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1.
Comput Biol Med ; 137: 104808, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34478925

RESUMO

Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. This evidence provides a solid ground for ongoing research aimed at identifying isoform-selective inhibitors. Among the isoforms, HDAC1 have particularly gained increased attention as a preferred target for the design of selective HDACIs. Accordingly, in this paper, we have developed a reliable virtual screening process, combining different ligand- and structure-based methods, to identify novel benzamide-based analogs with potential HDAC1 inhibitory activity. For this purpose, a focused library of 736,160 compounds from PubChem database was first compiled based on 80% structural similarity with four known benzamide-based HDAC1 inhibitors, Mocetinostat, Entinostat, Tacedinaline, and Chidamide. Our inclusive in-house 3D-QSAR model, derived from pharmacophore-based alignment, was then employed as a 3D-query to discriminate hits with the highest predicted HDAC1 inhibitory activity. The selected hits were subjected to subsequent structure-based approaches (induced-fit docking (IFD), MM-GBSA calculations and molecular dynamics (MD) simulation) to retrieve potential compounds with the highest binding affinity for HDAC1 active site. Additionally, in silico ADMET properties and PAINS filtration were also considered for selecting an enriched set of the best drug-like molecules. Finally, six top-ranked hit molecules, CID_38265326, CID_56064109, CID_8136932, CID_55802151, CID_133901641 and CID_18150975 were identified to expose the best stability profiles and binding mode in the HDAC1 active site. The IFD and MD results cooperatively confirmed the interactions of the promising selected hits with critical residues within HDAC1 active site. In summary, the presented computational approach can provide a set of guidelines for the further development of improved benzamide-based derivatives targeting HDAC1 isoform.


Assuntos
Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Inibidores de Histona Desacetilases/farmacologia , Ligantes , Simulação de Acoplamento Molecular
2.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371842

RESUMO

The aim of the present study was to investigate the possible protective effects of a garlic hydroalcoholic extract on the burden of oxidative stress and inflammation occurring on mouse heart specimens exposed to E. coli lipopolysaccharide (LPS), which is a well-established inflammatory stimulus. Headspace solid-phase microextraction combined with the gas chromatography-mass spectrometry (HS-SPME/GC-MS) technique was applied to determine the volatile fraction of the garlic powder, and the HS-SPME conditions were optimized for each of the most representative classes of compounds. CIEL*a*b* colorimetric analyses were performed on the powder sample at the time of delivery, after four and after eight months of storage at room temperature in the dark, to evaluate the color changing. Freshly prepared hydroalcoholic extract was also evaluated in its color character. Furthermore, the hydroalcoholic extract was analyzed through GC-MS. The extract was found to be able to significantly inhibit LPS-induced prostaglandin (PG) E2 and 8-iso-PGF2α levels, as well as mRNA levels of cyclooxygenase (COX)-2, interleukin (IL)-6, and nuclear factor-kB (NF-kB), in heart specimens. Concluding, our findings showed that the garlic hydroalcoholic extract exhibited cardioprotective effects on multiple inflammatory and oxidative stress pathways.


Assuntos
Cardiotônicos/farmacologia , Alho/química , Coração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antioxidantes/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Microextração em Fase Sólida
3.
Eur J Pharm Sci ; 165: 105930, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265406

RESUMO

Drugs targeting epigenetic mechanisms are attracting the attention of scientists since it was observed that the modulation of this post-translational apparatus, could help to identify innovative therapeutic strategies. Among the epigenetic druggable targets, the positive modulation of SIRT1 has also been related to significant cardioprotective effects. Unfortunately, actual SIRT1 activators (natural products and synthetic molecules) suffer from several drawbacks, particularly poor pharmacokinetic profiles. Accordingly, in this article we present the development of an integrated screening platform aimed at identifying novel SIRT1 activators with favorable drug-like features as cardioprotective agents. Encompassing several competencies (in silico, medicinal chemistry, and pharmacology), we describe a multidisciplinary approach for rapidly identifying SIRT1 activators and their preliminary pharmacological characterization. In the first step, we virtually screened an in-house chemical library comprising synthetic molecules inspired by nature, against SIRT1 enzyme. To this end, we combined molecular docking-based approach with the estimation of relative ligand binding energy, using the crystal structure of SIRT1 enzyme in complex with resveratrol. Eleven computational hits were identified, synthesized and tested against the isolated enzyme for validating the in silico strategy. Among the tested molecules, five of them behave as SIRT1 enzyme activators. Due to the superior response in activating the enzyme and its favorable calculated physico-chemical properties, compound 8 was further characterized in ex vivo studies on isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R) period. The pharmacological profile of compound 8, suggests that this molecule represents a prototypic SIRT1 activator with satisfactory drug-like profile, paving the way for developing novel epigenetic cardioprotective agents.


