Alessandra Stacchiotti | University of Brescia (original) (raw)

Papers by Alessandra Stacchiotti

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...

Resveratrol - Adding Life to Years, Not Adding Years to Life, 2019

Reduced calorie intake is a religious and medical practice known since very old times, but its di... more Reduced calorie intake is a religious and medical practice known since very old times, but its direct influence on life span in all organisms, included humans, has been demonstrated in the modern era. Not only periodic fasting, but also natural or synthetic compounds that mimic this phenomenon are growing to slow aging and the onset of chronic morbidities. Resveratrol (RSV), a plant polyphenol, is an elixir of longevity for simple organisms and preclinical rodent models even if a beneficial role in humans is still debated. Its main rejuvenating mechanism copes with the activation of specific longevity genes called sirtuins. Among seven known mammalian sirtuins, sirtuin 1 is the most studied. This pleiotropic nicotinamide adenine dinucleotide (NAD)-based deacetylase maintains longevity by removing acetyl group in nuclear histones, transcription factors, and other DNA repairing proteins. Actually, an exciting challenge is to discover and test novel sirtuin 1 activators to extend life span and to treat age-associated disabilities. This chapter updates on the antiaging effect of RSV and sirtuin 1 activators in experimental animals and in humans. Finally, pros and cons on RSV analogues and sirtuin 1 activators tested in preclinical and clinical trials to hamper neurological deficit, cardiovascular complications, diabetes, bone and muscle deterioration, and cancer are discussed.

Toxicology Letters, 2010

S235 tein metabolism, is primarily excreted across the gill membranes. When the excretion of ammo... more S235 tein metabolism, is primarily excreted across the gill membranes. When the excretion of ammonia is impaired, the serum ammonia concentration increases. In the present study, an effect of elevated serum ammonia concentration on histopathology of gills and other tissues of common carp (Cyprinus carpio L.) was investigated. The fish were subjected to: (1) high water pH (10), (2) increased ammonia concentration at high water pH (10), (3) high water pH (10) and simultaneously per os administration of ammonium salt (NH 4 Cl) mixed into the amyloidal vehicle, and (4) combination of exposure and per os administration of ammonia. In all the treatment groups, significant elevation of serum ammonia was observed after 24 h compared to control, which was kept in ammonia-free water at pH of 6.3 and per os administrated by ammonia-free amyloidal vehicle. The serum ammonia concentrations were as follows: control-282 ± 21 mol l −1 , group 1-948 ± 66 mol l −1 , group 2-1098 ± 73 mol l −1 , group 3-2965 ± 149 mol l −1 , group 4-4466 ± 233 mol l −1 N-ammonia. All the treatments caused histopathological changes in gills of common carp similar to toxic necrosis, but the severity of these changes was positively correlated with the ammonia concentration in the blood serum. Therefore, the results showed that elevated ammonia concentrations in blood serum and toxic necrosis of carp gills as well can also be caused by high pH of water whereas the effect of pH can be even higher when the fish are fed with diet containing N-substances. Acknowledgements. This study was supported by the grant nos. MSM6007665809, QH82117 and MSM6215712402.

Toxicology, 2009

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

Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, ... more Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, H; Adams, CM; Adams, PD; Adeli, K; Adhihetty, PJ; Adler, SG; Agam, G; Agarwal, R; Aghi, MK; Agnello, M; Agostinis, P; Aguilar, PV; Aguirre-Ghiso, J; Airoldi, EM; Ait-Si-Ali, S; Akematsu, T; Akporiaye, ET; Al-Rubeai, M; Albaiceta, GM; Albanese, C; Albani, D; Albert, ML; Aldudo, J; Algul, H; Alirezaei, M; Alloza, I; Almasan, A; Almonte-Beceril, M; Alnemri, ES; Alonso, C; Altan-Bonnet, N; Altieri, DC; Alvarez, S; Alvarez-Erviti, L; Alves, S; Amadoro, G; Amano, A; Amantini, C; Ambrosio, S; Amelio, I; Amer, AO; Amessou, M; Amon, A; An, Z; Anania, FA; Andersen, SU; Andley, UP; Andreadi, CK; Andrieu-Abadie, N; Anel, A; Ann, DK; Anoopkumar-Dukie, S; Antonioli, M; Aoki, H; Apostolova, N; Aquila, S; Aquilano, K; Araki, K; Arama, E; Aranda, A; Araya, J; Arcaro, A; Arias, E; Arimoto, H; Ariosa, AR; Armstrong, JL; Arnould, T; Arsov, I; Asanuma, K; Askanas, V; Asselin, E; Atarashi, R; Atherton, SS; At...

