Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Calcif Tissue Int ; 111(2): 196-210, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35451627

RESUMEN

Isovitexin (apigenin-6C-glucopyranose) is found in several food items and medicinal plants. Recently, we showed that isovitexin stimulated osteoblast differentiation through mitochondrial biogenesis and respiration that required adiponectin receptors (AdipoRs). Here, we studied whether oral isovitexin has a bone anabolic effect in vivo. At first, using a femur osteotomy model in adult mice, we compared the bone regenerative effect of isovitexin and apigenin. Whereas isovitexin-stimulated bone formation at the osteotomy site at 2.5 mg/kg and 5 mg/kg dose, apigenin had no effect. Subsequently, we tested the effect of isovitexin (5 mg/kg) in ovariectomized (OVX) osteopenic mice and observed that it restored bone mass and architecture of trabecular bones (femur metaphysis and fifth lumbar vertebra/L5) and cortical bones (femur diaphysis). Isovitexin completely restored bone strength at L5 (compressive strength) and femur (bending strength) in OVX mice. The bone anabolic effect of isovitexin was demonstrated by the increased surface referent bone formation parameters, increased expression of osteogenic genes (Runx2, bone morphogenetic protein-2 and type 1 collagen) in bones, and increased serum procollagen type 1N-terminal propeptide in OVX mice and these were on a par with teriparatide. Isovitexin inhibited bone and serum sclerostin as well as the serum type I collagen cross-linked C-telopeptide in OVX mice. Isovitexin has an oral bioavailability of 14.58%. Taken together, our data show that isovitexin had a significant oral bioavailability that translated to osteoanabolic effect equivalent to teriparatide and inhibited bone resorption, which implied a durable effect over teriparatide.


Asunto(s)
Anabolizantes , Teriparatido , Administración Oral , Anabolizantes/farmacología , Animales , Apigenina/farmacología , Densidad Ósea , Femenino , Ratones , Osteogénesis , Ovariectomía , Teriparatido/farmacología
2.
Molecules ; 26(11)2021 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-34073781

RESUMEN

Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of ß-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERß-ERE luc expression system with greater response through ERß in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERß through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.


Asunto(s)
Glucosa/metabolismo , Imitación Molecular , Músculo Esquelético/metabolismo , Fitoestrógenos/farmacología , Sitoesteroles/farmacología , Transportador de Glucosa de Tipo 4/metabolismo , Células HEK293 , Humanos , Células MCF-7 , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Músculo Esquelético/citología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Sitoesteroles/química
3.
Cytokine ; 127: 154958, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31923815

RESUMEN

Current study demonstrates the immunogenic role of biopolymer coated green synthesized copper oxide nanoparticles by the induction of cellular immunity through the activation immune cells. Alongside humoral immunity response was triggered by the surface coated NPs through IgG response which indicate the adjuvanic role of the nano conjugate. Th1 (Type 1 and Type 2 helper T cells) and Th2 cells were activated after the treatment with nano conjugate and act as an immunostimulant which would inhibit the proliferation of breast cancer (MCF-7) and cervical cancer (HeLa) cells in in vitro. Solid tumor induced by 4 T1 cells were also inhibited in in vivo Balb/C mice model. Secretion of pro-inflammatory cytokines and the increase in CD + 4 populations indicate the activation of immune cells in the current study. Immunotherapy by the help of metal nano conjugate can be an effective tool to eradicate the cancer cells from the system.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Quitosano/inmunología , Cobre/inmunología , Nanopartículas/administración & dosificación , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Línea Celular Tumoral , Células Cultivadas , Femenino , Células HeLa , Humanos , Inmunoterapia/métodos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C
4.
Haematologica ; 105(4): 971-986, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31371410

