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Apigenin, a flavonoid, has shown early promise in colon cancer (CC); thus, exploring potential mechanisms of Apigenin is obligatory. In this study, shared targets of Apigenin and CC were identified through online tools, which were then subjected to functional enrichment analyses, Gene Ontology and KEGG. Further, the protein-protein interaction network of the shared targets was developed (via STRING). The top targets of Apigenin in CC were identified by molecular docking; further investigated for differential gene and protein expression in CC and their influence on CC patient survival (using TCGA data). Out of 13 hub genes, the top 3 targets (HSP90AA1, MMP9, PTGS2) were selected based on docking score. Their expression was significantly elevated and related to poor overall survival in CC (except PTGS2). Molecular dynamics simulation further validated protein-ligand interactions and divulged HSP90AA1 as the best target of Apigenin in CC. Finally, the anti-cancer effects of Apigenin and its major metabolite, luteolin, were investigated in CC, which is involved in the cytotoxicity of CC cells (COLO-205) by reducing HSP90AA1 expression revealed by real-time PCR. Thus, HSP90AA1 was identified as one of the prime targets of Apigenin in CC, and Apigenin could be effective against CC.Communicated by Ramaswamy H. Sarma.
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Colorectal cancer (CRC), especially metastatic (mCRC) form, becomes a major reason behind cancer morbidity worldwide, whereas the treatment strategy is not optimum. Several novel targets are under investigation for mCRC including the autophagy pathway. Natural compounds including dietary lignans are sparsely reported as autophagy modulators. Nonetheless, the interaction between dietary lignans and core autophagy complexes are yet to be characterised. We aimed to describe the interaction between the dietary lignans from flaxseed (Linum usitatissimum) and sesame seeds (Sesamum indicum) along with the enterolignans (enterodiol and enterolactone) and the UNC-51-like kinase 1 and 2 (ULK1/2), important kinases required for the autophagy. A range of in-silico technologies viz. molecular docking, drug likeness, and ADME/T was employed to select the best fit modulator and/or inhibitor of the target kinases from the list of selected lignans. Drug likeness and ADME/T studied further selected the best-suited lignans as potential autophagy inhibitor. Molecular dynamic simulation (MDS) analyses were used to validate the molecular docking results. Binding free energies of the protein-ligand interactions by MM-PBSA method further confirmed best-selected lignans as ULK1 and/or ULK2 inhibitor. In conclusion, three dietary lignans pinoresinol, medioresinol, and lariciresinol successfully identified as dual ULK1/2 inhibitor/modifier, whereas enterodiol emerged as a selective ULK2 inhibitor/modifier.
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Homólogo de la Proteína 1 Relacionada con la Autofagia , Neoplasias Colorrectales , Lignanos , Humanos , Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Lignanos/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Protein tyrosine phosphatase 1B (PTP1B) has emerged as one of the links between obesity and colon cancer (CC). Anti-obesity and anti-CC attributes of sweet potato (Ipomoea batatas) reported sparsely. Here, we aimed to study the potential of PTP1B as a target in CC, particularly in obese population. Expression and genomic alteration frequency of PTPN1 (PTP1B) were checked in CC. Interacting partners of PTP1B through STRING and hub genes through Cytoscape (MCODE) were identified. Hub genes were subjected to functional enrichment analyses (via Metascape), differential gene expression, copy number variation, and single nucleotide variation analyses (GSCA database). Cancer-related pathways and associated immune infiltrates of the hub genes were checked too. Eleven sweet potato-derived compounds selected through drug likeness (DL) and toxicity filters were explored via molecular docking (AutoDock Vina) to reveal the interactions with PTP1B. Genomic alteration frequency of the PTPN1 was highest in CC compared to all the other TCGA cancers, and a high expression (RNA and protein) is also observed in CC that correlated well to a poor overall survival (OS). Furthermore, PTP1B and related proteins were enriched in different biological processes and signaling pathways related to carcinogenesis including epithelial-mesenchymal transition. Overall, PTP1B identified as a potential target in obesity-linked CC and sweet potato might exert its protective action by targeting the PTP1B. Sweet potato compounds (e.g., pelargonidin and luteolin) interacted with the catalytic P loop and the WPD loop of the PTP1B. Furthermore, MD simulation study ascertained that luteolin has the highest affinity against the PTP1B, whereas pelargonidin and quercetin showed good binding affinity too, thus can be explored further.
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Neoplasias del Colon , Ipomoea batatas , Neoplasias del Colon/genética , Variaciones en el Número de Copia de ADN , Humanos , Ipomoea batatas/genética , Ipomoea batatas/metabolismo , Luteolina/metabolismo , Simulación del Acoplamiento Molecular , Obesidad/complicaciones , Obesidad/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismoRESUMEN
Worldwide disease burden of colorectal cancer (CRC) increasing alarmingly, but a suitable therapeutic strategy is not available yet. Abnormal activation of the PI3K/Akt/mTOR signalling because of mutation in the PIK3CA gene is a driving force behind CRC development. Therefore, this study aimed to comprehensively characterise the potential of phenolic compounds from Olea europaea against the PI3K/Akt/mTOR axis by using in silico methodologies. Molecular docking was utilised to study key interactions between phenolic compounds of O. europaea and target proteins PI3K, Akt, mTOR with reference to known inhibitor of target. Drug likeness and ADME/T properties of selected phenols were explored by online tools. Dynamic properties and binding free energy of target-ligand interactions were studied by molecular dynamic simulation and MM-PBSA method respectively. Molecular docking revealed apigenin, luteolin, pinoresinol, oleuropein, and oleuropein aglycone as the top five phenolic compounds which showed comparable/better binding affinity than the known inhibitor of the respective target protein. Drug likeness and ADME/T properties were employed to select the top three phenols namely, apigenin, luteolin, and pinoresinol which shown to bind stably to the catalytic cleft of target proteins as confirmed by molecular dynamics simulations. Therefore, Apigenin, luteolin, and pinoresinol have the potential to be used as the non-toxic alternative to synthetic chemical inhibitors generally used in CRC treatment as they can target PI3K/Akt/mTOR axis. Particularly, pinoresinol showed great potential as dual PI3K/mTOR inhibitor. However, this study needs to be complemented with future in vitro and in vivo studies to provide an alternative way of CRC treatment. Communicated by Ramaswamy H. Sarma.