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...

Biological Trace Element Research, 2016

Italian Journal of Anatomy and Embryology Archivio Italiano Di Anatomia Ed Embriologia, 2010

Heat shock proteins and glucoseregulated proteins represent an extraordinary mechanism of defense... more Heat shock proteins and glucoseregulated proteins represent an extraordinary mechanism of defense induced in the kidney by chemicals or drugs and essential to survive. Here we resume our experience on the presence and regulation of stress proteins into acute and chronic nephro toxic models in rodents and in vitro. In acute renal damage, induced in rats by a single injection of inorganic mercury, stress pro teins enhanced in a dosedependent manner to recover cytoskeleton and mitochondria and maintain nuclear activity. When we pretreated mercury injectedrats with antioxidant melaton in or with bimoclomol, a stress proteinscoinducer, stress proteins expression was modulated together with tubular recovery. Similar data were obtained in ischemiareperfusion in rats treat ed with stannous chloride, that provided cytoprotection stimulating heme oxygenase induc tion. During nephrotoxicity induced by administration of cyclosporine A at therapeutic dos age for 12 months, stress protein overexpression well correlated with oxidative and cell death, but decreased if we counteracted renal damage using antioxidants. In aluminium intoxication through drinking water for 36 months, we detected a timedependent stress response in the rat kidney that was organ specifi c and different from the liver. In vitro studies on rat tubular proximal cells exposed to heavy metals demonstrated that stress protein expression was related to peculiar mechanisms of action of each metal. In conclusion, experimental studies on the renal chaperones can greatly contribute to understand their role, and agents able to modulate the stress response might be considered promising therapeutic tools to reduce nephrotoxicity.

PLOS ONE, 2016

Background Obesity is a common risk factor for non-alcoholic fatty liver disease (NAFLD). Current... more Background Obesity is a common risk factor for non-alcoholic fatty liver disease (NAFLD). Currently, there are no specific treatments against NAFLD. Thus, examining any molecule with potential benefits against this condition emerged melatonin as a molecule that influences metabolic dysfunctions. The aim of this study was to determine whether melatonin would function against NAFDL, studying morphological, ultrastuctural and metabolic markers that characterize the liver of ob/ob mice. Methods Lean and ob/ob mice were supplemented with melatonin in the drinking water for 8 weeks. Histology and stereology were performed to assess hepatic steatosis and glycogen deposition. Ultrastructural features of mitochondria, endoplasmic reticulum (ER) and their juxtapositions were evaluated in livers of all experimental groups. Furthermore, hepatic distribution and expression of markers of ER and mitochondria (calnexin, ATP sintase β, GRP78 and CHOP) and metabolic dysfunction (RPB4, β-catenin) and cellular longevity (SIRT1) were analyzed. Results Melatonin significantly reduced glycemia, identified also by a decrease of hepatic RBP4 expression, reversed macrosteatosis in microsteatosis at the hepatic pericentral zone, enlarged ER-mitochondrial distance and ameliorated the morphology and organization of these organelles in ob/ob mouse liver.

Nutrition Research, 2015

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.

Oxidative Medicine and Cellular Longevity, 2014

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...

