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Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.
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Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-ß), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.
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This study presents the classification of malaria-prone zones based on (a) meteorological factors, (b) demographics and (c) patient information. Observations are performed on extended features in dataset over the spiking and non-spiking classifiers including Quadratic Integrate and Fire neuron (QIFN) model as a benchmark. As per research studies, parasite transmission is highly dependent on the (i) stagnant water, (ii) population of area and the (iii) greenery of the locality. Considering these factors, three more attributes were added to the existing novel dataset and comparison on the results is presented. For four feature dataset, QIFN exhibited an accuracy of 97.08% in K10 protocol, and with extended dataset; QIFN yields an accuracy of 99.58% in K10 protocol. The benchmarking results showed reliability and stability. There is 12.47% improvement against multilayer perceptron (MLP) and 5.39% against integrate-and-fire neuron (IFN) model. The QIFN model performed the best over the conventional classifiers for deciphering the risk of acquiring malaria in different geographical regions worldwide.
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Algoritmos , Malaria/epidemiología , Conceptos Meteorológicos , Modelos Teóricos , Redes Neurales de la Computación , Máquina de Vectores de Soporte , Animales , Humanos , Incidencia , India/epidemiología , Insectos Vectores/parasitología , Malaria/parasitología , Reproducibilidad de los ResultadosRESUMEN
A polyphenolic flavonoid, Silymarin isolated from Silybum marianum is widely known for its hepatoprotective action. In the present study anti-plasmodial activity of Silymarin has been demonstrated for the first time having IC50 of 14 ± 0.33 µM against the NF-54 strain of P. falciparum with high selectivity index (>100). The parasitostatic action is exerted through inhibition of ß-hematin/hemozoin formation which is due to the interaction (Kd = 3.63 ± 0.9µM) of silymarin with free heme in a Stoichiometry of 1:1 Silymarin: heme complex resulting into heme-induced membrane damage in the parasite. Silymarin could hinder the glutathione and hydrogen peroxide-induced heme detoxification. Silymarin also induces apoptosis in the parasite through the elevation of caspase-3 level in a dose-dependent manner. Results from the docking studies suggest that Silymarin interacts with heme.
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Flavonoides/farmacología , Hemo/metabolismo , Plasmodium falciparum/efectos de los fármacos , Silimarina/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Hemoproteínas/antagonistas & inhibidores , Concentración 50 Inhibidora , Plasmodium falciparum/crecimiento & desarrollo , Silimarina/química , Silimarina/metabolismoRESUMEN
Cancer classification is one of the crucial tasks in medical field. The gene expression of cells helps in identifying the cancer. The high dimensionality of gene expression data hinders the classification performance of any machine learning models. Therefore, we propose, in this paper a methodology to classify cancer using gene expression data. We employ a bio-inspired algorithm called binary bat algorithm for feature selection and extreme learning machine for classification purpose. We also propose a novel fitness function for optimizing the feature selection process by binary bat algorithm. Our proposed methodology has been compared with original fitness function that has been found in the literature. The experiments conducted show that the former outperforms the latter. Graphical Abstract Classification using Binary Bat Optimization and Extreme Learning Machine.
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Neoplasias/genética , Algoritmos , Expresión Génica/genética , Humanos , Aprendizaje AutomáticoRESUMEN
AIMS: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry. mRNA and protein expression of various genes involves in INH induced toxicity was evaluated via Real-time PCR and western blot analysis respectively. Differential protein expression was performed by two-dimensional gel electrophoresis followed by identification using MALDI TOF/TOF. KEY FINDINGS: INH induced ROS and apoptosis in HepG2 as well as THLE-2 cells. Nuclear damage was also observed by INH treatment in HepG2 cells. Expression of apoptotic (Cytochrome C and Caspase 9) and antioxidative (Keap1 and Nrf2) genes were observed to increase. INH induced PKCδ phosphorylation and released Nrf2 from its inhibitor Keap1 in the cytoplasm of HepG2 cells. However, over-expression of Nrf2 did not affect nuclear Nrf2 protein level as well as its downstream target NQO1. Nrf2 importer, Karyopherin ß1 level was observed to decrease in HepG2 as well as THLE-2 cells following INH treatment. SIGNIFICANCE: These findings suggest that INH prevented Nrf2 translocation into the nucleus by inhibiting its importer Karyopherin ß1. Therefore Nrf2 might not able to bind ARE sequences from inducing antioxidative response for protecting the cells undergoing apoptosis.
