Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal ...stimuli. mTOR functions in two distinct complexes-mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR's enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.
Power ultrasound is being used as a novel technique for process intensification. In this study, the feasibility of using power ultrasound to improve the phenolic extraction from olive leaves was ...approached taking both compositional and kinetic issues into account and also determining the influence of the main process parameters (the electric power supplied, emitter surface and temperature). For this purpose, the extraction kinetics were monitored by measuring the total phenolic content and antioxidant capacity and mathematically described by Naik's model, and HPLC–DAD/MS–MS was used to identify and quantify the main polyphenols. The electric power supplied and the emitter surface greatly affected the effective ultrasonic power applied to the medium, and hence the extraction rate. However, the influence of temperature on ultrasound assisted extraction was not clear. Compared with conventional extraction, ultrasound assisted extraction reduced the extraction time from 24h to 15min and did not modify the extract composition.
Olive crop produces a significant quantity of byproducts (leaves, branches, solid and liquid wastes), coming from the tree pruning, fruit harvest and oil production, which are rich in phenolic compounds with bioactive properties. The extraction of the bioactive compounds could be an interesting option with which to increase the value of these byproducts, as it requires efficient extraction techniques in order to reduce processing costs and improve productivity. In this sense, ultrasound assisted extraction is considered a novel technique used as a means of intensifying a slow process, such as the leaching of polyphenols from vegetable matrices. In order to further address the industrial applications of ultrasound assisted extraction, a kinetic study should be carried out determining both the effective energy introduced into the medium, as well as its influence on the extract quality.
► The use of ultrasound in the phenolic extraction from olive leaves was addressed. ► The ultrasound effectiveness depended on the effective power applied to the medium. ► Ultrasound assisted extraction shortened the extraction time from 24h to 15min. ► The application of ultrasound did not modify the composition of olive leaf extracts.
Using non-small cell lung carcinoma (NSCLC) cells harboring the erlotinib-sensitizing Epidermal Growth Factor Receptor (EGFR) exon 19 mutation delE746-A750, we developed erlotinib-refractory ...derivatives in which hyperactive Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling associated with enrichment in epithelial-to-mesenchymal transition (EMT)-related morphological and transcriptional features. We then explored whether an IGF-1R/EMT crosstalk was sufficient to promote erlotinib refractoriness in the absence of second-site EGFR mutations, MET and AXL hyperactivation. Transforming Growth Factor-beta1 (TGFβ1)-induced mesenchymal trans-differentiation was sufficient to impede erlotinib functioning in the presence of drug-sensitive delE746-A750 EGFR mutation. Pharmacological blockade of IGF-1R fully prevented the TGFβ1's ability to activate an EMT protein signature E-cadherin low/vimentin high. The sole presence of erlotinib was capable of rapidly activate an IGF-1R-dependent, vimentin-enriched mesenchymal-like phenotype in delE746-A750-mutated epithelial cells. Even if transient, NSCLC cells' intrinsic plasticity to undergo crosstalk between IGF-1R and EMT signaling pathways can sufficiently eliminate the erlotinib-sensitizing effect of highly prevalent EGFR mutations and suggests the urgent need for dual IGF-1R/EMT-targeting strategies to circumvent erlotinib resistance.
Objective
To assess the in vitro efficacy on antioxidant potential, protection against global oxidative stress, and effect on collagen neosynthesis of minimalist formula (Peptide‐C ampoules product) ...containing 10% natural vitamin C, rice and lupin bio‐peptides, hyaluronic acid, and Vichy volcanic mineralizing water (active mix).
Methods
In‐tube quantitative tests (“in‐tube screening”) assessed global antioxidant properties, anti‐lipid peroxidation, anti‐protein glycosylation, and metalloproteinase inhibition (anti‐collagenase, anti‐elastase, and anti‐hyaluronidase activity) properties of the formula. Protection against oxidative stress was evaluated on human keratinocyte monolayer cultures, and collagen neosynthesis was quantified on fibroblast monolayer cultures treated with supernatants from product‐treated reconstructed human epidermis.
Results
Product (5% concentration) showed high antioxidant ability (blocking 99.0% oxidation), protection against oxidative stress damage (51.8% lipid peroxidation and 37.8% protein glycosylation decreases), and inhibition of hyaluronidase (21.9%), elastase (47.1%), and collagenase (61.8%). The protective effect was validated on human keratinocyte monolayer cultures in the presence of active mix (0.025%). Oxidative stress (ROS) was reduced by 99.0%, while global oxidative stress (RMS) induced by pollution, UVA radiation, and a combination of both factors was reduced by 48.94%, 8.7%, and 96.28%, respectively. The product increased collagen neosynthesis (11.21%) by cellular dialogue in fibroblasts incubated with product/mix‐treated‐RHE supernatants.
