Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins

Corominas-Faja, Bruna; Santangelo, Elvira; Cuyàs, Elisabet; Micol, Vicente; Joven, Jorge; Ariza, Xavier; Segura-Carretero, Antonio; Garcia, Jordi; Menendez, Javier A.

doi:10.18632/aging.100691

Cited by 26 publications

(19 citation statements)

References 44 publications

(32 reference statements)

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“…Research on mitochondriotropic antioxidants has been increasing over the last years. One viable and promising strategy involves the use of dietary polyphenolic antioxidants templates along with the chemical modulation of their properties, including mitochondrial targeting ability, efficacy, and toxicity 25 . In this context, some mitochondria-targeted polyphenolic-based molecules have been developed including MitoResveratrol, MitoCurcumin, and MitoQuercetin 26–28 .…”

Section: Resultsmentioning

confidence: 99%

Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid

Teixeira

Oliveira

Borges

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells. Moreover, AntiOxBEN3 presented robust iron-chelation and antioxidant properties in both isolated liver mitochondria and cultured rat and human cell lines. Along with its low toxicity profile and high antioxidant activity, AntiOxBEN3 strongly inhibited the calcium-dependent mitochondrial permeability transition pore (mPTP) opening. From our data, AntiOxBEN3 can be considered as a lead compound for the development of a new class of mPTP inhibitors and be used as mPTP de-sensitiser for basic research or clinical applications or emerge as a therapeutic application in mitochondria dysfunction-related disorders.

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“…Although molecular dynamics and Austin Model 1 (AM1) level computational mapping of oleuropein have been developed, the downstream mechanisms are not fully understood [ 16 , 17 ]. This is one of the drawbacks of important bioavailable olive BPsecos, their concentration present in olive products, and their biomolecular structures [ 34 ]. Acid-catalyzed oleuropein downstream pathways, however, could evolve via dynamic pre-equilibrium to oleuropein + H + isomers ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Probing Downstream Olive Biophenol Secoiridoids

Sivakumar

Uccella²,

Gentile

2018

IJMS

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Numerous bioactive biophenol secoiridoids (BPsecos) are found in the fruit, leaves, and oil of olives. These BPsecos play important roles in both the taste of food and human health. The main BPseco bioactive from green olive fruits, leaves, and table olives is oleuropein, while olive oil is rich in oleuropein downstream pathway molecules. The aim of this study was to probe olive BPseco downstream molecular pathways that are alike in biological and olive processing systems at different pHs and reaction times. The downstream molecular pathway were analyzed by high performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI/MS) and typed neglected of different overlap (TNDO) computational methods. Our study showed oleuropein highest occupied molecular orbital (HOMO) and HOMO-1 triggered the free radical processes, while HOMO-2 and lowest unoccupied molecular orbital (LUMO) were polar reactions of glucoside and ester groups. Olive BPsecos were found to be stable under acid and base catalylic experiments. Oleuropein aglycone opened to diales and rearranged to hydroxytyrosil-elenolate under strong reaction conditions. The results suggest that competition among olive BPseco HOMOs could induce glucoside hydrolysis during olive milling due to native olive β-glucosidases. The underlined olive BPsecos downstream molecular mechanism herein could provide new insights into the olive milling process to improve BPseco bioactives in olive oil and table olives, which would enhance both the functional food and the nutraceuticals that are produced from olives.

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“…Improved prediction of drug performance prior to lengthy experimentation would cut waste [ 21 , 22 ]. Vast datasets now exist that enable such prediction with the help of sophisticated computational methods [ 23 , 24 ]. Two particularly valuable datasets in this respect are the literally millions of gene expression profiles stored in repositories such as GEO [ 25 , 26 ] and a number of increasingly diverse compound screening libraries [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

Aliper¹,

Belikov

Garazha

et al. 2016

Aging

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Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

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“…Natural compounds represent an extraordinary inventory of high diversity structural scaffolds that can offer promising candidates in the major healthcare challenge of delaying ageing [ 29 ]. Plant extracts provide a substantial source of potentially active compounds, however so far only few natural compounds have been reported to have anti-senescence effects [ 30 - 34 ]. Based on our previous research results [ 2 ], we developed an assay that uses Pten null cells as a tool to rapidly identify compounds that decrease senescence in primary cells.…”