Current Trends in Atherogenesis, 2013

tension both in animal models and in clinical patients [11,12]. Remarkably this event is early de... more tension both in animal models and in clinical patients [11,12]. Remarkably this event is early detectable in the endothelial cells [13], sometimes concurrent with other well-known atherogenic processes, like inflammation, oxidative damage and endothelial cell death. Nevertheless considering the focal distribution of plaques and their cumulative progression during the whole lifespan [14], it is mandatory to consider the role of ER stress signaling in the circulatory bed, in order to maintain the proper ER function, so preventing or reducing the progression into irreversible cardiovascular dysfunctions, such as atherosclerosis, hypertension and ischemic heart disease [15-17]. We firmly believe that focusing integrated basic and applied research on ER stress in the artery tree and in the heart might open new avenues in the treatment and management of invalidating cardiovascular complications [18,19]. 2. The endothelium and the endoplasmic reticulum homeostasis According to the most accredited theory that indicates inflammation as the first pathogenic mechanism of atherosclerosis, the endothelium is really the crucial target of circulating molecules or cells and constitutes the main entrance for LDL during the initial step of asymptomatic artery wall changes that end into plaques or atheromata and their dramatic clinical evolution [20-23]. Recent studies have outlined that in atherosusceptible sites in the artery tree, endothelial cells acquire a proinflammatory phenotype which is permissive in the plaque development by expressing pro-inflammatory sensors such as Toll-like receptors (TLRs), that in turn attract leukocytes adhesion in the intima layer. Mainly TLR 2 and TLR4 are active in mouse in the progression of atherosclerosis and their signals stimulate a downstream adaptor molecule, called Toll/IL-1 receptor domain-related adaptor protein that induces interferon or TRIF. Indeed also in human vascular tree, by immunostaining and mRNA survey TLR2 and TLR4 have been well characterized in selected sites, including the aorta, subclavia, carotid, mesenteric, iliac and temporal arteries [24]. Nevertheless an important concept to remind here is that the relationship between the vascular endothelium and the blood is not only "passive" in receiving inflammatory or metabolic stimuli, but instead "active", with pleiotropic activities like the secretion of regulatory factors for cholesterol and lipid homeostasis, platelets recruitment, and the adaptation to local changes of blood flow and pressure [25,26]. Moreover the artery wall, in particular in healthy resistance arteries, is not a static but a dynamic and plastic structure, able to remodel its diameter and structure, adapting to rapid changes in the systemic pressure [27]. Indeed also artery geometry directly influences the athero-susceptibility and the distribution of mechanical forces associated to blood flux, that impair the endothelium [25,28,29]. In particular during unstable hemodynamic flux and changes in blood direction, mainly in arterial branches and bifurcations, it is particularly evident the heterogeneity of endothelial

Transplantation Proceedings, 2007

Frontiers in Cell and Developmental Biology

International Journal of Molecular Sciences

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...

Cells

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...

Cells

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...

Resveratrol - Adding Life to Years, Not Adding Years to Life, 2019

Reduced calorie intake is a religious and medical practice known since very old times, but its di... more Reduced calorie intake is a religious and medical practice known since very old times, but its direct influence on life span in all organisms, included humans, has been demonstrated in the modern era. Not only periodic fasting, but also natural or synthetic compounds that mimic this phenomenon are growing to slow aging and the onset of chronic morbidities. Resveratrol (RSV), a plant polyphenol, is an elixir of longevity for simple organisms and preclinical rodent models even if a beneficial role in humans is still debated. Its main rejuvenating mechanism copes with the activation of specific longevity genes called sirtuins. Among seven known mammalian sirtuins, sirtuin 1 is the most studied. This pleiotropic nicotinamide adenine dinucleotide (NAD)-based deacetylase maintains longevity by removing acetyl group in nuclear histones, transcription factors, and other DNA repairing proteins. Actually, an exciting challenge is to discover and test novel sirtuin 1 activators to extend life span and to treat age-associated disabilities. This chapter updates on the antiaging effect of RSV and sirtuin 1 activators in experimental animals and in humans. Finally, pros and cons on RSV analogues and sirtuin 1 activators tested in preclinical and clinical trials to hamper neurological deficit, cardiovascular complications, diabetes, bone and muscle deterioration, and cancer are discussed.