RESUMEN

Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia (CML) and BCR-ABL1 inhibitor monotherapy fails to eliminate these cells, thereby necessitating alternate therapeutic strategies for patients CML. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone downregulates signal transducer and activator of transcription 5 (STAT5) and in combination with imatinib induces complete molecular response in imatinib-refractory patients by eroding leukemia stem cells. Thiazolidinediones such as pioglitazone are, however, associated with severe side effects. To identify alternate therapeutic strategies for CML we screened Food and Drug Administration-approved drugs in K562 cells and identified the leprosy drug clofazimine as an inhibitor of viability of these cells. Here we show that clofazimine induced apoptosis of blood mononuclear cells derived from patients with CML, with a particularly robust effect in imatinib-resistant cells. Clofazimine also induced apoptosis of CD34+38- progenitors and quiescent CD34+ cells from CML patients but not of hematopoietic progenitor cells from healthy donors. Mechanistic evaluation revealed that clofazimine, via physical interaction with PPARγ, induced nuclear factor kB-p65 proteasomal degradation, which led to sequential myeloblastoma oncoprotein and peroxiredoxin 1 downregulation and concomitant induction of reactive oxygen species-mediated apoptosis. Clofazimine also suppressed STAT5 expression and consequently downregulated stem cell maintenance factors hypoxia-inducible factor-1α and -2α and Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). Combining imatinib with clofazimine caused a far superior synergy than that with pioglitazone, with clofazimine reducing the half maximal inhibitory concentration (IC50) of imatinib by >4 logs and remarkably eroding quiescent CD34+ cells. In a K562 xenograft study clofazimine and imatinib co-treatment showed more robust efficacy than the individual treatments. We propose clinical evaluation of clofazimine in imatinib-refractory CML.


Asunto(s)
Lepra , Leucemia Mielógena Crónica BCR-ABL Positiva , Preparaciones Farmacéuticas , Apoptosis , Clofazimina/farmacología , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/farmacología , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , PPAR gamma
5.
Bioconjug Chem ; 30(6): 1754-1762, 2019 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-31181889

RESUMEN

Current treatment approaches for hepatocellular carcinoma (HCC) have a narrow therapeutic index and alternate modes of treatment are thus required. We have utilized a gene delivery vector containing inducible caspase 9 (iCasp9) gene, which is a synthetic analogue based on the mammalian caspase 9 and fused to a human FK506 binding protein that allows its conditional dimerization to a synthetic, small molecule [chemical inducer of dimerization, AP20187] and results in target cell apoptosis. In our studies, we have tested these synthetic vectors based on an adeno-associated virus platform for their potential anti-tumorigenic effect in human HCC cells in vitro and in a HCC tumor model developed in nude mice. Our data demonstrates that the iCasp9-AP20187 bioconjugate is able to trigger terminal effectors of cellular apoptosis and presents a viable approach for the potential treatment of HCC.


Asunto(s)
Carcinoma Hepatocelular/terapia , Caspasa 9/genética , Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos/uso terapéutico , Neoplasias Hepáticas/terapia , Animales , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Terapia Genética , Vectores Genéticos/genética , Humanos , Neoplasias Hepáticas/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Unión a Tacrolimus/genética
6.
Cytokine ; 113: 162-176, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30025979

RESUMEN

Tumor associated macrophages (TAMs) are pertinent to cancer cell growth in the tumor microenvironment. Indeed, TAMs differentiate from monocytes (MΦ) due to specific growth factors present in the tumor microenvironment. TAMs show mostly an M2-like phenotype is due to the absence of pro-inflammatory signals and supply fuel to tumor growth. Several attempts have been taken to switch TAMs into a pro-immunogenic type. To address context, we used a tumor microenvironment by in vitro coculturing human blood MΦ with cancer cell conditioned media (TC-MΦ). We showed that the antigen cobalt oxide nanoparticles (Ag-NPs) can reprogram TC-MΦ to pro-immunogenic type to build up an antitumor immune response. Our results demonstrate that NPs-Ag induced a marked activation of NADPH oxidase in TC-MΦ, likely through stimulation of ROS linked to activation of p38 MAPK. These activated p38 MAPK up-regulated the IFN-γ, TNF-α and initial IL-12 production, in turn, the activation of IFN-γ prolonged IL-12 production.


Asunto(s)
Antígenos/farmacología , Macrófagos/efectos de los fármacos , NADPH Oxidasas/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Cocultivo/métodos , Medios de Cultivo Condicionados/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Células Jurkat , Macrófagos/metabolismo , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Microambiente Tumoral/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos
7.
Toxicol Appl Pharmacol ; 348: 22-31, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29649498

