The prevalence of microplastic pollution in nature and foodstuffs is fairly well identified. However, studies of micro- or nanoplastics' cell membrane permeation and health effects in humans are ...lacking. Our study focuses on examining the interactions of polyethylene (PE) and polyethylene terephthalate (PET) with bilayer membranes. We have performed molecular dynamics simulations to study how plastic oligomers behave in bilayers. In addition, we have studied membrane permeation of PE and Bis(2-hydroxyethyl) terephthalate (BHET), a type of PET monomer, with Parallel Artificial Membrane Permeability Assay (PAMPA). As a result, in simulations the molecules exhibited different movements and preferred locations in membrane. PAMPA studies suggested similar preferences in membrane, especially for PE plastic. Our results suggest that passive diffusion could be an important transport mechanism into cells for some small plastic oligomers. Both molecular dynamics simulations and PAMPA have potential for micro- and nanoplastics research.
N-Acylethanolamines Bind to SIRT6 Rahnasto-Rilla, Minna; Kokkola, Tarja; Jarho, Elina ...
Chembiochem : a European journal of chemical biology,
January 1, 2016, Letnik:
17, Številka:
1
Journal Article
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Odprti dostop
Sirtuin 6 (SIRT6) is an NAD+‐dependent histone deacetylase enzyme that is involved in multiple molecular pathways related to aging. Initially, it was reported that SIRT6 selectively deacetylated ...H3K9Ac and H3K56Ac; however, it has more recently been shown to preferentially hydrolyze long‐chain fatty acyl groups over acetyl groups in vitro. Subsequently, fatty acids were demonstrated to increase the catalytic activity of SIRT6. In this study, we investigated whether a series of N‐acylethanolamines (NAEs), quercetin, and luteolin could regulate SIRT6 activity. NAEs increased SIRT6 activity, with oleoylethanolamide having the strongest activity (EC50 value of 3.1 μm). Quercetin and luteolin were demonstrated to have dual functionality with respect to SIRT6 activity; namely, they inhibited SIRT6 activity with IC50 values of 24 and 2 μm, respectively, and stimulated SIRT6 activity more than sixfold (EC50 values of 990 and 270 μm, respectively).
SIRTainly novel: We have identified a series of N‐acylethanolamines as sirtuin 6 (SIRT6) activators (+) and quercetin as having dual SIRT6 activity (−/+) by using a newly developed SIRT6 H3K9Ac deacetylation assay. The involvement of sirtuins in aging, cancer, and metabolic diseases gives these compounds potential for future drug development.
High-risk neuroblastoma is a devastating malignancy with very limited therapeutic options. Here, we identify withaferin A (WA) as a natural ferroptosis-inducing agent in neuroblastoma, which acts ...through a novel double-edged mechanism. WA dose-dependently either activates the nuclear factor-like 2 pathway through targeting of Kelch-like ECH-associated protein 1 (noncanonical ferroptosis induction) or inactivates glutathione peroxidase 4 (canonical ferroptosis induction). Noncanonical ferroptosis induction is characterized by an increase in intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which is sufficient to induce ferroptosis. This double-edged mechanism might explain the superior efficacy of WA as compared with etoposide or cisplatin in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing the growth and relapse rate of neuroblastoma xenografts. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced accumulation at the tumor site. Collectively, our data propose a novel therapeutic strategy to efficiently kill cancer cells by ferroptosis.
In recent years many investigators have been concerned about the toxicity and potential health hazards of micro- and nanoplastics. However, we are still lacking a good understanding of the methods of ...their transport into the human body and subsequently within cells. This is especially true at the lower nanometer scale; these particles are potentially more dangerous than their micrometer counterparts due to their easier permeation into cells. In this study we used both unbiased molecular dynamics simulations and steered umbrella sampling simulations to explore the interactions of polyethylene terephthalate (PET) and polyethylene (PE) oligomers in phospholipid bilayers. Our simulations revealed that the bilayers did not represent significant energy barriers to the small oligomers; not only did they readily enter the cell membrane but they also became concentrated into specific parts of the membrane. The larger PET tetramers exhibited a strong aggregation in water but were the least likely to permeate through or into the membranes. It is possible that PE monomers and tetramers can become concentrated into membranes while PET monomers are more likely to pass through or concentrate just inside the membrane surface. Passive transport of microplastics into cells is, however, likely limited to particles of a few nanometers in diameter.
Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied ...extensively in drug development. They have been shown to modulate the activity of a NAD
-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD
binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.
Sirtuins are NAD(+)-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, ...senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative ...disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC50 of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein ...family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl‐ ases such as sirtuin 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro‐inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age‐related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins.
Epigenetic proteins entwined: We demonstrate remarkable upregulation and activation of an important histone deacetylase SIRT1 by inhibition of epigenetic readers, BET proteins. This treatment was found to relieve inflammation in a cellular lung disease model.
L‐Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood–brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the ...brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier‐mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q2=0.53, R2=0.75, Q2 SE=0.77, R2 SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with L‐tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1‐targeted high‐affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1‐binding prodrugs and other compounds that bind to LAT1.
High‐latitude LAT1 binders: Herein we report the first 3 D QSAR for compounds that bind to L‐type amino acid transporter 1 (LAT1). A CoMFA model was successfully used to guide the synthesis of new LAT1‐binding compounds, resulting in new high‐affinity LAT1 prodrugs. This indicates that the model generated in this study can be used for the rational design of novel prodrugs and other compounds that bind efficiently to LAT1.
Sirtuin 2 (SIRT2), a member of the NAD
-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the ...progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (
), we identified in this study the potent mechanism-based inactivator KPM-2 (
), which is selective toward SIRT2. Compound
engages in a nucleophilic attack toward NAD
at the active site of SIRT2, which affords a stable
-ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the "selectivity pocket" and the NAD
-binding site. Moreover,
exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.
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