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1.
Nutrients ; 13(11)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34836326

RESUMO

Doxorubicin (Doxo) is a widely used antineoplastic drug which often induces cardiomyopathy, leading to congestive heart failure through the intramyocardial production of reactive oxygen species (ROS). Icariin (Ica) is a flavonoid isolated from Epimedii Herba (Berberidaceae). Some reports on the pharmacological activity of Ica explained its antioxidant and cardioprotective effects. The aim of our study was to assess the protective activities of Ica against Doxo-detrimental effects on rat heart-tissue derived embryonic cardiac myoblasts (H9c2 cells) and to identify, at least in part, the molecular mechanisms involved. Our results showed that pretreatment of H9c2 cells with 1 µM and 5 µM of Ica, prior to Doxo exposure, resulted in an improvement in cell viability, a reduction in ROS generation, the prevention of mitochondrial dysfunction and mPTP opening. Furthermore, for the first time, we identified one feasible molecular mechanism through which Ica could exerts its cardioprotective effects. Indeed, our data showed a significant reduction in Caveolin-1(Cav-1) expression levels and a specific inhibitory effect on phosphodiesterase 5 (PDE5a) activity, improving mitochondrial function compared to Doxo-treated cells. Besides, Ica significantly prevented apoptotic cell death and downregulated the main pro-autophagic marker Beclin-1 and LC3 lipidation rate, restoring physiological levels of activation of the protective autophagic process. These results suggest that Ica might have beneficial cardioprotective effects in attenuating cardiotoxicity in patients requiring anthracycline chemotherapy through the inhibition of oxidative stress and, in particular, through the modulation of Cav-1 expression levels and the involvement of PDE5a activity, thereby leading to cardiac cell survival.

2.
Nutrients ; 13(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34371986

RESUMO

Cardiovascular disease is the leading cause of death and disability in the Western world. In order to safeguard the structure and the functionality of the myocardium, it is extremely important to adequately support the cardiomyocytes. Two cellular organelles of cardiomyocytes are essential for cell survival and to ensure proper functioning of the myocardium: mitochondria and the sarcoplasmic reticulum. Mitochondria are responsible for the energy metabolism of the myocardium, and regulate the processes that can lead to cell death. The sarcoplasmic reticulum preserves the physiological concentration of the calcium ion, and triggers processes to protect the structural and functional integrity of the proteins. The alterations of these organelles can damage myocardial functioning. A proper nutritional balance regarding the intake of macronutrients and micronutrients leads to a significant improvement in the symptoms and consequences of heart disease. In particular, the Mediterranean diet, characterized by a high consumption of plant-based foods, small quantities of red meat, and high quantities of olive oil, reduces and improves the pathological condition of patients with heart failure. In addition, nutritional support and nutraceutical supplementation in patients who develop heart failure can contribute to the protection of the failing myocardium. Since polyphenols have numerous beneficial properties, including anti-inflammatory and antioxidant properties, this review gathers what is known about the beneficial effects of polyphenol-rich bergamot fruit on the cardiovascular system. In particular, the role of bergamot polyphenols in mitochondrial and sarcoplasmic dysfunctions in diabetic cardiomyopathy is reported.


Assuntos
Cardiomiopatias Diabéticas/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Óleos Vegetais/farmacologia , Polifenóis/farmacologia , Retículo Sarcoplasmático/efeitos dos fármacos , Animais , Suplementos Nutricionais , Humanos , Miocárdio/metabolismo , Azeite de Oliva/farmacologia
3.
Int J Mol Sci ; 22(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805912

RESUMO

The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Suplementos Nutricionais , Inflamação/metabolismo , Obesidade/metabolismo , Termogênese , Adipogenia , Tecido Adiposo/metabolismo , Animais , Curcumina/química , Dieta , Retículo Endoplasmático/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Resistência à Insulina , Intestinos/química , Lipídeos/química , Macrófagos/metabolismo , Polifenóis/química , Resveratrol/farmacologia , Transdução de Sinais
4.
Antioxidants (Basel) ; 10(3)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807637

RESUMO

Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.

5.
J Cardiovasc Med (Hagerstown) ; 22(4): 268-278, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33633042

RESUMO

AIMS: Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes. METHODS: For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot. RESULTS: Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia. CONCLUSION: Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.

6.
Pharmacol Res ; 165: 105427, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453372

RESUMO

Skeletal muscles and bone tissue form the musculoskeletal apparatus, a complex system essential for the voluntary movement. The loss of muscle mass and muscle strength is often associated with a loss of bone mass, in a "hazardous duet" which implies the co-existence of sarcopenia-osteoporosis and exposes patients to a deterioration in quality of life and increased mortality. From the mechanostat theory to the recent definition of the osteosarcopenia syndrome, many aspects of muscle-bone interaction have been investigated in recent decades. The mechanical interaction is now accepted, considering the close anatomical relationship between the two tissues, however, much remains to be discovered regarding the biochemical muscle-bone interaction. Skeletal muscle has been defined as an endocrine organ capable of exerting an action on other tissues. Myokines, bioactive polypeptides released by the muscle, could represent the encrypted message in the communication between muscle and bone. These two tissues have a reciprocal influence on their metabolisms and respond in a similar way to the multiple external factors. The aim of this review is to stimulate the understanding of the encrypted language between muscle and bone, highlighting the role of catabolic pathways and oxidative stress in the musculoskeletal apparatus to elucidate the shared mechanisms and the similarity of response to the same stimuli by different tissues. Our understanding of muscle-bone interactions it could be useful to identify and develop new strategies to treat musculoskeletal diseases, together with pharmacological, nutritional and exercise-based approaches, which are already in use for the treatment of these pathologies.