RESUMEN

Modafinil is primarily prescribed for treatment of narcolepsy and other sleep-associated disorders. However, its off-prescription use as a cognition enhancer increased considerably, specially among youths. Given its increasing use in young adults the effect of modafinil on peak bone accrual is an important issue but has never been investigated. Modafinil treatment to young male rats caused trabecular and cortical bone loss in tibia and femur, and reduction in biomechanical strength. Co-treatment of modafinil with alendronate (a drug that suppresses bone resorption) reversed the trabecular bone loss but failed to prevent cortical loss. Modafinil increased serum type 1 pro-collagen N-terminal protein (P1NP) and collagen type 1 cross-linked C-telopeptide (CTX-1) indicating a high turnover bone loss. The drug also increased receptor activator of nuclear factor κB ligand (RANKL) to osteoprotegerin (OPG) ratio in serum which likely resulted in increased osteoclast number per bone surface. Furthermore, conditioned medium from modafinil treated osteoblasts increased the expression of osteoclastogenic genes in bone marrow-derived macrophages and the effect was blocked by RANKL neutralizing antibody. In primary osteoblasts, modafinil stimulated cAMP production and using pharmacological approach, we showed that modafinil signalled via adenosine receptors (A2AR and A2BR) which resulted in increased RANKL expression. ZM-241,385 (an A2AR inhibitor) and MRS 1754 (an A2BR inhibitor) suppressed modafinil-induced upregulation of RANKL/OPG ratio in the calvarium of new born rat pups. Our data suggests that by activating osteoblast adenosine receptors modafinil increases the production of osteoclastogenic cytokine, RANKL that in turn results in high turnover bone loss in young rats.


Asunto(s)
Agonistas del Receptor de Adenosina A2/toxicidad , Compuestos de Bencidrilo/toxicidad , Remodelación Ósea/efectos de los fármacos , Hueso Esponjoso/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoporosis/inducido químicamente , Ligando RANK/metabolismo , Receptor de Adenosina A2A/efectos de los fármacos , Receptor de Adenosina A2B/efectos de los fármacos , Promotores de la Vigilia/toxicidad , Animales , Fenómenos Biomecánicos , Hueso Esponjoso/metabolismo , Hueso Esponjoso/patología , Hueso Esponjoso/fisiopatología , Células Cultivadas , Hueso Cortical/efectos de los fármacos , Hueso Cortical/metabolismo , Hueso Cortical/patología , Hueso Cortical/fisiopatología , AMP Cíclico/metabolismo , Masculino , Modafinilo , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Osteoporosis/patología , Osteoporosis/fisiopatología , Osteoprotegerina/metabolismo , Ligando RANK/genética , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2B/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia Arriba
8.
J Biol Inorg Chem ; 22(6): 893-918, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28643149

RESUMEN

Currently toxicological research in Silver nanoparticle is a leading issue in medical science. The surface chemistry and physical dimensions of silver nanoparticles (Ag-NPs) play an important role in toxicity. The aim of this present study was to evaluate the in vitro and in vivo toxicity of Ag-NPs as well as the alteration of toxicity profile due to surface functionalization (PEG and BSA) and the intracellular signaling pathways involved in nanoparticles mediated oxidative stress and apoptosis in vitro and in vivo system. Ag-NPs released excess Ag+ ions leads to activation of NADPH oxidase and helps in generating the reactive oxygen species (ROS). Silver nanoparticles elicit the production of excess amount of ROS results activation of TNF-α. Ag-NPs activates caspase-3 and 9 which are the signature of mitochondrial pathway. Ag-NPs are responsible to decrease the antioxidant enzymes and imbalance the oxidative status into the cells but functionalization with BSA and PEG helps to protect the adverse effect of Ag-NPs on the cells. This study suggested that Ag-NPs are toxic to normal cells which directly lead with human health. Surface functionalization may open the gateway for further use of Ag-NPs in different area such as antimicrobial and anticancer therapy, industrial use or in biomedical sciences.


Asunto(s)
Nanopartículas del Metal/toxicidad , Plata/química , Plata/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Bovinos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Hemólisis/efectos de los fármacos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Polietilenglicoles/química , Albúmina Sérica Bovina/química , Relación Estructura-Actividad , Propiedades de Superficie
9.
Org Biomol Chem ; 14(4): 1501, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26732709

RESUMEN

Correction for 'Pyrido[1,2-a]pyrimidinium ions - a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties' by Susanta Kumar Manna et al., Org. Biomol. Chem., 2015, 13, 8037-8047.