Assuntos
Cardiotônicos , Sirtuína 1 , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Simulação de Acoplamento Molecular , Ratos , Resveratrol , Bibliotecas de Moléculas Pequenas
4.
Nutrients ; 13(5)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063322

RESUMO

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.


Assuntos
Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Vitis/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anticoagulantes/farmacologia , Anti-Hipertensivos/farmacologia , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Trombofilia/tratamento farmacológico , Vasodilatadores/farmacologia
5.
Toxicol In Vitro ; 75: 105199, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34097953

RESUMO

In vitro reconstructed human corneal tissue models are closer to in vivo human corneal tissue in term of morphology, biochemical and physiological properties, and represent a valid alternative to animal use for evaluating the pharmacological effects ophthalmic topically applied medical devices. In this experimental work the in vitro reconstructed human corneal tissues have been used for assessing the potential beneficial effects of an innovative ophthalmic formulation containing hyaluronic acid, glycyrrhizin and TS-polysaccharide for the treatment of symptomatic states on the eye surface including dry eye, itching, foreign body sensation and redness due allergic reaction. Corneal tissues have been treated with benzalkonium chloride for 24 h to induce cell damage and then treated with the tested items for 16 h. After the incubation period, tissue viability, TNF-α, IL-6 and MMP-9 have been assessed. Diclofenac has been used as reference anti-inflammatory drug. The novel formulation protected the tissues against benzalkonium chloride damage, while exerted a mild but not significant reduction of the anti-inflammatory mediator TNF-α.

6.
Eur J Med Chem ; 221: 113517, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33984803

RESUMO

Glucocorticoids represent the standard gold treatment of inflammation in asthmatic patients. More recently, H2S has been described to exert positive effect on this disease. Bearing in mind that an improved pharmacological activity and a reduced toxicity can be obtained through hybridization of different molecules, simultaneously modulating multiple targets, we designed and synthesized novel betamethasone 17-valerate and triamcinolone acetonide hybrids with well-known H2S-donor moieties. Synthesized compounds have been evaluated for the potential H2S-releasing profile both in cell-free environment and into the cytosol of bronchial smooth muscle cells (BSMCs). The two hybrids 4b and 5b were investigated by molecular modelling studies and results indicated that the steric accessibility of the isothiocyanate carbon atom can account for their different H2S releasing properties. Furthermore, the most promising derivatives 4b and 5b have been tested for inhibitory effect on mast cell degranulation and for the ability to induce cell membrane hyperpolarization in BSMCs. Significant inhibitory effect on mast cell degranulation was assessed, resulting to reduce ß-hexosaminidase release more efficiently than the corresponding native drugs. Both compounds determined a massive membrane hyperpolarization of BSMCs and proved to be 4-fold more effective compared to reference compound NS1619. These effects represent an enrichment of the pharmacological activity of the native drugs.


Assuntos
Valerato de Betametasona/farmacologia , Brônquios/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Mastócitos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Triancinolona Acetonida/farmacologia , Valerato de Betametasona/química , Brônquios/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Sulfeto de Hidrogênio/química , Mastócitos/metabolismo , Modelos Moleculares , Estrutura Molecular , Miócitos de Músculo Liso/metabolismo , Relação Estrutura-Atividade , Triancinolona Acetonida/química
8.
Artigo em Inglês | MEDLINE | ID: mdl-33557740

RESUMO

Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue.