Section: Introductionmentioning

confidence: 99%

Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay

Matic¹,

Revandkar²,

Chen

et al. 2016

Aging

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Cellular senescence is a stable cell cycle arrest that is the causative process of aging. The PI3K/AKT/mTOR pathway is implicated in the control of cellular senescence and inhibitors of this pathway have been successfully used for life span prolongation experiments in mammals. PTEN is the major regulator of the PI3K/AKT/mTOR pathway and loss of PTEN promotes a senescence response termed PICS. Here we report a novel-screening assay, for the identification of compounds that block different types of senescence response. By testing a library of more than 3000 natural and chemical compounds in PTEN deficient cells we have found that an extract from Salvia haenkei (SH), a native plant of Bolivia is a potent inhibitor of PICS. SH also decreases replicative and UV-mediated senescence in human primary fibroblasts and in a model of in vitro reconstructed human epidermis. Mechanistically, SH treatment affects senescence driven by UV by interfering with IL1-ɑ signalling. Pre-clinical and clinical testing of this extract by performing toxicity and irritability evaluation in vitro also demonstrate the safety of SH extract for clinical use as anti-aging skin treatment.

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“…Later studies have described the biological activity spectra for 3,4‐DHPEA‐EA and 3,4‐DHPEA‐EDA using PASS (Prediction of Activity Spectra for Substances) software. These reports indicate that the oleuropein derivatives, 3,4‐DHPEA‐EA and 3,4‐DHPEA‐EDA exhibit two naturally occurring isomeric structures with different expected biological activity from hemiacetalic versus dialdehydic forms, and that 3,4‐DHPEA‐EDA favors the open dialdehydic form, which appears to be more conformationally free, and adaptable to interact with a suitable target .…”

Section: Introductionmentioning

confidence: 96%

Application and comparison of high‐speed countercurrent chromatography and high‐performance liquid chromatography in semi‐preparative separation of decarboxymethyl oleuropein aglycone (3,4‐DHPEA‐EDA), a bioactive secoiridoid from extra‐virgin olive oil

Jiménez-Sánchez¹,

Lozano-Sánchez²,

Brüggemann³

et al. 2016

Eur. J. Lipid Sci. Technol.

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This paper primarily extends research on applying and comparing high‐speed countercurrent chromatography (HSCCC) and high‐performance liquid chromatography (HPLC) in semi‐preparative isolation of decarboxymethyl oleuropein aglycone (3,4‐DHPEA‐EDA), a bioactive secoiridoid, from extra‐virgin olive oil (EVOO). An EVOO phenolic extract (EVOO‐PE) was obtained by solid‐phase extraction (SPE), and this extract was subjected to one run using the maximum loading capacity of each methodology without loss of resolution. For this sample set, the HSCCC method proved to be a more efficient approach regarding loading capacity, solvent consumption, and throughput compared with the HPLC method. However, the purity of the target from HPLC was superior to that of HSCCC, as the number of theoretical plates could not match that of HPLC. Therefore, we propose that HPLC should be used when higher purities are required, despite higher costs. In addition, HPLC is orthogonal and complementary to HSCCC, and can often provide straightforward resolution of otherwise difficult separations by HSCCC. Practical applications: Our results indicate that the optimized HSCCC is an economic process, and hence, a good candidate for further scaling‐up to preparative and industrial scales, as long as the chromatographic profile of the sample itself is simple enough to achieve good resolution, or a very high purity of the compound of interest is not required. For those cases, HPLC would provide superior target purity but would result in higher costs. This paper compares high‐speed countercurrent chromatography (HSCCC) and high‐performance liquid chromatography (HPLC) in semi‐preparative isolation of decarboxymethyl oleuropein aglycone (3,4‐DHPEA‐EDA), a bioactive secoiridoid, from extra‐virgin olive oil (EVOO). An EVOO phenolic extract (EVOO‐PE) was obtained by solid‐phase extraction (SPE), and this extract was subjected to one run using the maximum loading capacity of each methodology without loss of resolution. For this sample set, the HSCCC method proved to be a more efficient approach regarding loading capacity, solvent consumption, and throughput compared with the HPLC method. However, the purity of the target from HPLC was superior to that of HSCCC, as the number of theoretical plates could not match that of HPLC.

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Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins

Cited by 26 publications

References 44 publications

Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid

Probing Downstream Olive Biophenol Secoiridoids

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay

Application and comparison of high‐speed countercurrent chromatography and high‐performance liquid chromatography in semi‐preparative separation of decarboxymethyl oleuropein aglycone (3,4‐DHPEA‐EDA), a bioactive secoiridoid from extra‐virgin olive oil

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