10.
J Biol Inorg Chem ; 20(1): 123-141, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25534662

RESUMEN

The aim of this work is to understand the potential health effects of metal nanoparticles by exposing human leukemic cell lines (jurkat, K562 and KG1A cells) to nanosize phosphonomethyl iminodiacetic acid coated cobalt oxide (PMIDA-CoO) NPs. The synthesized PMIDA-CoO NPs were characterized by XRD, dynamic light scattering, transmission electron microscopy and scanning electron microscopy. Our results showed that exposure of leukemic cell lines to PMIDA-CoO NPs caused reactive oxygen species (ROS) generation by increasing the concentration of free Co(++) ions in cancer microenvironment. But at physiological pH, PMIDA-CoO liberates little amount of Co(++) ions into media and exerts lower toxicity to normal cells up to a certain dose. PMIDA-CoO NPs caused DNA damage in leukemic cell lines, which was reflected by an increase in apoptosis of jurkat, KG-1A and K562 cells. PMIDA-CoO NPs induced apoptosis by increasing pro-inflammatory cytokines, primarily TNF-α. The in vivo study shows that PMIDA-CoO NPs were efficiently killed DLA cells. These findings have important implications for understanding the potential anticancer property induced by surface-modified cobalt oxide nanoparticles.


Asunto(s)
Antineoplásicos/farmacología , Cobalto/farmacología , Iminoácidos/farmacología , Sistema de Señalización de MAP Quinasas , Nanopartículas , Óxidos/farmacología , Animales , Antineoplásicos/química , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Supervivencia Celular/efectos de los fármacos , Cobalto/química , Citocinas/metabolismo , Fragmentación del ADN , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Iminoácidos/química , Células Jurkat , Células K562 , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Ratones , Estrés Oxidativo , Óxidos/química , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
11.
Org Biomol Chem ; 13(29): 8037-47, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-26130466

RESUMEN

A novel class of bridgehead nitrogen heterocycles, pyrido[1,2-a]pyrimidinium ions, has been readily synthesized by a two-step one-pot reaction in high yields (up to 93%). These ionic compounds are bench stable and moisture tolerant and have highly fluorescent properties (quantum yield up to 0.65). A characteristic bright bluish fluorescence was observed in polar solvents such as acetonitrile and fluorescent intensity gradually diminishes with decreasing the polarity of the medium, which becomes almost negligible in toluene. These compounds also show interesting bioactivity. DNA interaction, imaging, and viability experiments with human leukemic Jurkat and KG-1A cells revealed that they are potential candidates for cancer diagnosis.


Asunto(s)
ADN/metabolismo , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Imagen Molecular/métodos , Nitrógeno/química , Piridinas/química , Pirimidinas/química , Animales , Calorimetría , Bovinos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Compuestos Heterocíclicos/farmacología , Humanos , Iones , L-Lactato Deshidrogenasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Solventes/química , Espectrometría de Fluorescencia
12.
Bioorg Chem ; 63: 85-100, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26469741

RESUMEN

The main complication in betulinic acid (BA) based drug delivery has been observed due to its bulk structure. The present study demonstrates the potential effects of self assembled nano size betulinic acid (SA-BA) by treating human leukemic cell lines (KG-1A and K562) and its normal counterpart. Self assembly property of BA was investigated using SEM and DLS study which showed that the BA forms fibrous structure having few nanometers in diameter. Selective anti-leukemic efficacy study of SA-BA was investigated by cell viability assay. Mode of leukemic cell death and probable pathway of apoptosis was monitored by measuring ROS level, pro and anti-inflammatory cytokine status and expression of caspase-8 and caspage-3 by immunocytochemistry. Higher efficacy of SA-BA over non-assemble BA was monitored toward cancer cells, with no relevant toxicity to normal blood cells. SA-BA facilitated reactive oxygen species (ROS) mediated leukemic cell death, confirmed by pre-treatment of N-acetyl-L-cysteine. Induction of apoptosis by SA-BA treatment increased pro-inflammatory cytokines, specifically potentiated TNF-α mediated cell death, confirmed by expression of caspase-8 and caspage-3 by immunocytochemistry. This study explored the better anti-leukemic efficacy of SA-BA over BA and this modification will enrich the use of BA in cancer therapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Leucemia/patología , Nanofibras/química , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Estructura Molecular , Triterpenos Pentacíclicos , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/química , Ácido Betulínico
13.
J Appl Toxicol ; 35(6): 603-13, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25639670