Conclusion
The combination of ingredients in the product showed high global antioxidant capacity, as well as a protective effect against oxidative stress induced by UVA, pollution, or both combined factors and an ability to stimulate collagen neosynthesis in in vitro studies, which support the clinical efficacy of this product.
Aging is a complex process characterized by an ongoing decline in physiological functions, leading to degenerative diseases and an increased probability of death. Cellular senescence has been ...typically considered as an anti-proliferative process; however, the chronic accumulation of senescent cells contributes to tissue dysfunction and aging. In this review, we discuss some of the most important hallmarks and biomarkers of cellular senescence with a special focus on skin biomarkers, reactive oxygen species (ROS), and senotherapeutic strategies to eliminate or prevent senescence. Although most of them are not exclusive to senescence, the expression of the senescence-associated beta-galactosidase (SA-β-gal) enzyme seems to be the most reliable biomarker for distinguishing senescent cells from those arrested in the cell cycle. The presence of a stable DNA damage response (DDR) and the accumulation of senescence-associated secretory phenotype (SASP) mediators and ROS are the most representative hallmarks for senescence. Senotherapeutics based on natural compounds such as quercetin, naringenin, and apigenin have shown promising results regarding SASP reduction. These compounds seem to prevent the accumulation of senescent cells, most likely through the inhibition of pro-survival signaling pathways. Although studies are still required to verify their short- and long-term effects, these therapies may be an effective strategy for skin aging.
Reviews have traditionally been based on extensive searches of the available bibliography on the topic of interest. However, this approach is frequently influenced by the authors' background, leading ...to possible selection bias. Artificial intelligence applied to natural language processing (NLP) is a powerful tool that can be used for systematic reviews by speeding up the process and providing more objective results, but its use in scientific literature reviews is still scarce. This manuscript addresses this challenge by developing a reproducible tool that can be used to develop objective reviews on almost every topic. This tool has been used to review the antibacterial activity of
genus plant extracts as proof of concept, providing a comprehensive and objective state of the art on this topic based on the analysis of 1601 research manuscripts and 136 patents. Data were processed using a publicly available Jupyter Notebook in Google Collaboratory here. NLP, when applied to the study of antibacterial activity of
plants, is able to recover the main scientific manuscripts and patents related to the topic, avoiding any biases. The NLP-assisted literature review reveals that
and
are the first and second most studied
species respectively. Leaves and fruits are the most commonly used plant parts and methanol, followed by butanol and water, the most widely used solvents to prepare plant extracts. Furthermore,
followed by
are the most studied bacterial species, which are also the most susceptible bacteria in all studied assays. This new tool aims to change the actual paradigm of the review of scientific literature to make the process more efficient, reliable, and reproducible, according to Open Science standards.
The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract (
Dolabella auricularia,
NB) and its different effects in ...colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.
•Flavonoids and diterpenes show greater absorption in small intestine.•Metabolites from several diterpenes were detected in small intestine.•Glucuronidation reaction is the main route of metabolism ...of diterpenes.•The bioactive absorbed compounds interact with the colon through bloodstream.•The mechanism of non-absorbed compounds consists in interactions with the microbiota.
Phenolic compounds in rosemary have shown antiproliferative/cytotoxic activity against colorectal cancer cells. The aim of this work was to study in depth the absorption and metabolism of the compounds present in a rosemary extract. An in-situ perfusion assay was performed in mice, for which samples of gastrointestinal liquid taken at different times and plasma obtained at the end of the experiment were analysed by HPLC-ESI-QTOF-MS. The absorption-rate coefficients showed that flavonoids and diterpenes were highly absorbed compared to triterpenes. Several diterpenes and their metabolites were also bioavailable in plasma, highlighting the higher concentrations of glucuronide metabolites compared to non-metabolised phenolic compounds. The antiproliferative/cytotoxic properties could be attributed to the absorbed diterpenes and metabolites, which could reach the colon through bloodstream. On the other hand, compounds poorly absorbed, such as triterpenes and some diterpenes, could exhibit their bioactivity in the large intestine by a mechanism of direct interaction with the microbiota.
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