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Neoplasias Colorrectales , Olea , Humanos , Olea/química , Fosfatidilinositol 3-Quinasas/genética , Fenoles/farmacología , Fenoles/química , Proteínas Proto-Oncogénicas c-akt , Apigenina/química , Luteolina , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasa Clase I/genética , Serina-Treonina Quinasas TOR , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
Colorectal cancer (CRC) is one of the major causes of death across the world and incidence rate of CRC increasing alarmingly each passing year. Diet, genomic anomalies, inflammation and deregulated signalling pathways are among the major causes of CRC. Because of numerous side effects of CRC therapies available now, researchers all over the world looking for alternative treatment/preventive strategy with lesser/no side effects. Olive oil which is part of Mediterranean diet contains numerous phenolic compounds that fight against free radicals and inflammation and also well-known for protective role against CRC. The current review focused on the recent evidences where olive oil and its phenolic compounds such as hydroxytyrosol, oleuropein and oleocanthal showed activities against CRC as well to analyse the cellular and molecular signalling mechanism through which these compounds act on. These compounds shown to combat CRC by reducing proliferation, migration, invasion and angiogenesis through regulation of numerous signalling pathways including MAPK pathway, PI3K-Akt pathway and Wnt/ß-catenin pathway and at the same time, induce apoptosis in different CRC model. However, further research is an absolute necessity to establish these compounds as nutritional supplements and develop therapeutic strategy in CRC.
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Neoplasias Colorrectales , Fosfatidilinositol 3-Quinasas , Humanos , Aceite de Oliva , Suplementos Dietéticos , Inflamación , Aceites de Plantas/farmacologíaRESUMEN
Inflammation has been associated with the progression of many neurological diseases. Peripheral inflammation has also been vaguely linked to depression-like symptoms in animal models, but the underlying pathways that orchestrate inflammation-induced behavioral or molecular changes in the brain are still elusive. We have recently shown that intraperitoneal injections of lipopolysaccharide (LPS) to Swiss albino mice triggers systemic inflammation, leading to an activated immune response along with changes in monoamine levels in the brain. Herein we pinpoint the fundamental pathways linking peripheral inflammation and depression-like behavior in a mouse model, thereby identifying suitable targets of intervention to combat the situation. We show that LPS-induced peripheral inflammation provoked a depression-like behavior in mice and a distinct pro-inflammatory bias in the hippocampus, as evident from increased microglial activation and elevated levels of pro-inflammatory cytokines IL-6 and TNF-α, and activation of NFκB-p65 pathway. Significant alterations in Nrf2-dependent cellular redox status, coupled with altered autophagy and increased apoptosis were noticed in the hippocampus of LPS-exposed mice. We and others have previously shown that, fluoxetine (an anti-depressant) has effective anti-inflammatory and antioxidant properties by virtue of its abilities to regulate NFκB and Nrf2 signaling. We observed that treatment with fluoxetine or the Nrf2 activator tBHQ (tert-butyl hydroquinone), could reverse depression-like-symptoms and mitigate alterations in autophagy and cell death pathways in the hippocampus by activating Nrf2-dependent gene expressions. Taken together, the data suggests that systemic inflammation potentiates Nrf2-dependent changes in cell death and autophagy pathway in the hippocampus, eventually leading to major pathologic sequelae associated with depression. Therefore, targeting Nrf2 could be a novel approach in combatting depression and ameliorating its associated pathogenesis.
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Apoptosis , Autofagia , Conducta Animal , Fluoxetina/farmacología , Hipocampo/patología , Inflamación/patología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Catalasa/metabolismo , Depresión/patología , Glutatión/metabolismo , Hidroquinonas , Lipopolisacáridos , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Dietary supplementation of polyphenol-rich pomegranate extract (POMx) has been shown to have anti-oxidant and anti-inflammatory activities. Here, we evaluate the efficacy of POMx in mitigating pancreatitis in mice and provide a mechanistic outline of the process. Age-matched male Swiss albino mice were injected with Lipopolysaccharide (LPS) and given POMx supplement alone or in combination with LPS. After 4 weeks of treatment histological scoring for pancreatic edema and vacuolization was performed. Serum insulin levels were estimated and the glucose tolerance test (IPGTT) data revealed that POMx reduced inflammation induced hyperglycemia in mice. Analysis of TLR4, IκB expression, and NF-κB nuclear translocation, and concentrations of IL-6 and TNFα showed that POMx is able to modulate the molecular instigators of inflammatory responses. Annexin V assay indicated that POMx protects against inflammation-mediated apoptosis in the pancreas. Expression profile of SAPK/JNK pathway, p53, Bax, Bcl-2 and Caspase-3 validate an apoptotic to survival shift in POMx treatment group. Co-immunoprecipitation studies show that POMx stabilizes p21 and Nrf2 interaction and increases its nuclear translocation. The study also proves that the nuclear fraction of Nrf2 is able to bind to the Bcl-2 promoter and activate an anti-apoptotic program. The findings of our study underline an anti-inflammatory, anti-oxidative and anti-apoptotic role of POMx and provide a mechanistic idea of how POMx confers protection during pancreatitis.