RESUMEN

The purpose of this study was to determine the intracellular signaling transduction pathways involved in oxidative stress induced by nanoparticles in cancer cells. Activation of reactive oxygen species (ROS) has some therapeutic benefits in arresting the growth of cancer cells. Cobalt oxide nanoparticles (CoO NPs) are an interesting compound for oxidative cancer therapy. Our results showed that CoO NPs elicited a significant (P <0.05) amount of ROS in cancer cells. Co-treatment with N-aceyltine cystine (an inhibitor of ROS) had a protective role in cancer cell death induced by CoO NPs. In cultured cells, the elevated level of tumor necrosis factor-alpha (TNF-α) was noted after CoO NPs treatment. This TNF-α persuaded activation of caspase-8 followed by phosphorylation of p38 mitogen-activated protein kinase and induced cell death. This study showed that CoO NPs induced oxidative stress and activated the signaling pathway of TNF-α-Caspase-8-p38-Caspase-3 to cancer cells.


Asunto(s)
Caspasa 8/fisiología , Cobalto/efectos adversos , Leucemia Experimental/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nanopartículas del Metal/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Óxidos/efectos adversos , Factor de Necrosis Tumoral alfa/fisiología , Acetilcisteína/farmacología , Animales , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Microscopía Electrónica de Transmisión , Trasplante de Neoplasias , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier
14.
Antimicrob Agents Chemother ; 58(10): 5909-15, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25070111

RESUMEN

Malaria is a major public health problem in tropical and subtropical countries, including India. This study elucidates the cause of chloroquine treatment failure (for Plasmodium falciparum infection) before the introduction of artemisinin combination therapy. One hundred twenty-six patients were randomized to chloroquine treatment, and the therapeutic efficacy was monitored from days 1 to 28. An in vitro susceptibility test was performed with all isolates. Parasitic DNA was isolated, followed by PCR and restriction digestion of different codons of the pfcrt gene (codons 72 to 76) and the pfmdr1 gene (N86Y, Y184F, S1034C, N1042D, and D1246Y). Finally, sequencing was done to confirm the mutations. Forty-three (34.13%) early treatment failure cases and 16 (12.69%) late treatment failure cases were observed after chloroquine treatment. In vitro chloroquine resistance was found in 103 isolates (81.75%). Twenty-six (60.47%) early treatment failure cases and 6 (37.5%) late treatment failure cases were associated with the CVMNK-YYSNY allele (the underlined amino acids are those that were mutated). Moreover, the CVIEK-YYSNY allele was found in 8 early treatment failure (18.60%) and 2 late treatment failure (12.5%) cases. The presence of the wild-type pfcrt (CVMNK) and pfmdr1 (YYSNY) double mutant allele in chloroquine-nonresponsive cases was quite uncommon. In vivo chloroquine treatment failure and in vitro chloroquine resistance were strongly correlated with the CVMNK-YYSNY and CVIEK-YYSNY haplotypes (P < 0.01).


Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Resistencia a Medicamentos/genética , Malaria Falciparum/tratamiento farmacológico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Humanos , India , Malaria Falciparum/genética , Mutación , Plasmodium falciparum/patogenicidad
15.
J Biol Inorg Chem ; 19(8): 1377-84, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25338205

RESUMEN

This work investigated a simple and versatile modification to a solid substrate to develop antibody recognition using nanoparticles. The new immobilized metal ion affinity adsorbent containing nanoparticles and hydrophilic resins is proposed here to improve the binding of antigen on its surface. The light-scattering properties of submicroscopic metal particles ranging from 100 to 120 nm in diameter were confirmed by scanning electron microscopy. We found that synthesized nanoparticles have an inherent enzyme mimetic activity similar to that found in natural peroxidases. The synthesized nanoparticles were coated with Salmonella typhi and Salmonella paratyphi antigens and were allowed to react with Salmonella-infected serum. Positive reactions were detected visually with the naked eye. The color changes of substrate (TMB) were observed even in 1:800 dilutions. This report helps in developing a specific immunoassay using nano-conjugated antigen for the rapid detection of S. typhi and S. paratyphi antibodies in infected serum.


