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Alternative splicing is the process of generating different mRNAs from the same primary transcript, which contributes to increase the transcriptome and proteome diversity. Abnormal splicing has been associated with the development of several diseases including cancer. Given that mutations and abnormal levels of the RIPK2 transcript and RIP-2 protein are frequent in tumors, and that RIP-2 modulates immune and inflammatory responses, we investigated alternative splicing events that result in partial deletions of the kinase domain at the N-terminus of RIP-2. We also investigated the structure and expression of the RIPK2 truncated variants and isoforms in different environments. In addition, we searched data throughout Supraprimates evolution that could support the biological importance of RIPK2 alternatively spliced products. We observed that human variants and isoforms were differentially regulated following temperature stress, and that the truncated transcript was more expressed than the long transcript in tumor samples. The inverse was found for the longer protein isoform. The truncated variant was also detected in chimpanzee, gorilla, hare, pika, mouse, rat, and tree shrew. The fact that the same variant has been preserved in mammals with divergence times up to 70 million years raises the hypothesis that it may have a functional significance., Competing Interests: Conflicts of Interest The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Chagas disease is a well-known Neglected Tropical Disease, mostly endemic in continental Latin America, but that has spread to North America and Europe. Unfortunately, current treatments against such disease are ineffective and produce known and undesirable side effects. To find novel effective drug candidates to treat Chagas disease, we uniquely explore the Trypanosoma cruzi proteasome as a recent biological target and, also, apply drug repurposing through different computational methodologies. For this, we initially applied protein homology modeling to build a robust model of proteasome β4/β5 subunits, since there is no crystallographic structure of this target. Then, we used it on a drug repurposing via a virtual screening campaign starting with more than 8,000 drugs and including the methodologies: ligand-based similarity, toxicity predictions, and molecular docking. Three drugs were selected concerning their favorable interactions at the protein binding site and subsequently submitted to molecular dynamics simulations, which allowed us to elucidate their behavior and compare such theoretical results with experimental ones, obtained in biological assays also described in this paper.Communicated by Ramaswamy H. Sarma.

Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact peripherally with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC 12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular dynamics (MD) studies disclose that both complexes were stable by analyzing the RMSD (root mean square deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Skin Cancer (SC) is among the most common type of cancers worldwide. The search for SC therapeutics using molecular modeling strategies as well as considering natural plant-derived products seems to be a promising strategy. The phytochemical Rocaglamide A (Roc-A) and its derivatives rise as an interesting set of reference compounds due to their in vitro cytotoxic activity with SC cell lines. In view of this, we performed a hierarchical virtual screening study considering Roc-A and its derivatives, with the aim to find new chemical entities with potential activity against SC. For this, we selected 15 molecules (Roc-A and 14 derivatives) and initially used them in docking studies to predict their interactions with Checkpoint kinase 1 (Chk1) as a target for SC. This allowed us to compile and use them as a training set to build robust pharmacophore models, validated by Pearson's correlation ( p ) values and hierarchical cluster analysis (HCA), subsequentially submitted to prospective virtual screening using the Molport ® database. Outputted compounds were then selected considering their similarities to Roc-A, followed by analyses of predicted toxicity and pharmacokinetic properties as well as of consensus molecular docking using three software. 10 promising compounds were selected and analyzed in terms of their properties and structural features and, also, considering their previous reports in literature. In this way, the 10 promising virtual hits found in this work may represent potential anti-SC agents and further investigations concerning their biological tests shall be conducted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation, though no other collaboration, with several of the authors GS, CS at the time of the review., (Copyright © 2022 dos Santos, Borges, Silva, de Lima, Bastos, Ramos, Silva, da Silva and dos Santos.)