Toxicology Letters, 2010

S235 tein metabolism, is primarily excreted across the gill membranes. When the excretion of ammo... more S235 tein metabolism, is primarily excreted across the gill membranes. When the excretion of ammonia is impaired, the serum ammonia concentration increases. In the present study, an effect of elevated serum ammonia concentration on histopathology of gills and other tissues of common carp (Cyprinus carpio L.) was investigated. The fish were subjected to: (1) high water pH (10), (2) increased ammonia concentration at high water pH (10), (3) high water pH (10) and simultaneously per os administration of ammonium salt (NH 4 Cl) mixed into the amyloidal vehicle, and (4) combination of exposure and per os administration of ammonia. In all the treatment groups, significant elevation of serum ammonia was observed after 24 h compared to control, which was kept in ammonia-free water at pH of 6.3 and per os administrated by ammonia-free amyloidal vehicle. The serum ammonia concentrations were as follows: control-282 ± 21 mol l −1 , group 1-948 ± 66 mol l −1 , group 2-1098 ± 73 mol l −1 , group 3-2965 ± 149 mol l −1 , group 4-4466 ± 233 mol l −1 N-ammonia. All the treatments caused histopathological changes in gills of common carp similar to toxic necrosis, but the severity of these changes was positively correlated with the ammonia concentration in the blood serum. Therefore, the results showed that elevated ammonia concentrations in blood serum and toxic necrosis of carp gills as well can also be caused by high pH of water whereas the effect of pH can be even higher when the fish are fed with diet containing N-substances. Acknowledgements. This study was supported by the grant nos. MSM6007665809, QH82117 and MSM6215712402.

Toxicology, 2009

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

Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, ... more Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, H; Adams, CM; Adams, PD; Adeli, K; Adhihetty, PJ; Adler, SG; Agam, G; Agarwal, R; Aghi, MK; Agnello, M; Agostinis, P; Aguilar, PV; Aguirre-Ghiso, J; Airoldi, EM; Ait-Si-Ali, S; Akematsu, T; Akporiaye, ET; Al-Rubeai, M; Albaiceta, GM; Albanese, C; Albani, D; Albert, ML; Aldudo, J; Algul, H; Alirezaei, M; Alloza, I; Almasan, A; Almonte-Beceril, M; Alnemri, ES; Alonso, C; Altan-Bonnet, N; Altieri, DC; Alvarez, S; Alvarez-Erviti, L; Alves, S; Amadoro, G; Amano, A; Amantini, C; Ambrosio, S; Amelio, I; Amer, AO; Amessou, M; Amon, A; An, Z; Anania, FA; Andersen, SU; Andley, UP; Andreadi, CK; Andrieu-Abadie, N; Anel, A; Ann, DK; Anoopkumar-Dukie, S; Antonioli, M; Aoki, H; Apostolova, N; Aquila, S; Aquilano, K; Araki, K; Arama, E; Aranda, A; Araya, J; Arcaro, A; Arias, E; Arimoto, H; Ariosa, AR; Armstrong, JL; Arnould, T; Arsov, I; Asanuma, K; Askanas, V; Asselin, E; Atarashi, R; Atherton, SS; At...

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...

Biological Trace Element Research, 2016

Italian Journal of Anatomy and Embryology Archivio Italiano Di Anatomia Ed Embriologia, 2010

Heat shock proteins and glucoseregulated proteins represent an extraordinary mechanism of defense... more Heat shock proteins and glucoseregulated proteins represent an extraordinary mechanism of defense induced in the kidney by chemicals or drugs and essential to survive. Here we resume our experience on the presence and regulation of stress proteins into acute and chronic nephro toxic models in rodents and in vitro. In acute renal damage, induced in rats by a single injection of inorganic mercury, stress pro teins enhanced in a dosedependent manner to recover cytoskeleton and mitochondria and maintain nuclear activity. When we pretreated mercury injectedrats with antioxidant melaton in or with bimoclomol, a stress proteinscoinducer, stress proteins expression was modulated together with tubular recovery. Similar data were obtained in ischemiareperfusion in rats treat ed with stannous chloride, that provided cytoprotection stimulating heme oxygenase induc tion. During nephrotoxicity induced by administration of cyclosporine A at therapeutic dos age for 12 months, stress protein overexpression well correlated with oxidative and cell death, but decreased if we counteracted renal damage using antioxidants. In aluminium intoxication through drinking water for 36 months, we detected a timedependent stress response in the rat kidney that was organ specifi c and different from the liver. In vitro studies on rat tubular proximal cells exposed to heavy metals demonstrated that stress protein expression was related to peculiar mechanisms of action of each metal. In conclusion, experimental studies on the renal chaperones can greatly contribute to understand their role, and agents able to modulate the stress response might be considered promising therapeutic tools to reduce nephrotoxicity.

