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1.
Exp Cell Res ; 429(2): 113669, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37276997

RESUMEN

Discovery of CARF (Collaborator of ARF)/CDKN2AIP as an ARF-interacting protein that promotes ARF-p53-p21WAF1 signaling and cellular senescence, initially established its role in genomic stress. Multiple reports further unraveled its role in regulation of senescence, growth arrest, apoptosis, or malignant transformation of cells in response to a variety of stress conditions in cultured human cells. It has been established as an essential protein. Whereas CARF-compromised cells undergo apoptosis, its enrichment has been recorded in a variety of cancer cells and has been associated with malignant transformation. We earlier demonstrated its role in stress-induced cell phenotypes that ranged from growth arrest, apoptosis, or malignant transformation. In the present study, we assessed the molecular mechanism of quantitative impact of change in CARF expression level on these cell fates. Stress-induced changes in CARF expression were assessed quantitatively with proteins involved in proteotoxicity, oxidative, genotoxic, and cytotoxic stress. These comparative quantitative analyses confirmed that (i) CARF responds to diverse stresses in a quantitative manner, (ii) its expression level serves as a reliable predictive measure of cell fates (iii) it correlates more with the DNA damage and MDA levels than the oxidative and proteotoxic signatures and (iv) CARF-expression based quantitative assay may be recruited for stress diagnostic applications.


Asunto(s)
Apoptosis , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Senescencia Celular/fisiología , Proliferación Celular , Proteínas Reguladoras de la Apoptosis/genética , Transformación Celular Neoplásica , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo
2.
J Nat Prod ; 80(10): 2756-2760, 2017 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-29043807

RESUMEN

2,3-Dihydro-3ß-methoxy withaferin-A (3ßmWi-A) is a natural withanolide that is structurally close to withaferin-A (Wi-A), is cytotoxic to human cancer cells, and is a candidate anticancer natural compound. Using cell-based biochemical, molecular, and imaging assays, we report that Wi-A and 3ßmWi-A possess contrasting activities. Whereas Wi-A caused oxidative stress to normal cells, 3ßmWi-A was well tolerated at even 10-fold higher concentrations. Furthermore, it promoted survival and protected normal cells against oxidative, UV radiation, and chemical stresses. We provide molecular evidence that 3ßmWi-A induces antistress and pro-survival signaling through activation of the pAkt/MAPK pathway. We demonstrate that 3ßmWi-A (i) contrary to Wi-A is safe and possesses stress-relieving activity, (ii) when given subsequent to a variety of stress factors including Wi-A, protects normal cells against their toxicity, and (iii) is a vital compound that may guard normal cells against the toxicity associated with various targeted therapeutic regimes in clinical practice.


Asunto(s)
Citoprotección/efectos de los fármacos , Witanólidos/farmacología , Potenciales de Acción , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Estructura Molecular , Estrés Oxidativo , Transducción de Señal , Witanólidos/química
3.
J Biol Chem ; 290(13): 8447-56, 2015 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-25645922

RESUMEN

Mortalin/mtHsp70/Grp75 (mot-2), a heat shock protein 70 family member, is an essential chaperone, enriched in cancers, and has been shown to possess pro-proliferative and anti-apoptosis functions. An allelic form of mouse mortalin (mot-1) that differs by two amino acids, M618V and G624R, in the C terminus substrate-binding domain has been reported. Furthermore, genome sequencing of mortalin from Parkinson disease patients identified two missense mutants, R126W and P509S. In the present study, we investigated the significance of these mutations in survival, proliferation, and oxidative stress tolerance in human cells. Using mot-1 and mot-2 recombinant proteins and specific antibodies, we performed screening to find their binding proteins and then identified ribosomal protein L-7 (RPL-7) and elongation factor-1 α (EF-1α), which differentially bind to mot-1 and mot-2, respectively. We demonstrate that mot-1, R126W, or P509S mutant (i) lacks mot-2 functions involved in carcinogenesis, such as p53 inactivation and hTERT/hnRNP-K (heterogeneous nuclear ribonucleoprotein K) activation; (ii) causes increased level of endogenous oxidative stress; (iii) results in decreased tolerance of cells to exogenous oxidative stress; and (iv) shows differential binding and impact on the RPL-7 and EF-1α proteins. These factors may mediate the transformation of longevity/pro-proliferative function of mot-2 to the premature aging/anti-proliferative effect of mutants, and hence may have significance in cellular aging, Parkinson disease pathology, and prognosis.


