Ácido Fólico/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Nanosferas/ultraestructura , Tamaño de la Partícula , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Esferoides Celulares/efectos de los fármacos
12.
Exp Parasitol ; 223: 108079, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524381

RESUMEN

Chagas disease is caused by Trypanosoma cruzi, and it is an important cause of morbidity and mortality in Latin America. There are no vaccines, and the chemotherapy available to treat this infection has serious side effects. In a search for alternative treatments, we determined the in vitro susceptibility of epimastigote and trypomastigote forms of T. cruzi and the cytotoxic effects on peripheral blood mononuclear cells (PBMCs) of ethanolic extracts obtained from six different plant species. The ethanolic extracts of Ageratina vacciniaefolia, Clethra fimbriata and Siparuna sessiliflora showed antiprotozoal activity against epimastigotes and low cytotoxicity in mammalian cells. However, only the ethanolic extract of C. fimbriata showed activity against T. cruzi trypomastigotes, and it had low cytotoxicity in PBMCs. An analysis on the phytochemical composition of C. fimbriata extract showed that its metabolites were primarily represented by two families of compounds: flavonoids and terpenoids. Lastly, we analyzed whether the A. vacciniaefolia, C. fimbriata, or S. sessiliflora ethanolic extracts induced IFN-γ or TNF-α production. Significantly, ethanolic extracts of C. fimbriata induced TNF-α production and S. sessiliflora induced both cytokines. In addition, C. fimbriata and S. sessiliflora induced the simultaneous secretion of IFN-γ and TNF-α in CD8+ T cells. The antiprotozoal and immunomodulatory activity of C. fimbriata may be related to the presence of flavonoid and triterpene compounds in the extract. Thus, these findings suggest that C. fimbriata may represent a valuable source of new bioactive compounds for the therapeutic treatment of Chagas disease that combines trypanocidal activity with the capacity to boost the immune response.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Trypanosoma cruzi/efectos de los fármacos , Adulto , Ageratina/química , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Cromatografía Líquida de Alta Presión , Clethraceae/química , Colombia , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Interferón gamma/metabolismo , Laurales/química , Masculino , Medicina Tradicional , Extractos Vegetales/toxicidad , Espectrometría de Masa por Ionización de Electrospray , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
13.
Nat Commun ; 12(1): 488, 2021 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473130

RESUMEN

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 µM and an effective antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PLproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for antiviral drug discovery targeting PLpro.


Asunto(s)
Antivirales/química , Antivirales/farmacología , /química , /efectos de los fármacos , /metabolismo , /genética , Citocinas/metabolismo , Descubrimiento de Drogas , Interacciones Farmacológicas , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Pandemias , Conformación Proteica , /metabolismo , Ubiquitinas/metabolismo
14.
Nat Commun ; 12(1): 269, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431834

RESUMEN

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.


Asunto(s)
Antimaláricos/uso terapéutico , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Malaria/transmisión , Pandemias , Aedes/parasitología , Animales , Antimaláricos/química , Antimaláricos/farmacología , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/epidemiología , Masculino , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo
15.
Nat Commun ; 12(1): 150, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420011

RESUMEN

Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.


Asunto(s)
Antibacterianos/farmacología , Cloro/metabolismo , Girasa de ADN/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Alanina/química , Alanina/metabolismo , Antibacterianos/química , Cristalografía por Rayos X , Girasa de ADN/química , ADN-Topoisomerasas de Tipo II , ADN de Cadena Simple/metabolismo , Diseño de Fármacos , Canal de Potasio ERG1/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Células Hep G2 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Inhibidores de Topoisomerasa II/química
16.
mBio ; 12(1)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33468688

RESUMEN

The etiologic agent of COVID-19 is highly contagious and has caused a severe global pandemic. Until now, there has been no simple and reliable system available in a lower-biosafety-grade laboratory for SARS-CoV-2 virologic research and inhibitor screening. In this study, we reported a replicon system which consists of four plasmids expressing the required segments of SARS-CoV-2. Our study revealed that the features for viral RNA synthesis and responses to antivirus drugs of the replicon are similar to those of wild-type viruses. Further analysis indicated that ORF6 provided potent in trans stimulation of the viral replication. Some viral variations, such as 5'UTR-C241T and ORF8-(T28144C) L84S mutation, also exhibit their different impact upon viral replication. Besides, the screening of clinically used drugs identified that several tyrosine kinase inhibitors and DNA-Top II inhibitors potently inhibit the replicon, as well as authentic SARS-CoV-2 viruses. Collectively, this replicon system provides a biosafety-worry-free platform for studying SARS-CoV-2 virology, monitoring the functional impact of viral mutations, and developing viral inhibitors.IMPORTANCE COVID-19 has caused a severe global pandemic. Until now, there has been no simple and reliable system available in a lower-biosafety-grade laboratory for SARS-CoV-2 virologic research and inhibitor screening. We reported a replicon system which consists of four ordinary plasmids expressing the required segments of SARS-CoV-2. Using the replicon system, we developed three application scenarios: (i) to identify the effects of viral proteins on virus replication, (ii) to identify the effects of mutations on viral replication during viral epidemics, and (iii) to perform high-throughput screening of antiviral drugs. Collectively, this replicon system would be useful for virologists to study SARS-CoV-2 virology, for epidemiologists to monitor virus mutations, and for industry to develop antiviral drugs.