9.
Bioorg Chem ; 107: 104572, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33418316

RESUMO

Mitochondria play a key role for deciding fate of cells and thus are considered an attractive target for pharmacological interventions focused on containment of myocardial ischemia/reperfusion (I/R) injury. Notably, the activation of mitochondrial potassium (mitoK) channels produces a mild depolarization of mitochondrial membrane, that contributes to reduce the driving force to calcium uptake and prevents the formation of mitochondrial transition membrane pore (MPTP); these events underlie anti-ischemic cardioprotection. However, an ideal mitoK channel opener should possess the fundamental requirement to be delivered at mitochondrial level; therefore, to improve the mitochondrial delivery of a previously characterized spirocyclic benzopyrane F81, new compounds have been developed. The three original triphenylphosphonium (TPP+)-derivatives of F81 (1-3), were evaluated for their cardioprotective activity on both isolated cardiac mitochondria and cardiac H9c2 cell line. Compound 1 was further investigated in an in vivo infarct model. This work confirms that the TPP+ strategy applied to mitoKATP openers could foster mitochondrial delivery and enhance the cardioprotective effects of mitochondrial activators of potassium channels.


Assuntos
Cardiotônicos/síntese química , Canais de Potássio/metabolismo , Animais , Benzopiranos/química , Benzopiranos/metabolismo , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Compostos Organofosforados/química , Canais de Potássio/agonistas , Ratos , Ratos Wistar , Compostos de Espiro/química
10.
Med Res Rev ; 41(4): 1890-1926, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33460162

RESUMO

Growing evidence points out the importance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of cardiovascular diseases (CVDs), including hypertension, myocardial infarct (MI), ischemia, cardiomyopathies (CMs), heart failure (HF), and atherosclerosis. In this regard, intensive research efforts both in humans and in animal models of CVDs are being focused on the characterization of the pathophysiological role of NLRP3 inflammasome signaling in CVDs. In addition, clinical and preclinical evidence is coming to light that the pharmacological blockade of NLRP3 pathways with drugs, including novel chemical entities as well as drugs currently employed in the clinical practice, biologics and phytochemicals, could represent a suitable therapeutic approach for prevention and management of CVDs. On these bases, the present review article provides a comprehensive overview of clinical and preclinical studies about the role of NLRP3 inflammasome in the pathophysiology of CVDs, including hypertension, MI, ischemic injury, CMs, HF and atherosclerosis. In addition, particular attention has been focused on current evidence on the effects of drugs, biologics, and phytochemicals, targeting different steps of inflammasome signaling, in CVDs.

11.
Phytother Res ; 35(4): 1817-1846, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33118671

RESUMO

Type 2 diabetes mellitus (T2DM) represents the most common age-related metabolic disorder, and its management is becoming both a health and economic issue worldwide. Moreover, chronic hyperglycemia represents one of the main risk factors for cardiovascular complications. In the last years, the emerging evidence about the role of the endogenous gasotransmitter hydrogen sulfide (H2 S) in the pathogenesis and progression of T2DM led to increasing interest in the pharmacological modulation of endogenous "H2 S-system". Indeed, H2 S directly contributes to the homeostatic maintenance of blood glucose levels; moreover, it improves impaired angiogenesis and endothelial dysfunction under hyperglycemic conditions. Moreover, H2 S promotes significant antioxidant, anti-inflammatory, and antiapoptotic effects, thus preventing hyperglycemia-induced vascular damage, diabetic nephropathy, and cardiomyopathy. Therefore, H2 S-releasing molecules represent a promising strategy in both clinical management of T2DM and prevention of macro- and micro-vascular complications associated to hyperglycemia. Recently, growing attention has been focused on dietary organosulfur compounds. Among them, garlic polysulfides and isothiocyanates deriving from Brassicaceae have been recognized as H2 S-donors of great pharmacological and nutraceutical interest. Therefore, a better understanding of the therapeutic potential of naturally occurring H2 S-donors may pave the way to a more rational use of these nutraceuticals in the modulation of H2 S homeostasis in T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/prevenção & controle , Sulfeto de Hidrogênio/uso terapêutico , Hiperglicemia/tratamento farmacológico , Humanos , Sulfeto de Hidrogênio/metabolismo
12.
Phytother Res ; 35(4): 1983-1990, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33141966

RESUMO

Obesity is currently considered a major source of morbidity, with dramatic complications on health status and life expectancy. Several studies demonstrated the positive effects of Brassicaceae vegetables on obesity and related diseases, partially attributing these beneficial properties to glucosinolates and their derivatives isothiocyanates. Recently, isothiocyanates have been described as a hydrogen sulfide (H2 S)-releasing moiety, suggesting that H2 S may be at least in part responsible for the beneficial effects of Brassicaceae. In this work, the metabolic effects of an extract obtained from Eruca sativa Mill. seeds (E.S., Brassicaceae), containing high levels of glucoerucin, were evaluated in an experimental model of obesity. Male balb/c mice were fed for 10 weeks with standard (Std) diet or high fat (HF) diet supplemented with E.S. E.S. significantly contained the body weight gain in this obesity model, improving also glucose homeostasis. Interestingly, lower values of white adipose tissue mass and a significant reduction of adipocytes size were also observed. Moreover, E.S. enhanced the adipocytes metabolism, improving the citrate synthase activity and reduced triglyceride levels in mice fed with HF diet. Taken together, these results suggest that E.S. is endowed with an interesting translational and nutraceutical value in the prevention of metabolic disorders, suggesting that H2 S could be a key player.


Assuntos
Brassica/química , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Extratos Vegetais/química , Sementes/química , Animais , Hipoglicemiantes/farmacologia , Masculino , Camundongos
13.
Expert Opin Drug Discov ; 16(4): 411-427, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33256484

RESUMO

Introduction: Preservation of vascular endothelium integrity and maintenance of its full functionality are fundamental aspects in order to avoid both cardiovascular and non-cardiovascular diseases.Areas covered: Although a massive endothelial disruption is a rare condition, caused by acute and uncontrolled inflammatory responses (e.g. the cytokine storm induced by SARS-CoV-2 infection), more frequently the vascular tree is the first target of slowly progressive inflammatory processes which affect the integrity of endothelium and its 'barrier' function, supporting the onset of atherosclerotic plaque and spreading inflammation. This endothelial dysfunction leads to decrease NO biosynthesis, impaired regulation of vascular tone, and increased platelet aggregation. Such chronic subclinic inflammation leads to macrophage infiltration in atherosclerotic lesions. Therefore, many efforts should be addressed to find useful approaches to preserve vascular endothelium from inflammation. In this review, the authors have evaluated the most recent strategies to counteract this pathological condition.Expert opinion: The therapeutic and nutraceutical approaches represent useful tools to treat or prevent different phases of vascular inflammation. In particular, the pharmacological approach should be used in advanced phases characterized by clinical signs of vascular disease, whilst the nutraceutical approach may represent a promising preventive strategy to preserve the integrity of the endothelial tissue.


Assuntos
Aterosclerose/etiologia , COVID-19/complicações , Síndrome da Liberação de Citocina/etiologia , Inflamação/etiologia , SARS-CoV-2 , Humanos
14.
Eur J Med Chem ; 210: 112983, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33168231

RESUMO

This review discusses the rational for further studies of COX-2 inhibitors-NO releaser hybrids (NO-Coxibs) in the pharmacological treatment of the airway inflammation in Cystic Fibrosis (CF). Our research group developed several classes of NO-Coxibs for the pharmacological treatment of arthritis, and among them several compounds showed an outstanding in vivo efficacy and good pharmacokinetic properties. The good antiinflammatory properties displayed by these compounds during the previous screening could, by itself, suggest appropriate candidates for further testing in CF.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Fibrose Cística/tratamento farmacológico , Óxido Nítrico/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Fibrose Cística/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estrutura Molecular , Óxido Nítrico/química
15.
Life Sci ; 267: 118954, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359670

RESUMO

The scientific interest in irisin, a myokine discovered in 2012, has grown exponentially in recent years. Irisin, which is mainly produced in skeletal muscle, influences the browning process of adipose tissue and lipid and energy metabolism. Recent discoveries highlight that the potential of this hormone may have been underestimated. In the first part of this review, reports on irisin structure and molecules involved in its metabolic pathway are shown. Furthermore, data related to unclear aspects are also reported: distribution, different gene expression of its precursors in different tissues, physiological levels of circulating irisin, and pharmacokinetic and pharmacodynamic profile. The second part of this work focuses on exogenous stimuli and pharmacological agents which regulate the metabolic pathway of irisin and its serum concentration. In addition to physical exercise and exposure to low temperatures, which were early recognized as exogenous stimuli able to promote the production of this myokine, preclinical and clinical evidence demonstrates the ability of natural and synthetic molecules to interfere with this metabolic pathway. Current experimental data on irisin cannot dissolve all doubts related to this interesting molecule, but they certainly underline its potential for therapeutic purposes. Thus, identification of new pharmacological tools able to act on the irisin pathway is a challenging issue for biomedical research.


Assuntos
Fibronectinas/metabolismo , Fibronectinas/farmacologia , Fibronectinas/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Energético/fisiologia , Exercício Físico/fisiologia , Humanos , Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo
16.
Methods Protoc ; 3(4)2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33147693

RESUMO

The human eye is a specialized organ with a complex anatomy and physiology, because it is characterized by different cell types with specific physiological functions. Given the complexity of the eye, ocular tissues are finely organized and orchestrated. In the last few years, many in vitro models have been developed in order to meet the 3Rs principle (Replacement, Reduction and Refinement) for eye toxicity testing. This procedure is highly necessary to ensure that the risks associated with ophthalmic products meet appropriate safety criteria. In vitro preclinical testing is now a well-established practice of significant importance for evaluating the efficacy and safety of cosmetic, pharmaceutical, and nutraceutical products. Along with in vitro testing, also computational procedures, herein described, for evaluating the pharmacological profile of potential ocular drug candidates including their toxicity, are in rapid expansion. In this review, the ocular cell types and functionality are described, providing an overview about the scientific challenge for the development of three-dimensional (3D) in vitro models.

17.
Molecules ; 25(22)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198198

RESUMO

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 µM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 µM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 µM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 µM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 µM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.


Assuntos
Antiprotozoários/farmacologia , Arginase/antagonistas & inibidores , Cinamatos/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Animais , Sítios de Ligação , Ácidos Cafeicos/química , Bovinos , Cinamatos/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas Recombinantes/química
18.
Foods ; 9(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019655

RESUMO

A growing body of literature is available about the valorization of food by-products to produce functional foods that combine the basic nutritional impact with the improvement of the health status of consumers. In this context, this study had two main objectives: (i) An innovative multistep extraction process for the production of a refined olive oil enriched with phenolic compounds (PE-ROO) extracted from olive pomace, olive leaves, or grape marc was presented and discussed. (ii) The most promising PE-ROOs were selected and utilized in in vitro and in vivo trials in order to determine their effectiveness in the management of high fat diet-induced-metabolic syndrome and oxidative stress in rats. The best results were obtained when olive leaves were used as source of phenols, regardless of the chemical composition of the solvent utilized for the extraction. Furthermore, while ethanol/hexane mixture was confirmed as a good solvent for the extraction of phenols compounds soluble in oil, the mix ROO/ethanol also showed a good extracting power from olive leaves. Besides, the ROO enriched with phenols extracted from olive leaves revealed an interesting beneficial effect to counteract high fat diet-induced-metabolic disorder and oxidative stress in rats, closely followed by ROO enriched by utilizing grape marc.

20.
Br J Pharmacol ; 177(21): 4931-4941, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32783196

RESUMO

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H2 S levels and severity of COVID-19. Therefore, repurposing of H2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Sulfeto de Hidrogênio/metabolismo , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2
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