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood-brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000 mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Glioblastoma is an aggressive primary tumor of the central nervous system (CNS). Is the most aggressive among infiltrative gliomas arising from the CNS. This tumor has low patient survival rate and several studies aiming at developing new drugs have increased. Patients with this cancer type face significant morbidity and mortality. This study evaluated the antineoplastic activity of synthetic chalcones ( 3a-3f ) using in vitro glioblastoma models and molecular modeling. Cytotoxicity assay showed that Astrocitoma Hospital Ofir Loyola No 1 (AHOL1) and Uppsala 87 neoplastic glioblastoma lines (U87) cellular viability were significantly reduced compared to Healthy human fibroblasts cell lines (AN27) when exposed to chalcones. Interaction with the serine amino acid was present in the most promising and the reference binder docking, suggesting its importance inhibiting cell growth. Comparative analysis between the reference ligands and the molecules showed that the amino acid LYS352 present in all fittings, suggesting that this is the main amino acid for interaction with tubulin and are consistent with those in cytotoxicity assay, suggesting antineoplastic potential in glioblastoma. Long trajectory molecular dynamics studies were also carried out in order to investigate stability and conformations amongst the chalcones bound tubulin as well, in comparison to doxorubicin (here used as control), however future studies are needed to further assess the mechanism of inhibition of chalcones used in this investigation.Communicated by Ramaswamy H. Sarma.

Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC 50 ) of 9.6 ± 3 μM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Food allergies are known as the public health problem, affecting people of all age groups, but more commonly in babies and children, with consequences for nutritional status and quality of life. The increase in the consumption of healthy foods has consequently led to an increased demand for functional foods with specific health benefits. Thus, the pharmaceutical industry's interest in natural products has grown every time and is therefore considered as an alternative to synthetic drugs. Kefir has been outstanding for several years as promising in the manufacture of various pharmaceutical products, due to its nutritional and therapeutic properties for the treatment of many diseases. Currently, a wide variety of new functional foods are appearing on the market, representing an important segment. Postbiotics, for example, has stood out for being a product with action similar to probiotics, without offering side effects. The kefiran is the postbiotic from kefir that promotes potential beneficial effects on food allergy from the intestinal microbiome to the immune system. In this context, it is necessary to know the main promoting component of this functional effect. This review compiles the benefits that kefir, and especially its postbiotic, kefiran, can bring to food allergy. In addition, it serve as a subsidy for studies on the development of innovative nutraceutical products, including the use of kefiran as an alternative therapy in food allergy.

Models validation in QSAR, pharmacophore, docking and others can ensure the accuracy and reliability of future predictions in design and selection of molecules with biological activity. In this study, pyriproxyfen was used as a pivot/template to search the database of the Maybridge Database for potential inhibitors of the enzymes acetylcholinesterase and juvenile hormone as well. The initial virtual screening based on the 3D shape resulted in 2000 molecules with Tanimoto index ranging from 0.58 to 0.88. A new reclassification was performed on the overlapping of positive and negative charges, which resulted in 100 molecules with Tanimoto's electrostatic score ranging from 0.627 to 0.87. Using parameters related to absorption, distribution, metabolism and excretion and the pivot molecule, the molecules selected in the previous stage were evaluated regarding these criteria, and 21 were then selected. The pharmacokinetic and toxicological properties were considered and for 12 molecules, the DEREK software not fired any alert of toxicity, which were thus considered satisfactory for prediction of biological activity using the Web server PASS. In the molecular docking with insect acetylcholinesterase, the Maybridge3_002654 molecule had binding affinity of -11.1 kcal/mol, whereas in human acetylcholinesterase, the Maybridge4_001571molecule show in silico affinity of -10.2 kcal/mol, and in the juvenile hormone, the molecule MCULE-8839595892 show in silico affinity value of -11.6 kcal/mol. Subsequent long-trajectory molecular dynamics studies indicated considerable stability of the novel molecules compared to the controls.AbbreviationsQSARquantitative structure-activity relationshipsPASSprediction of activity spectra for substancesCommunicated by Ramaswamy H. Sarma.

The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (M pro ), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for M pro , we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against M pro . In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the M pro catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global A. fumigatus phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the Δ sakA , Δ mpkC , and Δ sakA Δ mpkC mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in Δ sakA , Δ mpkC , and Δ sakA Δ mpkC mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. IMPORTANCE Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the Δ sakA and Δ mpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence., (Copyright © 2020 Mattos et al.)

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β-amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.

Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (R), squared correlation coefficient (R 2 ), explanatory variance (adjusted R 2 ), standard error of estimate (SEE), and variance ratio (F). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein's backbone remained stable after the introduction of ligands.