Asunto(s)
Antivirales/farmacología , ARN Viral/biosíntesis , Replicón/efectos de los fármacos , /genética , Evaluación Preclínica de Medicamentos/métodos , Femenino , Ingeniería Genética , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Mutación , Pandemias , ARN Viral/genética , Replicón/genética , Replicación Viral/efectos de los fármacos
17.
Cell Rep ; 34(5): 108699, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33485405

RESUMEN

Several potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been identified. However, antibody-dependent enhancement (ADE) has not been comprehensively studied for SARS-CoV-2, and the relationship between enhancing versus neutralizing activities and antibody epitopes remains unknown. Here, we select a convalescent individual with potent IgG neutralizing activity and characterize his antibody response. Monoclonal antibodies isolated from memory B cells target four groups of five non-overlapping receptor-binding domain (RBD) epitopes. Antibodies to one group of these RBD epitopes mediate ADE of entry in Raji cells via an Fcγ receptor-dependent mechanism. In contrast, antibodies targeting two other distinct epitope groups neutralize SARS-CoV-2 without ADE, while antibodies against the fourth epitope group are poorly neutralizing. One antibody, XG014, potently cross-neutralizes SARS-CoV-2 variants, as well as SARS-CoV-1, with respective IC50 (50% inhibitory concentration) values as low as 5.1 and 23.7 ng/mL, while not exhibiting ADE. Therefore, neutralization and ADE of human SARS-CoV-2 antibodies correlate with non-overlapping RBD epitopes.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo , Epítopos/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/uso terapéutico , Reacciones Antígeno-Anticuerpo , /inmunología , Línea Celular , Niño , Análisis por Conglomerados , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Dominios Proteicos/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven
18.
Int J Nanomedicine ; 16: 269-281, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33469286

RESUMEN

Background: Rapamycin is a promising agent for treating tumors, but clinical applications of rapamycin are limited due to its poor water solubility and low bioavailability. This paper constructs a liposome delivery system for rapamycin to improve the effect in treating colorectal cancer. Methods: We prepared the rapamycin liposomes using the ethanol injection method. The cellular uptake and biodistribution were detected by LC-MS and in vivo imaging system. MTT assay, transwell migration experiment, flow cytometry, and Western blot analysis evaluated the antitumor effect of rapamycin liposomes in vitro. Furthermore, HCT-116 tumor-bearing mice were used to assess the therapeutic efficacy of rapamycin liposomes in vivo. Results: The prepared rapamycin liposomes had a particle size of 100±5.5 nm and with a narrow size distribution. In vitro cellular uptake experiments showed that the uptake of rapamycin liposomes by colorectal cells was higher than that of free rapamycin. Subsequently, in vivo imaging experiments also demonstrated that rapamycin liposomes exhibited higher tumor accumulation. Therefore, the ability of rapamycin liposomes to inhibit tumor proliferation, migration and to induce tumor apoptosis is superior to that of free rapamycin. We also demonstrated in vivo good antitumor efficacy of the rapamycin liposomes in HCT-116 xenograft mice. In addition, rapamycin liposomes and 5-FU can synergistically improve the efficacy of colorectal cancer via the Akt/mTOR and P53 pathways. Conclusion: Collectively, rapamycin liposomes are a potential treatment for colorectal cancer, as it not only improves rapamycin's antitumor effect but also synergistically enhances 5-FU's chemotherapy effect.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Sirolimus/administración & dosificación , Sirolimus/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Sinergismo Farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Humanos , Concentración 50 Inhibidora , Liposomas , Ratones , Tamaño de la Partícula , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Distribución Tisular , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Viruses ; 13(1)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451132

RESUMEN

In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to theCoronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.


Asunto(s)
Antivirales/farmacología , Ácido Etacrínico/farmacología , Inhibidores de Proteasas/farmacocinética , /efectos de los fármacos , Antivirales/química , Dominio Catalítico , /metabolismo , Bases de Datos Factuales , Reposicionamiento de Medicamentos , Ácido Etacrínico/química , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/química , /enzimología
20.
Sci Rep ; 11(1): 2229, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33500537

RESUMEN

The development of specific antiviral compounds to SARS-CoV-2 is an urgent task. One of the obstacles for the antiviral development is the requirement of biocontainment because infectious SARS-CoV-2 must be handled in a biosafety level-3 laboratory. Replicon, a non-infectious self-replicative viral RNA, could be a safe and effective tool for antiviral evaluation. Herein, we generated a PCR-based SARS-CoV-2 replicon. Eight fragments covering the entire SARS-CoV-2 genome except S, E, and M genes were amplified with HiBiT-tag sequence by PCR. The amplicons were ligated and in vitro transcribed to RNA. The cells electroporated with the replicon RNA showed more than 3000 times higher luminescence than MOCK control cells at 24 h post-electroporation, indicating robust translation and RNA replication of the replicon. The replication was drastically inhibited by remdesivir, an RNA polymerase inhibitor for SARS-CoV-2. The IC50 of remdesivir in this study was 0.29 µM, generally consistent to the IC50 obtained using infectious SARS-CoV-2 in a previous study (0.77 µM). Taken together, this system could be applied to the safe and effective antiviral evaluation without using infectious SARS-CoV-2. Because this is a PCR-based and transient replicon system, further improvement including the establishment of stable cell line must be achieved.


Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , /efectos de los fármacos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Células CHO , Chlorocebus aethiops , Cricetulus , Evaluación Preclínica de Medicamentos , Electroporación , Genoma Viral , Células HEK293 , Humanos , Concentración 50 Inhibidora , Cinética , Sistemas de Lectura Abierta , Reacción en Cadena de la Polimerasa , ARN Viral , Regiones no Traducidas , Células Vero , Virión , Replicación Viral/efectos de los fármacos
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