Asunto(s)
Proteínas HSP70 de Choque Térmico/genética , Enfermedad de Parkinson/genética , Mutación Puntual , Transporte Activo de Núcleo Celular , Carcinogénesis/genética , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/fisiología , Humanos , Proteínas Mitocondriales/fisiología , Mutación Missense
4.
BMC Cancer ; 14: 775, 2014 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-25336399

RESUMEN

BACKGROUND: Embelin, a quinone derivative, is found in the fruits of Embelia ribes Burm (Myrsinaceae). It has been shown to have a variety of therapeutic potentials including anthelmintic, anti-tumor, anti-diabetic, anti-bacterial and anti-inflammation. Inflammation is an immunological response to external harmful stimuli and is regulated by an endogenous pyrogen and pleiotropic pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α). TNF-α production has been implicated in a variety of other human pathologies including neurodegeneration and cancer. Several studies have shown that the anti-inflammatory activity of embelin is mediated by reduction in TNF-α. The latter is synthesized as a membrane anchored protein (pro-TNF-α); the soluble component of pro-TNF-α is then released into the extracellular space by the action of a protease called TNF-α converting enzyme (TACE). TACE, hence, has been proposed as a therapeutic target for inflammation and cancer. METHODS: We used molecular docking and experimental approaches to investigate the docking potential and molecular effects of embelin to TACE and human cancer cell characteristics, respectively. RESULTS: We demonstrate that embelin is a potential inhibitor of TACE. Furthermore, in vitro studies revealed that it inhibits malignant properties of cancer cells through inactivation of metastatic signaling molecules including MMPs, VEGF and hnRNP-K in breast cancer cells. CONCLUSION: Based on the molecular dynamics and experimental data, embelin is proposed as a natural anti-inflammatory and anticancer drug.


Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Benzoquinonas/farmacología , Neoplasias/metabolismo , Neoplasias/patología , Proteínas ADAM/química , Proteína ADAM17 , Benzoquinonas/química , Dominio Catalítico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Unión Proteica , Ensayo de Tumor de Célula Madre
5.
Front Neurosci ; 18: 1433061, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39385850

RESUMEN

Serotonin is an essential neuromodulator that affects behavioral and cognitive functions. Previous studies have shown that activation of serotonergic neurons in the dorsal raphe nucleus (DRN) promotes patience to wait for future rewards. However, it is still unclear whether serotonergic neurons also regulate persistence to act for future rewards. Here we used optogenetic activation and inhibition of DRN serotonergic neurons to examine their effects on sustained motor actions for future rewards. We trained mice to perform waiting and repeated lever-pressing tasks with variable reward delays and tested effects of optogenetic activation and inhibition of DRN serotonergic neurons on task performance. Interestingly, in the lever-pressing task, mice tolerated longer delays as they repeatedly pressed a lever than in the waiting task, suggesting that lever-pressing actions may not simply be costly, but may also be subjectively rewarding. Optogenetic activation of DRN serotonergic neurons prolonged waiting duration in the waiting task, consistent with previous studies. However, its effect on lever presses was nuanced, and was detected only by focusing on the period before premature reward check and by subtracting the trends within and across sessions using generalized linear model. While optogenetic inhibition decreased waiting, it did not affect lever pressing time or numbers. These results revealed that the necessity of motor actions may increase motivation for delayed rewards and that DRN serotonergic neurons more significantly promote waiting rather than persistent motor actions for future rewards.

7.
Drug Discov Today ; 28(8): 103652, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37290639

RESUMEN

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no known cure, which has prompted the exploration of novel therapeutic approaches. The clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) tool has generated significant interest for its potential in AD therapeutics by correcting faulty genes. Our report comprehensively reviews emerging applications for CRISPR-Cas9 in developing in vitro and in vivo models for AD research and therapeutics. We further assess its ability to identify and validate genetic markers and potential therapeutic targets for AD. Moreover, we review the current challenges and delivery strategies for the in vivo application of CRISPR-Cas9 in AD therapeutics.