7.
Nutrients ; 13(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477916

RESUMO

Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.


Assuntos
Doenças Cardiovasculares/terapia , Miócitos Cardíacos/fisiologia , Extratos Vegetais/farmacologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Diferenciação Celular , Suplementos Nutricionais , Humanos , Miócitos Cardíacos/citologia , Regeneração , Células-Tronco/citologia
8.
Pharmacol Res ; 163: 105215, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007421

RESUMO

Cholesterol homeostasis is a highly regulated process in human body because of its several functions underlying the biology of cell membranes, the synthesis of all steroid hormones and bile acids and the need of trafficking lipids destined to cell metabolism. In particular, it has been recognized that peripheral and central nervous system cholesterol metabolism are separated by the blood brain barrier and are regulated independently; indeed, peripherally, it depends on the balance between dietary intake and hepatic synthesis on one hand and its degradation on the other, whereas in central nervous system it is synthetized de novo to ensure brain physiology. In view of this complex metabolism and its relevant functions in mammalian, impaired levels of cholesterol can induce severe cellular dysfunction leading to metabolic, cardiovascular and neurodegenerative diseases. The aim of this review is to clarify the role of cholesterol homeostasis in health and disease highlighting new intriguing aspects of the cross talk between its central and peripheral metabolism.

9.
Molecules ; 25(23)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297504

RESUMO

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Benzoatos/farmacologia , Cicloeptanos/farmacologia , Ferula/química , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Benzoatos/química , Benzoatos/uso terapêutico , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Cicloeptanos/química , Cicloeptanos/uso terapêutico , Relação Dose-Resposta a Droga , Transporte de Elétrons/efeitos dos fármacos , Terapia de Reposição Hormonal , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Fitoestrógenos/química , Fitoestrógenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico
10.
Int J Mol Sci ; 21(20)2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050121

RESUMO

Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a "frail" myocardial tissue unable to adapt itself to stress.


Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Proteínas de Transporte/genética , Suscetibilidade a Doenças , Hiperglicemia/complicações , Metaloproteinase 2 da Matriz/metabolismo , Receptores de GABA-A/genética , Canal de Ânion 1 Dependente de Voltagem/genética , Animais , Biomarcadores , Cardiomiopatias/fisiopatologia , Proteínas de Transporte/metabolismo , Isoenzimas , Modelos Biológicos , Contração Miocárdica , NADPH Oxidases/metabolismo , Ligação Proteica , Transporte Proteico , Ratos , Receptores de GABA-A/metabolismo , Disfunção Ventricular/etiologia , Disfunção Ventricular/metabolismo , Disfunção Ventricular/fisiopatologia , Canal de Ânion 1 Dependente de Voltagem/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-32740426

RESUMO

AIMS: Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes. METHODS: For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot. RESULTS: Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia. CONCLUSION: Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.

12.
Biomedicines ; 8(9)2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854210

RESUMO

Polyunsaturated fatty acids (n-3 PUFAs) are long-chain polyunsaturated fatty acids with 18, 20 or 22 carbon atoms, which have been found able to counteract cardiovascular diseases. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in particular, have been found to produce both vaso- and cardio-protective response via modulation of membrane phospholipids thereby improving cardiac mitochondrial functions and energy production. However, antioxidant properties of n-3 PUFAs, along with their anti-inflammatory effect in both blood vessels and cardiac cells, seem to exert beneficial effects in cardiovascular impairment. In fact, dietary supplementation with n-3 PUFAs has been demonstrated to reduce oxidative stress-related mitochondrial dysfunction and endothelial cell apoptosis, an effect occurring via an increased activity of endogenous antioxidant enzymes. On the other hand, n-3 PUFAs have been shown to counteract the release of pro-inflammatory cytokines in both vascular tissues and in the myocardium, thereby restoring vascular reactivity and myocardial performance. Here we summarize the molecular mechanisms underlying the anti-oxidant and anti-inflammatory effect of n-3 PUFAs in vascular and cardiac tissues and their implication in the prevention and treatment of cardiovascular disease.

13.
Nutrients ; 12(5)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455840

RESUMO

Metabolic syndrome (MetS) represents a set of clinical findings that include visceral adiposity, insulin-resistance, high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and hypertension, which is linked to an increased risk of developing type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). The pathogenesis of MetS involves both genetic and acquired factors triggering oxidative stress, cellular dysfunction and systemic inflammation process mainly responsible for the pathophysiological mechanism. In recent years, MetS has gained importance due to the exponential increase in obesity worldwide. However, at present, it remains underdiagnosed and undertreated. The present review will summarize the pathogenesis of MetS and the existing pharmacological therapies currently used and focus attention on the beneficial effects of natural compounds to reduce the risk and progression of MetS. In this regard, emerging evidence suggests a potential protective role of bergamot extracts, in particular bergamot flavonoids, in the management of different features of MetS, due to their pleiotropic anti-oxidative, anti-inflammatory and lipid-lowering effects.


Assuntos
Antioxidantes/farmacologia , Citrus/química , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Obesidade/tratamento farmacológico , Obesidade Abdominal/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico
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