Melatonin (MEL) is a pleiotropic indoleamine produced by the pineal gland with a regulatory role ... more Melatonin (MEL) is a pleiotropic indoleamine produced by the pineal gland with a regulatory role of biorhythms, but acts also as powerful antioxidant and anti- inflammatory drug in metabolic diseases [1]. MEL, due to its lipophilic nature, is highly diffusible in any cellular site, comprising the nucleus where it regulates gene transcriptional activity. Nevertheless, its beneficial activity in the liver has been asso- ciated to membrane bound receptor 1 (MT1) that is involved also in pancreatic islets secretion. Sirtuin 1 (Sirt1) is an enzyme with NAD-dependent class III histone dea- cetylase activity, which maintains longevity and proper metabolism in mammalians. Different antioxidant compounds, like resveratrol, have been described as Sirt1 regu- lators but data on melatonin are still limited. So in the present study we extended to the liver the observations on beneficial melatonin role on kidneys of obese leptin- deficient (ob/ob) mice [2], by focusing on the distribution of Sirt...
Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effect... more Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.
A. Stacchiotti , F. Bonomini, A. Lavazza, I. Golic, A. Korac, M. Monsalve, G. Favero and R. Rezza... more A. Stacchiotti , F. Bonomini, A. Lavazza, I. Golic, A. Korac, M. Monsalve, G. Favero and R. Rezzani 1 Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. *alessandra.stacchiotti@unibs.it 2 Virology Unit, Istituto Zooprofilattico Sperimentale, Via A. Bianchi 7/9, 25124 Brescia, Italy 3 Centre for Electron Microscopy, University of Belgrade, Studentski trg 3, 11000 Belgrade, Serbia 4 Instituto de Investigaciones Biomédicas “Alberto Sols” c/o Arturo Duperier 4, 28029 Madrid, Spain
Atherosclerosis is a chronic disease of the arterial wall and a leading cause of death and loss o... more Atherosclerosis is a chronic disease of the arterial wall and a leading cause of death and loss of productive life years worldwide. It is considered a chronic inflam-matory vascular disease characterized of monocyte extravasation into the arterial wall (Libby et al., 2011). Researches into the disease have led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke (Ross, 1999). The last several decades have witnessed aburgeoning growth of understanding of the molecular pathways involved in atherogenesis, atherosclerotic lesion progression and the pathoge-netic mechanisms involved. In this study was evaluated the role of cyclophilin A (CyPA) in early phase of ath-erosclerosis, the beneficial effects of melatonin in vascular remodelling due to its ability to modulate rolling of mononuclear cells and its acting on vascular smooth muscle cell proliferation and neointima formation. In parti...
The increasing incidence of obesity, leading to metabolic complications, is now recognized as a m... more The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The deregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a deregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.
Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakne... more Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h) before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Diffe...
Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates ... more Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human...
Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary cos... more Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut–muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of...
Since the pioneering discovery of heat shock proteins in Drosophila by Ferruccio Ritossa in 1960s... more Since the pioneering discovery of heat shock proteins in Drosophila by Ferruccio Ritossa in 1960s, a long and exciting journey has been undertaken by molecular biologists and researchers worldwide. Not only lower organisms like worms, yeast, amoeba, and flies but also eukaryotes share common cellular response signals to stressful conditions that can arise from the outside but also from the inside. Moreover, extraordinary interplay between nucleus and subcellular organelles, and between different organelles, like mitochondria and the endoplasmic reticulum called mitochondria-associated endoplasmic reticulum membranes (MAMs), are involved in aging and human diseases like obesity, diabetes, inflammation, neurodegeneration, autoimmune diseases, atherosclerosis, and cancer. Actually, we know that to hit abnormal proteostasis and lipid exchanges in the endoplasmic reticulum is crucial to best guide effective therapies or discover new drugs. Indeed, restoration or impairment of endoplasmic...
Melatonin (MEL) is a pleiotropic indoleamine produced by the pineal gland with a regulatory role ... more Melatonin (MEL) is a pleiotropic indoleamine produced by the pineal gland with a regulatory role of biorhythms, but acts also as powerful antioxidant and anti- inflammatory drug in metabolic diseases [1]. MEL, due to its lipophilic nature, is highly diffusible in any cellular site, comprising the nucleus where it regulates gene transcriptional activity. Nevertheless, its beneficial activity in the liver has been asso- ciated to membrane bound receptor 1 (MT1) that is involved also in pancreatic islets secretion. Sirtuin 1 (Sirt1) is an enzyme with NAD-dependent class III histone dea- cetylase activity, which maintains longevity and proper metabolism in mammalians. Different antioxidant compounds, like resveratrol, have been described as Sirt1 regu- lators but data on melatonin are still limited. So in the present study we extended to the liver the observations on beneficial melatonin role on kidneys of obese leptin- deficient (ob/ob) mice [2], by focusing on the distribution of Sirt...
Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effect... more Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.
A. Stacchiotti , F. Bonomini, A. Lavazza, I. Golic, A. Korac, M. Monsalve, G. Favero and R. Rezza... more A. Stacchiotti , F. Bonomini, A. Lavazza, I. Golic, A. Korac, M. Monsalve, G. Favero and R. Rezzani 1 Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. *alessandra.stacchiotti@unibs.it 2 Virology Unit, Istituto Zooprofilattico Sperimentale, Via A. Bianchi 7/9, 25124 Brescia, Italy 3 Centre for Electron Microscopy, University of Belgrade, Studentski trg 3, 11000 Belgrade, Serbia 4 Instituto de Investigaciones Biomédicas “Alberto Sols” c/o Arturo Duperier 4, 28029 Madrid, Spain
Atherosclerosis is a chronic disease of the arterial wall and a leading cause of death and loss o... more Atherosclerosis is a chronic disease of the arterial wall and a leading cause of death and loss of productive life years worldwide. It is considered a chronic inflam-matory vascular disease characterized of monocyte extravasation into the arterial wall (Libby et al., 2011). Researches into the disease have led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke (Ross, 1999). The last several decades have witnessed aburgeoning growth of understanding of the molecular pathways involved in atherogenesis, atherosclerotic lesion progression and the pathoge-netic mechanisms involved. In this study was evaluated the role of cyclophilin A (CyPA) in early phase of ath-erosclerosis, the beneficial effects of melatonin in vascular remodelling due to its ability to modulate rolling of mononuclear cells and its acting on vascular smooth muscle cell proliferation and neointima formation. In parti...
The increasing incidence of obesity, leading to metabolic complications, is now recognized as a m... more The increasing incidence of obesity, leading to metabolic complications, is now recognized as a major public health problem. The adipocytes are not merely energy-storing cells, but they play crucial roles in the development of the so-called metabolic syndrome due to the adipocyte-derived bioactive factors such as adipokines, cytokines, and growth factors. The deregulated production and secretion of adipokines seen in obesity is linked to the pathogenesis of the metabolic disease processes. In this study, we hypothesized that dietary melatonin administration would support an anti-inflammatory response and play an important role in energy metabolism in subcutaneous and visceral adipose tissues of obese mice and so may counteract some of the disruptive effects of obesity. Lean and obese mice (ob/ob) received melatonin or vehicle in drinking water for 8 weeks. Thereafter, they were evaluated for morphologic alteration, inflammatory cell infiltration, and the adipokine patterns in visceral and subcutaneous white fat depots. In obese mice treated with vehicle, we observed a significant increase in fat depots, inflammation, and a deregulation of the adipokine network. In particular, we measured a significant reduction of adiponectin and an increase of tumor necrosis factor α, resistin, and visfatin in adipose tissue deposits. These changes were partially reversed when melatonin was supplemented to obese mice. Melatonin supplementation by regulating inflammatory infiltration ameliorates obesity-induced adipokine alteration, whereas melatonin administration in lean mice was unaffected. Thus, it is likely that melatonin would be provided in supplement form to control some of the disruptive effects on the basis of obesity pathogenic process.
Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakne... more Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 μM CisPt challenged myotubes (4 h–8 h) before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Diffe...
Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates ... more Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human...
Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary cos... more Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut–muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of...
Since the pioneering discovery of heat shock proteins in Drosophila by Ferruccio Ritossa in 1960s... more Since the pioneering discovery of heat shock proteins in Drosophila by Ferruccio Ritossa in 1960s, a long and exciting journey has been undertaken by molecular biologists and researchers worldwide. Not only lower organisms like worms, yeast, amoeba, and flies but also eukaryotes share common cellular response signals to stressful conditions that can arise from the outside but also from the inside. Moreover, extraordinary interplay between nucleus and subcellular organelles, and between different organelles, like mitochondria and the endoplasmic reticulum called mitochondria-associated endoplasmic reticulum membranes (MAMs), are involved in aging and human diseases like obesity, diabetes, inflammation, neurodegeneration, autoimmune diseases, atherosclerosis, and cancer. Actually, we know that to hit abnormal proteostasis and lipid exchanges in the endoplasmic reticulum is crucial to best guide effective therapies or discover new drugs. Indeed, restoration or impairment of endoplasmic...
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