PLOS ONE, 2016

Background Obesity is a common risk factor for non-alcoholic fatty liver disease (NAFLD). Current... more Background Obesity is a common risk factor for non-alcoholic fatty liver disease (NAFLD). Currently, there are no specific treatments against NAFLD. Thus, examining any molecule with potential benefits against this condition emerged melatonin as a molecule that influences metabolic dysfunctions. The aim of this study was to determine whether melatonin would function against NAFDL, studying morphological, ultrastuctural and metabolic markers that characterize the liver of ob/ob mice. Methods Lean and ob/ob mice were supplemented with melatonin in the drinking water for 8 weeks. Histology and stereology were performed to assess hepatic steatosis and glycogen deposition. Ultrastructural features of mitochondria, endoplasmic reticulum (ER) and their juxtapositions were evaluated in livers of all experimental groups. Furthermore, hepatic distribution and expression of markers of ER and mitochondria (calnexin, ATP sintase β, GRP78 and CHOP) and metabolic dysfunction (RPB4, β-catenin) and cellular longevity (SIRT1) were analyzed. Results Melatonin significantly reduced glycemia, identified also by a decrease of hepatic RBP4 expression, reversed macrosteatosis in microsteatosis at the hepatic pericentral zone, enlarged ER-mitochondrial distance and ameliorated the morphology and organization of these organelles in ob/ob mouse liver.

Nutrition Research, 2015

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.

Oxidative Medicine and Cellular Longevity, 2014

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...

Current Trends in Atherogenesis, 2013

tension both in animal models and in clinical patients [11,12]. Remarkably this event is early de... more tension both in animal models and in clinical patients [11,12]. Remarkably this event is early detectable in the endothelial cells [13], sometimes concurrent with other well-known atherogenic processes, like inflammation, oxidative damage and endothelial cell death. Nevertheless considering the focal distribution of plaques and their cumulative progression during the whole lifespan [14], it is mandatory to consider the role of ER stress signaling in the circulatory bed, in order to maintain the proper ER function, so preventing or reducing the progression into irreversible cardiovascular dysfunctions, such as atherosclerosis, hypertension and ischemic heart disease [15-17]. We firmly believe that focusing integrated basic and applied research on ER stress in the artery tree and in the heart might open new avenues in the treatment and management of invalidating cardiovascular complications [18,19]. 2. The endothelium and the endoplasmic reticulum homeostasis According to the most accredited theory that indicates inflammation as the first pathogenic mechanism of atherosclerosis, the endothelium is really the crucial target of circulating molecules or cells and constitutes the main entrance for LDL during the initial step of asymptomatic artery wall changes that end into plaques or atheromata and their dramatic clinical evolution [20-23]. Recent studies have outlined that in atherosusceptible sites in the artery tree, endothelial cells acquire a proinflammatory phenotype which is permissive in the plaque development by expressing pro-inflammatory sensors such as Toll-like receptors (TLRs), that in turn attract leukocytes adhesion in the intima layer. Mainly TLR 2 and TLR4 are active in mouse in the progression of atherosclerosis and their signals stimulate a downstream adaptor molecule, called Toll/IL-1 receptor domain-related adaptor protein that induces interferon or TRIF. Indeed also in human vascular tree, by immunostaining and mRNA survey TLR2 and TLR4 have been well characterized in selected sites, including the aorta, subclavia, carotid, mesenteric, iliac and temporal arteries [24]. Nevertheless an important concept to remind here is that the relationship between the vascular endothelium and the blood is not only "passive" in receiving inflammatory or metabolic stimuli, but instead "active", with pleiotropic activities like the secretion of regulatory factors for cholesterol and lipid homeostasis, platelets recruitment, and the adaptation to local changes of blood flow and pressure [25,26]. Moreover the artery wall, in particular in healthy resistance arteries, is not a static but a dynamic and plastic structure, able to remodel its diameter and structure, adapting to rapid changes in the systemic pressure [27]. Indeed also artery geometry directly influences the athero-susceptibility and the distribution of mechanical forces associated to blood flux, that impair the endothelium [25,28,29]. In particular during unstable hemodynamic flux and changes in blood direction, mainly in arterial branches and bifurcations, it is particularly evident the heterogeneity of endothelial

Transplantation Proceedings, 2007

Frontiers in Cell and Developmental Biology

International Journal of Molecular Sciences

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...

Cells

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...

Cells

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...