Asunto(s)
Nanocompuestos , Plata , Fiebre Tifoidea/diagnóstico , Reacciones Antígeno-Anticuerpo , Antígenos Bacterianos/inmunología , Humanos , Salmonella paratyphi A/inmunología , Salmonella typhi/inmunología , Plata/inmunología , Fiebre Tifoidea/sangre , Fiebre Tifoidea/inmunología
16.
J Biol Inorg Chem ; 19(7): 1099-111, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24916127

RESUMEN

Six zinc(II) complexes have been synthesized from two designed Mannich-base ligands which consist of three dinuclear complex [Zn2(L(1))2X2] (1-3) and three mononuclear complex [ZnH(L(2))X2] (4-6), respectively, where X = Cl(-) (1,4), Br(-) (2,5), I(-) (3,6), as reported earlier by us (Sanyal et al., Inorg Chem 53:85-96, 2014). The catecholase activity of the complexes has been investigated under completely aerobic conditions in DMF-water medium (9:1) at pH 8.5 against the model substrate 3,5-di-tert-butylcatechol (3,5-DTBC). Saturation kinetic studies show that the order of conversion of substrate to product (quinone) follows the trend 5 > 4 > 2 > 1 while 3 and 6 are inactive. The generation of phenoxyl radicals, confirmed by UV-vis and EPR spectral studies, is supposed to be responsible for the oxidation of 3,5-DTBC. The in vitro evaluation of 1-6 comprises the study of their DNA-cleaving ability using plasmid DNA and the assessment of their cytotoxic activity against Jurkat (T cell lymphoma) cell line by MTT assay. The mechanisms of toxicity appeared to be predominantly by reactive oxygen species (ROS). The comparative analysis helps to arrive at the following facts under experimental conditions: (1) mononuclear species prevail over the dinuclear ones, unlike the behavior in phosphatase activity as reported in Inorganic Chemistry; (2) the halide substituents at the active site control the overall activity in the order: (a) In catecholase activity, Cl(-) < Br(-) (dinuclear) and Cl(-) > Br(-) (mononuclear) and (b) in biological activity, Cl(-) > Br(-) > I(-) regardless of nuclearity.


Asunto(s)
Antineoplásicos/química , Catecol Oxidasa/química , Complejos de Coordinación/química , División del ADN/efectos de los fármacos , Bases de Mannich/química , Zinc/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Materiales Biomiméticos/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Humanos , Células Jurkat , Ligandos , Bases de Mannich/síntesis química , Bases de Mannich/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Zinc/farmacología
17.
J Biol Inorg Chem ; 19(3): 399-414, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24445996

RESUMEN

The objective of this study was to develop chitosan-based delivery of cobalt oxide nanoparticles to human leukemic cells and investigate their specific induction of apoptosis. The physicochemical properties of the chitosan-coated cobalt oxide nanoparticles were characterized using transmission electron microscopy, dynamic light scattering, X-ray diffraction, and Fourier transform infrared spectroscopy. The solubility of chitosan-coated cobalt oxide nanoparticles was higher at acidic pH, which helps to release more cobalt ions into the medium. Chitosan-coated cobalt oxide nanoparticles showed good compatibility with normal cells. However, our results showed that exposure of leukemic cells (Jurkat cells) to chitosan-coated cobalt oxide nanoparticles caused an increase in reactive oxygen species generation that was abolished by pretreatment of cells with the reactive oxygen species scavenger N-acetyl-L-cysteine. The apoptosis of Jurkat cells was confirmed by flow-cytometric analysis. Induction of TNF-α secretion was observed from stimulation of Jurkat cells with chitosan-coated cobalt oxide nanoparticles. We also tested the role of TNF-α in the induction of Jurkat cell death in the presence of TNF-α and caspase inhibitors. Treatment of leukemic cells with a blocker had a greater effect on cancer cell viability. From our findings, oxidative stress and caspase activation are involved in cancer cell death induced by chitosan-coated cobalt oxide nanoparticles.


Asunto(s)
Apoptosis/fisiología , Quitosano/química , Cobalto/química , Leucemia de Células T/metabolismo , Nanopartículas del Metal/química , Óxidos/química , Factor de Necrosis Tumoral alfa/fisiología , Apoptosis/efectos de los fármacos , Quitosano/farmacología , Quitosano/uso terapéutico , Cobalto/farmacología , Cobalto/uso terapéutico , Relación Dosis-Respuesta a Droga , Humanos , Células Jurkat , Leucemia de Células T/tratamiento farmacológico , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Óxidos/farmacología , Óxidos/uso terapéutico , Factor de Necrosis Tumoral alfa/farmacología , Difracción de Rayos X
18.
J Appl Toxicol ; 34(11): 1130-44, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24477783