Asunto(s)
Enfermedad de Alzheimer , Sistemas CRISPR-Cas , Humanos , Sistemas CRISPR-Cas/genética , Edición Génica , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Terapia Genética
8.
Genes Dis ; 10(4): 1367-1401, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37397557

RESUMEN

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

9.
Biomed Pharmacother ; 146: 112555, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34954639

RESUMEN

Human exposure to radiation has expanded considerably in recent years, due to a wide range of medical, agricultural, and industrial applications. Despite its beneficial utilities, radiation is also known to have a deleterious effect on cells and tissues, largely through the creation of free radicals, which cause severe damage to biological systems through processes such as DNA double/single-strand fragmentation, protein modification, and upregulation of lipid peroxidation pathways. In addition, radiation damages genetic material while inducing hereditary genotoxicity. Developing measures to counter radiation-induced damage is thus considered to be of significant importance. Considering the inherent capability of plants to survive radiative conditions, certain plants and natural compounds have been the subject of investigations to explore and harness their natural radioprotective abilities. Podophyllum hexandrum, an Indian medicinal plant with several known traditional phytotherapeutic uses, is considered in particular to be of immense therapeutic importance. Recent studies have been conducted to validate its radioprotective potential alongside discovering its protective mechanisms following γ-radiation-induced mortality and disorder in both mice and human cells. These findings show that Podophyllum and its constituents/natural compounds protect the lungs, gastrointestinal tissues, hemopoietic system, and testis by inducing DNA repair pathways, apoptosis inhibition, free radical scavenging, metal chelation, anti-oxidation and anti-inflammatory mechanisms. In this review, we have provided an updated, comprehensive summary of ionizing radiations and their impacts on biological systems, highlighting the mechanistic and radioprotective role of natural compounds from Podophyllum hexandrum.


Asunto(s)
Berberidaceae , Extractos Vegetales/farmacología , Protectores contra Radiación/farmacología , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quelantes/farmacología , Reparación del ADN/efectos de los fármacos , Depuradores de Radicales Libres/metabolismo , Dosis Máxima Tolerada , Medicina Tradicional , Mitocondrias/efectos de los fármacos , Protectores contra Radiación/química
10.
Free Radic Biol Med ; 193(Pt 1): 134-157, 2022 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-36206930

RESUMEN

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Estrés Oxidativo/fisiología , Mitocondrias/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Progresión de la Enfermedad
11.
Biomedicines ; 9(11)2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34829969

RESUMEN

The emergence of a novel coronavirus viz., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 and its subsequent substantial spread produced the coronavirus disease 2019 (COVID-19) pandemic worldwide. Given its unprecedented infectivity and pathogenicity, the COVID-19 pandemic had a devastating impact on human health, and its clinical management has been a great challenge, which has led to the development and speedy trials of several vaccine candidates against SARS-CoV-2 at an exceptional pace. As a result, several COVID-19 vaccines were made commercially available in the first half of 2021. Although several COVID-19 vaccines showed promising results, crucial insights into their epidemiology, protective mechanisms, and the propensities of reinfection are not largely reviewed. In the present report, we provided insights into the prospects of vaccination against COVID-19 and assessed diverse vaccination strategies including DNA, mRNA, protein subunits, vector-based, live attenuated, and inactivated whole/viral particle-based vaccines. Next, we reviewed major aspects of various available vaccines approved by the World Health Organization and by the local administrations to use against COVID-19. Moreover, we comprehensively assessed the success of these approved vaccines and also their untoward effects, including the possibility of reinfection. We also provided an update on the vaccines that are under development and could be promising candidates in the future. Conclusively, we provided insights into the COVID-19 vaccine epidemiology, their potency, and propensity for SARS-CoV-2 reinfection, while a careful review of their current status, strategies, success, and future challenges was also presented.