The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The compounds were analyzed to ponatinib and WEHI-345, which also used as a control. At least one of the compounds exhibited suitable pharmacokinetic properties, low toxicity and an interesting binding affinity and high fitness compared with the crystallographic pose of WEHI-345 in complex with RIPK2. This compound also possessed suitable synthetic accessibility, rendering it a potential and very promising RIPK2 inhibitor to be further investigated in regards to different diseases, particularly inflammatory ones., Competing Interests: The authors declare no conflict of interest.

Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.

The knowledge of the bioactive conformation for an active hit is relevant because of the easier interpretation and the general quality of the recognition models of protein and ligand. With the aim of investigating potential bioactive conformations without previous structural knowledge of the molecular target, we present herewith a 'protocol' that could be used which includes generation of low-energy conformations, calculations of tridimensional descriptors and investigation of structural similarity via principal component analysis. The protocol was used in the search for potential bioactive conformations. An initial selection of targets was made from a set of protein-ligand complexes with structure deposited in the Protein Data Bank, which was systematically filtered by lead-like rules, resulting in 45 ligands of 8 important therapeutic targets. After extensive optimization of the protocol and parameters of both OMEGA and Pentacle softwares, the best results were obtained for series of compounds such as the beta-trypsin and urokinase inhibitors, which are more structurally related among each other, inside the respective therapeutic class. Future improvements of the protocol, including a suitable choice and combination of robust 3D descriptors, could yield more reliable and less restrictive results, with general and diverse applications in drug design, in particular for improving the 3D-QSAR methodologies as well as virtual screening experiments for a more reliable selection of new lead compounds for different molecular targets.

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

One of the cornerstones of rational drug development is the measurement of molecular parameters derived from ligand-receptor interaction, which guides therapeutic windows definition. Over the last decades, radioligand binding has provided valuable contributions in this field as key method for such purposes. However, its limitations spurred the development of more exquisite techniques for determining such parameters. For instance, safety risks related to radioactivity waste, expensive and controlled disposal of radioisotopes, radiotracer separation-dependence for affinity analysis, and one-site mathematical models-based fitting of data make radioligand binding a suboptimal approach in providing measures of actual affinity conformations from ligands and G proteincoupled receptors (GPCR). Current advances on high-throughput screening (HTS) assays have markedly extended the options of sparing sensitive ways for monitoring ligand affinity. The advent of the novel bioluminescent donor NanoLuc luciferase (Nluc), engineered from Oplophorus gracilirostris luciferase, allowed fitting bioluminescence resonance energy transfer (BRET) for monitoring ligand binding. Such novel approach named Nluc-based BRET (NanoBRET) binding assay consists of a real-time homogeneous proximity assay that overcomes radioligand binding limitations but ensures the quality in affinity measurements. Here, we cover the main advantages of NanoBRET protocol and the undesirable drawbacks of radioligand binding as molecular methods that span pharmacological toolbox applied to Drug Discovery. Also, we provide a novel perspective for the application of NanoBRET technology in affinity assays for multiple-state binding mechanisms involving oligomerization and/or functional biased selectivity. This new angle was proposed based on specific biophysical criteria required for the real-time homogeneity assigned to the proximity NanoBRET protocol., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The important role played by aryl hydrocarbon receptor activation in the pathophysiology of atherosclerosis induced by cigarette smoke exposure has spurred the clinical interest in the development of aryl hydrocarbon receptor antagonists with atheroprotective efficacy. A few aryl hydrocarbon receptor antagonists were developed but the lack of structural information regarding the receptor ligand binding domain resulted in several limitations in the pharmacological properties of these compounds including partial agonism, allosterism, non-selectivity, cytotoxicity and susceptibility to bioactivation. These limitations make the progress of preclinical and clinical assays with the available aryl hydrocarbon receptor antagonists difficult. There is a great interest in developing pure, competitive, selective, nontoxic and resistant to bioactivation aryl hydrocarbon receptor antagonists. Current technology permits the development of pharmacologically ideal antagonists based on the chemical features of the aryl hydrocarbon receptor ligand binding domain. According to these characteristics, chlorinated derivatives of trans-stilbene meta-substituted with electrophilic aromatic directing groups would be effective prototypes for pure, competitive, selective, nontoxic and resistant to bioactivation antagonists for such receptor., (Copyright © 2015 Elsevier B.V. All rights reserved.)

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis., (Copyright © 2015 Elsevier B.V. All rights reserved.)