RESUMEN

The aim of the present study was to develop zinc sulfide nanoparticles (ZnS NPs) and to study their cytotoxicity against the KG-1A (human acute myeloid leukemia) cell line. ZnS NPs were synthesized using the pyrolytic method and characterized by X-ray diffraction, dynamic light scattering, surface zeta potential, scanning electron microscopy and atomic force microscopy. Cell viability study and flow cytometric analysis confirmed the potent cytotoxic effects of ZnS NPs on cancer cells in a dose-dependent fashion. Successful uptakes of ZnS NPs by leukemic cells were confirmed by phase contrast fluorescence microscopy. pH-dependent dissolution of ZnS NPs was done using atomic absorption microscopy to understand the cell-specific internalization of Zn(+) . This internalization of NPs facilitated the generation of excess reactive oxygen species (ROS), followed by tumor necrosis factor alpha (TNF-α) secretion which caused severe DNA damage as observed in the comet assay and altered the mitochondrial membrane potential (MMP) in leukemic cells. Surprisingly ZnS NPs had no toxic effects on normal lymphocytes at doses up to 50 µg ml(-1) . Pre-treatment with ROS and TNF-α inhibitor confirmed that these nanoparticles were able to kill leukemic cells by generating an excess amount of ROS and thereby initiated TNF-α mediated apoptosis pathway. These findings clarify the mechanism with which ZnS NPs induced anticancer activities in vitro. To elicit its utilities and its application to cancer treatment in vivo is under investigation.


Asunto(s)
Daño del ADN , Nanopartículas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Sulfuros/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Compuestos de Zinc/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Glutatión/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Potencial de la Membrana Mitocondrial
19.
Eur J Pharmacol ; 978: 176800, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38950835

RESUMEN

Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC50: 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid ß-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents.


Asunto(s)
Apigenina , Glucósidos , Receptores de Adiponectina , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Animales , Humanos , Ratones , Apigenina/farmacología , Apigenina/uso terapéutico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Masculino , Células Hep G2 , Células HEK293 , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Proteínas Quinasas Activadas por AMP/metabolismo
20.
J Biol Inorg Chem ; 18(8): 957-73, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24043470

RESUMEN

The purpose of this study is to evaluate the prospect of using surface modified cobalt oxide(CoO) nanoparticles as carriers of cancerantigens to human macrophages. N-Phosnomethyliminodiacetic acid (PMIDA) was used for surface modification to overcome the toxic effect of CoO nanoparticles. Here, the phosphonate group of the PMIDA acts as a surface-anchoring agent and the remaining -COOH groups bind nonspecifically with tumor associated antigens. This modification allows the conjugation of human oral carcinoma (KB) cell lysate (CL) as an antigen with PMIDA coated CoO nanoparticles (CL-PMIDA-CoO). Particle characterization was performed by dynamic light scattering, atomic force microscopy, and scanning electron microscopy studies. Fourier transform IR spectroscopy was used to investigate conjugation of the protein with nanoparticles. Protein encapsulation was confirmed by protein gel electrophoresis. Active uptake of antigen-conjugated nanoparticles by macrophages was confirmed by fluorescence microscopy. The antitumor activity of the nanocomplex pulsed macrophages was investigated on a human oral carcinoma cell line (KB) in vitro. The modified nanocomplexes upregulate IFN-γ and TNF-α and induce an anticancer immune response by activating macrophages. The use of TNF-α inhibitor confirmed the ability of the CL-PMIDA-CoO nanocomplex to stimulate TNF-α mediated immunostimulation. CL-PMIDA-CoO nanoparticles efficiently increased the CD4(+) population. Thus, our findings provide insight into the use of PMIDA coated CoO nanoparticles as antigen delivery vehicles.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Neoplasias/administración & dosificación , Antineoplásicos/administración & dosificación , Cobalto/química , Portadores de Fármacos/química , Neoplasias de la Boca/terapia , Nanopartículas/química , Óxidos/química , Adyuvantes Inmunológicos/farmacología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/farmacología , Antineoplásicos/inmunología , Antineoplásicos/farmacología , Línea Celular Tumoral , Células Cultivadas , Humanos , Iminoácidos/química , Inmunoterapia , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Neoplasias de la Boca/inmunología , Factor de Necrosis Tumoral alfa/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA