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1.
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
2.
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
3.
Nutrients ; 13(5)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067632

RESUMO

Coenzyme Q10 (CoQ10) is an essential cofactor in oxidative phosphorylation (OXPHOS), present in mitochondria and cell membranes in reduced and oxidized forms. Acting as an energy transfer molecule, it occurs in particularly high levels in the liver, heart, and kidneys. CoQ10 is also an anti-inflammatory and antioxidant agent able to prevent the damage induced by free radicals and the activation of inflammatory signaling pathways. In this context, several studies have shown the possible inverse correlation between the blood levels of CoQ10 and some disease conditions. Interestingly, beyond cardiovascular diseases, CoQ10 is involved also in neuronal and muscular degenerative diseases, in migraine and in cancer; therefore, the supplementation with CoQ10 could represent a viable option to prevent these and in some cases might be used as an adjuvant to conventional treatments. This review is aimed to summarize the clinical applications regarding the use of CoQ10 in migraine, neurodegenerative diseases (including Parkinson and Alzheimer diseases), cancer, or degenerative muscle disorders (such as multiple sclerosis and chronic fatigue syndrome), analyzing its effect on patients' health and quality of life.


Assuntos
Suplementos Nutricionais , Ubiquinona/análogos & derivados , Disponibilidade Biológica , Humanos , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/terapia , Neoplasias/sangue , Neoplasias/terapia , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/terapia , Doenças Neuromusculares/sangue , Doenças Neuromusculares/terapia , Qualidade de Vida , Ubiquinona/uso terapêutico
5.
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
6.
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
7.
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
8.
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.

9.
Nutrients ; 12(6)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471156

RESUMO

: Recently the use of food by-products as natural sources of biologically active substances has been extensively investigated especially for the development of functional foods fortified with natural antioxidants. Due to their content of bioactive compounds, such as carotenoids, flavonoids and limonoids, citrus peels could be suitable to formulate enriched olive oils able to boost healthy nutrition. The aim of this study was: (i) to determine the compositional and sensory profiles of citrus olive oil; and (ii) to evaluate its nutraceutical properties in rats with high fat diet-induced metabolic syndrome and oxidative stress. The results obtained show the potential of using citrus peels as a source of bioactive compounds to improve the sensory profile as well as the phytochemical composition of olive oil. We demonstrated that the production system of Citrus x aurantium olive oil and Citrus limon olive oil improves its organoleptic properties without altering its beneficial effects, which, like control extra virgin olive oil, showed protective effects relating to glucose and serum lipid levels, metabolic activity of adipocytes, myocardial tissue functionality, oxidative stress markers and endothelial function at blood vessel level.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Citrus/química , Suplementos Nutricionais , Azeite de Oliva/farmacologia , Extratos Vegetais/farmacologia , Óleos Vegetais/farmacologia , Tecido Adiposo , Adulto , Animais , Antioxidantes/farmacologia , Biomarcadores , Carotenoides/farmacologia , Feminino , Flavonoides/farmacologia , Humanos , Limoninas/farmacologia , Masculino , Síndrome Metabólica , Pessoa de Meia-Idade , Azeite de Oliva/química , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Ratos , Adulto Jovem
10.
Int J Mol Sci ; 21(10)2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32429301

RESUMO

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aß, tau proteins, α-synuclein and IL-1ß were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aß on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1ß, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aß promoted IL-1ß release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aß decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Colo/patologia , Colo/fisiopatologia , Motilidade Gastrointestinal , Inflamação/patologia , Proteínas do Tecido Nervoso/metabolismo , Sintomas Prodrômicos , Peptídeos beta-Amiloides/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Claudina-1/metabolismo , Cognição , Eosinófilos/patologia , Fezes , Comportamento Alimentar , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Mucosa Intestinal/patologia , Camundongos , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Agregados Proteicos , Células THP-1 , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
11.
Oxid Med Cell Longev ; 2020: 4650207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047577

RESUMO

Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through in vitro assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through in silico studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-α and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.


Assuntos
Envelhecimento/fisiologia , Antioxidantes/uso terapêutico , Flavanonas/uso terapêutico , Miocárdio/patologia , Sirtuína 1/metabolismo , Animais , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Citrus , Citoproteção , Modelos Animais de Doenças , Humanos , Interleucina-6/metabolismo , Camundongos , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
Nutrients ; 11(10)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618877

RESUMO

Osteoporosis, a systemic skeleton disease, can be prevented by increasing calcium levels in serum via administration of calcium salts. However, traditional calcium-based formulations have not appeared to be effective, hence the purpose of the present work has been to prepare and test in vitro/vivo a formulation able to gradually release calcium during transit over the GI tract, thus increasing bioavailability and reducing daily dose, and hence, side effects. Calcium controlled-release granules based on zeolite and Precirol® were prepared. In the best case, represented by granules sized 1.2 mm, containing 20% Precirol®, 19% zeolite, 60% calcium (granule), the release lasted ≈6 h. The release is controlled by diffusion of calcium ions through the aqueous channels forming within granules, once these come into contact with physiological fluids. Such a diffusion is hindered by the interaction of calcium ions with the negatively charged surface of the zeolite. Ovariectomy was used to make rats osteopenic. For in vivo studies, rats were divided into the following groups. Sham: not treated; ova: ovariectomized (ova); CaCl2 1.0 g: ova, treated with 1.0 g/die Ca2+; CaCl2 0.5 g: ova, treated with 0.5 g/die Ca2+; granule 1.0 g, or granule 0.5 g: ova, treated with granules equivalent to 1.0 g/die or 0.5 g/die Ca2+ in humans. Ca2+ amounts in femur bone and bone marrow, femur mechanical characteristics, and femur medullary canalicule diameter were measured and the same efficacy rank order was obtained: ova < CaCl2 0.5 g < CaCl2 1.0 g < granule 0.5 g ≈ granule 1.0 g ≈ sham. The results show promise of an effective prevention of osteoporosis, based on a controlled-rate administration of a calcium dose half that administered by the current therapy, with reduced side effects.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Remodelação Óssea/efeitos dos fármacos , Cloreto de Cálcio/administração & dosagem , Diglicerídeos/administração & dosagem , Fêmur/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Zeolitas/administração & dosagem , Administração Oral , Animais , Biomarcadores/sangue , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/metabolismo , Cloreto de Cálcio/química , Cloreto de Cálcio/metabolismo , Preparações de Ação Retardada , Diglicerídeos/química , Modelos Animais de Doenças , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Fêmur/metabolismo , Fêmur/fisiopatologia , Humanos , Osteocalcina/sangue , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia , Tamanho da Partícula , Ratos Wistar , Zeolitas/química
13.
Nutrients ; 11(9)2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438562

RESUMO

Cardiovascular diseases represent the principal cause of morbidity and mortality worldwide. It is well-known that oxidative stress and inflammatory processes are strongly implicated in their pathogenesis; therefore, anti-oxidant and anti-inflammatory agents can represent effective tools. In recent years a large number of scientific reports have pointed out the nutraceutical and nutritional value of extra virgin olive oils (EVOO), strongholds of the Mediterranean diet, endowed with a high nutritional quality and defined as functional foods. In regard to EVOO, it is a food composed of a major saponifiable fraction, represented by oleic acid, and a minor unsaponifiable fraction, including a high number of vitamins, polyphenols, and squalene. Several reports suggest that the beneficial effects of EVOO are linked to the minor components, but recently, further studies have shed light on the health effects of the fatty fraction and the other constituents of the unsaponifiable fraction. In the first part of this review, an analysis of the clinical and preclinical evidence of the cardiovascular beneficial effects of each constituent is carried out. The second part of this review is dedicated to the main operating conditions during production and/or storage that can directly influence the shelf life of olive oil in terms of both nutraceutical properties and sensory quality.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Suplementos Nutricionais/análise , Azeite de Oliva/química , Azeite de Oliva/farmacologia , Humanos
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