12.
Cells ; 10(10)2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34685770

RESUMEN

Alzheimer's disease (AD) is one of the most prominent neurodegenerative diseases, which impairs cognitive function in afflicted individuals. AD results in gradual decay of neuronal function as a consequence of diverse degenerating events. Several neuroimmune players (such as cytokines and growth factors that are key players in maintaining CNS homeostasis) turn aberrant during crosstalk between the innate and adaptive immunities. This aberrance underlies neuroinflammation and drives neuronal cells toward apoptotic decline. Neuroinflammation involves microglial activation and has been shown to exacerbate AD. This review attempted to elucidate the role of cytokines, growth factors, and associated mechanisms implicated in the course of AD, especially with neuroinflammation. We also evaluated the propensities and specific mechanism(s) of cytokines and growth factors impacting neuron upon apoptotic decline and further shed light on the availability and accessibility of cytokines across the blood-brain barrier and choroid plexus in AD pathophysiology. The pathogenic and the protective roles of macrophage migration and inhibitory factors, neurotrophic factors, hematopoietic-related growth factors, TAU phosphorylation, advanced glycation end products, complement system, and glial cells in AD and neuropsychiatric pathology were also discussed. Taken together, the emerging roles of these factors in AD pathology emphasize the importance of building novel strategies for an effective therapeutic/neuropsychiatric management of AD in clinics.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Citocinas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Enfermedad de Alzheimer/inmunología , Quimiocinas/metabolismo , Humanos , Inflamación/patología , Modelos Biológicos
13.
Cell Stress Chaperones ; 25(3): 481-494, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32221864

RESUMEN

CARF (Collaborator of ARF) was discovered as an ARF-interacting protein that activated ARF-p53-p21WAF1 signaling involved in cellular response to a variety of stresses, including oxidative, genotoxic, oncogenic, or telomere deprotection stresses, leading to senescence, growth arrest, or apoptosis. Of note, whereas suppression of CARF was lethal, its enrichment was associated with increased proliferation and malignant transformation of cells. These reports have predicted that CARF could serve as a multi-stress marker with a predictive value for cell fates. Here, we recruited various in vitro stress models and examined their effect on CARF expression using human normal fibroblasts. We demonstrate that CARF levels in stress and post-stress conditions could predict the fate of cells towards either death or enhanced proliferation and malignant transformation. We provide extensive molecular evidence that (i) CARF expression changes in response to stress, (ii) it modulates cell death or survival signaling and determines the fate of cells, and (iii) it may serve as a predictive measure of cellular response to stress and an important marker for biosafety.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Transformación Celular Neoplásica , Proteínas de Unión al ARN/metabolismo , Estrés Fisiológico , Animales , Biomarcadores/metabolismo , Muerte Celular , Línea Celular , Proliferación Celular , Supervivencia Celular , Humanos , Ratones , Células 3T3 NIH
14.
Front Aging Neurosci ; 12: 561925, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33244299

RESUMEN

Cell-based screening of bioactive compounds has served as an important gateway in drug discovery. In the present report, using human neuroblastoma cells and enrolling an extensive three-step screening of 57 phytochemicals, we have identified caffeic acid phenethyl ester (CAPE) as a potent neurodifferentiating natural compound. Analyses of control and CAPE-induced neurodifferentiated cells revealed: (i) modulation of several key proteins (NF200, MAP-2, NeuN, PSD95, Tuj1, GAP43, and GFAP) involved in neurodifferentiation process; and (ii) attenuation of neuronal stemness (HOXD13, WNT3, and Msh-2) and proliferation-promoting (CDC-20, CDK-7, and BubR1) proteins. We anticipated that the neurodifferentiation potential of CAPE may be beneficial for the treatment of neurodegenerative diseases and tested it using the Drosophila model of Alzheimer's disease (AD) and mice model of amnesia/loss of memory. In both models, CAPE exhibited improved disease symptoms and activation of physiological functions. Remarkably, CAPE-treated mice showed increased levels of neurotrophin-BDNF, neural progenitor marker-Nestin, and differentiation marker-NeuN, both in the cerebral cortex and hippocampus. Taken together, we demonstrate the differentiation-inducing and therapeutic potential of CAPE for neurodegenerative diseases.

15.
Sci Rep ; 9(1): 17344, 2019 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-31757995

RESUMEN

Withaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3ß-methoxy analogue of Withaferin-A (3ßmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3ßmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3ßmWi-A was ineffective. Consistently, Wi-A, and not 3ßmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).