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Apoptosis/efectos de los fármacos , Isoniazida/toxicidad , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Animales , Antituberculosos/toxicidad , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/fisiología , Estrés Oxidativo/fisiologíaRESUMEN
Resveratrol (RES) is a natural polyphenol having anti-proliferative activity against breast cancer cells. RES in combination with other chemo modulatory agents, minimizes toxicity and increases efficacy of the treatment. Salinomycin (SAL), a monocarboxylic polyether ionophore is known for selectively targeting breast cancer stem cells. Purpose of the present study was to investigate whether RES in combination with SAL exerts synergistic anti-proliferative activity on breast cancer cells. We further evaluated the molecular mechanism behind SAL and RES mediated cell death. Cytotoxicity assay was performed to determine 50% inhibitory concentration (IC50) of SAL and RES in different human breast cancer cells (HBCCs). Drug synergism and combination index (CI) were calculated using CompuSyn software and effects of synergistic combinations (CI < 1) involving lower doses of SAL and RES were selected for further studies. This combination significantly induced apoptosis in HBCCs without affecting non tumorigenic human breast epithelial cells MCF-10A. Co-treatment enhanced apoptosis in MCF-7 cells via reactive oxygen species (ROS) mediated mitochondrial dysfunction. Oxidative stress disrupt redox homeostasis which altered antioxidant enzymes viz. CuZn Superoxide dismutase (SOD), MnSOD and catalase. Additionally, combination altered nuclear morphology, enhanced PARP cleavage and led to caspase activation. SAL and RES also synergistically modulated MAPK pathway. Study suggests that SAL and RES offer a novel combination approach for the treatment of breast cancer.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama/fisiopatología , Piranos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estilbenos/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células MCF-7 , Resveratrol , Ensayo de Tumor de Célula MadreRESUMEN
Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and protein levels in Hep3B cells. Whole genome expression analysis of Hep3B cells treated with Isoniazid has resulted in differential expression of various genes playing prime role in regulation of apoptotic, antioxidative, DNA damage, cell signaling, cell proliferation and differentiation pathways. Isoniazid increased cytosolic Nrf2 protein level while decreased nuclear Nrf2 protein level. It also decreased ERK1 phosphorylation and treatment of Hep3B cells with ERK inhibitor followed by Isoniazid resulting in increased apoptosis in these cells. Two dimensional gel electrophoresis results have also shown differential expression of various protein species including heat shock proteins, proteins playing important role in oxidative stress, DNA damage, apoptosis, cell proliferation and differentiation. Results suggest that Isoniazid induces apoptosis through oxidative stress and also prevents Nrf2 translocation into the nucleus by reducing ERK1 phosphorylation thus preventing cytoprotective effect.
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Antituberculosos/farmacología , Apoptosis/efectos de los fármacos , Isoniazida/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/agonistas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Hepatocitos , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Transporte de Proteínas , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
In the present work, a novel nanoemulsion laden with moxifloxacin has been developed for effective management of complicated intra-abdominal infections. Moxifloxacin nanoemulsion fabricated using high pressure homogenization was evaluated for various pharmaceutical parameters, pharmacokinetics (PK) and pharmacodynamics (PD) in rats with E. coli-induced peritonitis and sepsis. The developed nanoemulsion MONe6 (size 168 ± 28 nm and zeta potential (ZP) 24.78 ± 0.45 mV, respectively) was effective for intracellular delivery and sustaining the release of MOX. MONe6 demonstrated improved plasma (AUC(MONe6/MOX) = 2.38-fold) and tissue pharmacokinetics of MOX (AUC(MONe6/MOX) = 2.63 and 1.47 times in lung and liver, respectively). Calculated PK/PD index correlated well with a reduction in bacterial burden in plasma as well as tissues. Enhanced survival on treatment with MONe6 (65.44%) and as compared to the control group (8.22%) was a result of reduction in lipid peroxidation, neutrophil migration, and cytokine levels (TNF-α and IL6) as compared to untreated groups in the rat model of E. coli-induced sepsis. Parenteral nanoemulsions of MOX hold a promising advantage in the therapy of E. coli-induced complicated intra-abdominal infections and is helpful in the prevention of further complications like septic shock and death.
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Escherichia coli/patogenicidad , Fluoroquinolonas/uso terapéutico , Infecciones Intraabdominales/tratamiento farmacológico , Infecciones Intraabdominales/microbiología , Animales , Fluoroquinolonas/farmacocinética , Interleucina-6/metabolismo , Masculino , Moxifloxacino , Ratas , Sepsis/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Present investigation explores the cardiotoxicity of rosiglitazone (ROSI) using rat heart cardiomyocytes and db/db mice. In H9c2 cells, ROSI at 50 and 60 µM induced an increase in the percentage of apoptotic cells and superoxide generation, along with an increase in the expression of various subunits of NADPH oxidase and nitric oxide synthases, confirmed that ROSI-induced apoptosis in H9c2 cells is by ROS generation. The increase in the expression of the antioxidants like superoxide dismutase (SOD), catalase, glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) further confirmed this notion. Heme oxygenase-1, having an important role in cell protection against oxidative stress, was found to be increased along with induction of nuclear translocation of NF-E2-related factor and increased protein kinase C δ expression. Moreover, in db/db mice, oral administration of ROSI (10 mg/kg) for 10 days induced an increase in serum creatinine kinase-MB, tissue antioxidants like SOD, catalase, GR, GST, GPx expression, cardiac troponin T, and inducible nitric oxide synthase protein expression strongly support the in vitro findings. Furthermore, global gene expression studies also showed the perturbation of oxidative phosphorylation, fat cell differentiation, and electron transport chain following ROSI treatment in vivo. These results suggested that ROSI-induced cardiac damage is due to accelerated apoptosis both in vitro and in vivo.