Asunto(s)
Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Witanólidos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Biología Computacional , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ribonucleoproteína Heterogénea-Nuclear Grupo K/química , Humanos , Células MCF-7 , Modelos Moleculares , Simulación del Acoplamiento Molecular , Witanólidos/síntesis química , Witanólidos/química
16.
Oncogenesis ; 7(5): 39, 2018 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-29748568

RESUMEN

CARF (Collaborator of ARF)/CDKN2AIP was discovered as a novel ARF-binding protein. It has been established as an essential cell survival, p53-, and cell proliferation-regulatory protein. Although a moderate upregulation of CARF caused growth arrest and senescence, its excessively enriched levels were shown to facilitate aggressive proliferation and malignant transformation of cancer cells. Here, we examined the relevance of CARF levels in clinical tumors and found its amplification (both at gene and transcript levels) in a variety of invasive and metastatic malignancies. Consistent with the clinical readouts, enrichment of CARF in cancer cells promoted epithelial-mesenchymal transition (EMT). Cancer database and molecular analyses revealed that it activates Wnt/ß-catenin signaling axis, as evident by enhanced nuclear localization and function of ß-catenin marked by increased level of SNAIL1, SNAIL2, ZEB1, and TWIST1 and its downstream gene targets. Of note, targeted knockdown of CARF led to decrease in nuclear ß-catenin and its key downstream effectors, involved in EMT progression. Consistent with this, CARF targeting in vivo either by naked siRNA or CARF shRNA harboring adeno-oncolytic virus caused suppression of tumor progression and lung metastasis. Taken together, we report clinical and therapeutic relevance of CARF in EMT and cancer invasiveness/metastasis, and propose it as a potent therapeutic target of aggressive cancers.

17.
Mol Oncol ; 9(9): 1877-89, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26278998

RESUMEN

Collaborator of ARF (CARF), initially identified as a binding partner of ARF (Alternate Reading Frame), has been shown to activate ARF-p53 pathway by multiple ways including stabilization of ARF and p53 tumor suppressor proteins, and transcriptional repression of a p53 antagonist, HDM2. Level of CARF expression was shown to determine fate of cells. Whereas its knockdown caused apoptosis, its over- and super-expressions caused senescence and increase in malignant properties of cancer cells, respectively, and were closely linked to increase and decrease in p53 activity. Using p53-compromised cancer cells, we demonstrate that CARF induces growth arrest when wild type p53 is present and in p53-absence, it promotes carcinogenesis. Biochemical analyses on CARF-induced molecular signaling revealed that in p53-null cells, it caused transcriptional repression of p21(WAF1) leading to increase in CDK4, CDK6, pRb and E2F1 resulting in continued cell cycle progression. Furthermore, it instigated increase in migration and invasion of cancer cells that was marked by upregulation of MMP2, MMP3, MMP9, uPA, several interleukins and VEGF expression. Consistent with these findings, we found that human clinical samples of epithelial and glial cancers (frequently marked by loss of p53 function) possessed high level of CARF expression showing a relationship with cancer aggressiveness. The data demonstrated that CARF could be considered as a diagnostic marker and a therapeutic target in p53-compromised malignancies.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Carcinogénesis/genética , Neoplasias/genética , Proteínas de Unión al ARN/genética , Proteína p53 Supresora de Tumor/genética , Animales , Carcinogénesis/patología , Ciclo Celular , Línea Celular Tumoral , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Desnudos , Neoplasias/patología , Regulación hacia Arriba
18.
PLoS One ; 10(3): e0120554, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25789768

RESUMEN

BACKGROUND: Ashwagandha, a traditional Indian herb, has been known for its variety of therapeutic activities. We earlier demonstrated anticancer activities in the alcoholic and water extracts of the leaves that were mediated by activation of tumor suppressor functions and oxidative stress in cancer cells. Low doses of these extracts were shown to possess neuroprotective activities in vitro and in vivo assays. METHODOLOGY/PRINCIPAL FINDINGS: We used cultured glioblastoma and neuroblastoma cells to examine the effect of extracts (alcoholic and water) as well as their bioactive components for neuroprotective activities against oxidative stress. Various biochemical and imaging assays on the marker proteins of glial and neuronal cells were performed along with their survival profiles in control, stressed and recovered conditions. We found that the extracts and one of the purified components, withanone, when used at a low dose, protected the glial and neuronal cells from oxidative as well as glutamate insult, and induced their differentiation per se. Furthermore, the combinations of extracts and active component were highly potent endorsing the therapeutic merit of the combinational approach. CONCLUSION: Ashwagandha leaf derived bioactive compounds have neuroprotective potential and may serve as supplement for brain health.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ácido Glutámico/toxicidad , Humanos , Peróxido de Hidrógeno/toxicidad , Microscopía Fluorescente , Fármacos Neuroprotectores/química , Extractos Vegetales/química , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Ratas , Withania/química , Withania/metabolismo
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