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Introduction
Marco Giorgio currently works at the Department of Biomedical Sciences at the University of Padova. Marco does research in Biochemistry, Molecular Biology, Cell Biology and Genetics.
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Publications
Publications (154)
The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer’s Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD’s ‘main actor’ is thought to be Beta-Hydroxy-butyrate (BHB)...
Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR’s impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, let...
The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of D...
Metastasis represents the deadliest outcome in cancer, leading to the vast majority of cancer-related deaths. Understanding the progression from micro-to macro-metastasis might improve future therapeutic strategies aimed at blocking metastatic disease. However, the difficulty of investigating vital, clinically undetectable, micro-metastases hindere...
Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML) in which the PML/RARα fusion protein exerts oncogenic activities by recruiting repressive complexes to the promoter of specific target genes. Other epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently...
During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments endogenous DNA inducing inflammation by NFκB. The p66ShcA adapto...
Metabolic regulation of cancer cell growth via AMP-activated protein kinase (AMPK) activation is a widely studied strategy for cancer treatment, including leukemias. Recent notions that naturally occurring compounds might have AMPK activity led to the search for nutraceuticals with potential AMPK-stimulating activity. We found that hydroxycitric ac...
Aging is accompanied by the progressive decline in tissue regenerative capacity and functions of resident stem cells (SCs). Underlying mechanisms, however, remain unclear. Here we show that, during chronological aging, self-renewing mitoses of mammary SCs (MaSCs) are preferentially asymmetric and that their progeny divides less frequently, leading...
To detect the epigenetic drift of time passing, we determined the genome-wide distributions of mono- and tri-methylated lysine 4 and acetylated and tri-methylated lysine 27 of histone H3 in the livers of healthy 3, 6 and 12 months old C57BL/6 mice. The comparison of different age profiles of histone H3 marks revealed global redistribution of histon...
Background:
Early-life stress due to poor parental care has been suggested to increase cancer risk, though, so far, no experimental evidence established a link between defective parental behavior and spontaneous tumorigenesis in progeny. Essential maternal behavior is regulated, in particular, by the oxytocin (OT) hormonal circuit, which in turn r...
Background:
Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer's disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD.
Methods:
To investigate histone H3 modifications in AD, we com...
Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs...
Background
The anthocyanin class of flavonoids, including cyanidin-3-glucoside (C3G) present in berries, blood oranges and pigmented cereal crops, are food bioactives with antioxidant and anti-inflammatory action, capable to reduce myocardial ischemia/reperfusion (I/R) injury by unclear mechanism.
Objective
Assessing the value of sporadic benefici...
Background:
Epigenetic signals are fundamental in regulating neuronal functions (Sweatt JD, 2013) and have been proposed as biomarkers of AD (Klein HU et al, 2019). Advances in genomic technologies endorse genome wide studies of the histone code of aging and diseases, including LOAD in animal models or patients (Nativio R et al. 2020). Up to date...
Background:
Women represent the majority of Alzheimer's disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still u...
Aims:
Peripheral artery disease (PAD) is a severe complication of diabetes, characterized by defective traffic of hematopoietic stem/progenitor cells (HSPCs). We examined the hematopoietic versus non-hematopoietic role of p66Shc in regulating HSPC traffic and blood flow recovery after ischemia in diabetic mice.
Results:
Using streptozotocin-indu...
Importance: Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular diseases and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown.
Objective: Here, we studied the association of hematopoietic stem/progenitor cells (HSPCs) and molecular markers of in...
Background:
Different diets result in significantly different phenotypes through metabolic and genomic reprogramming. Epigenetic marks, identified in humans and mouse models through caloric restriction, a high-fat diet or the intake of specific bioactives, suggest that genomic reprogramming drives this metabolic reprogramming and mediates the effe...
To disclose the epigenetic drift of time passing, we determined the genome-wide distributions of mono- and tri-methylated lysine 4 and acetylated and tri-methylated lysine 27 of histone H3 in the livers of healthy 3, 6 and 12 months old C57BL/6 mice. The comparison of different age profiles of histone H3 marks revealed global redistribution of hist...
Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylat...
Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progre...
Aims:
Doxorubicin cardiomyopathy is a lethal pathology characterized by oxidative stress, mitochondrial dysfunction, and contractile impairment, leading to cell death. Although extensive research has been done to understand the pathophysiology of doxorubicin cardiomyopathy, no effective treatments are available. We investigated whether monoamine o...
Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are common reactions in biological systems and often part of regulatory circuits rather than accidental events.DNA alterations are particularly relevant since the unique role of nuclear an...
Diabetes impairs the mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM), which can worsen the outcomes of HSPC transplantation and of diabetic complications. In this study, we examined the oncostatin M (OSM)-p66Shc pathway as a mechanistic link between HSPC mobilopathy and excessive myelopoiesis. We found that str...
Background
The introduction of pathology tissue-chromatin immunoprecipitation (PAT-ChIP), a technique allowing chromatin immunoprecipitation (ChIP) from formalin-fixed paraffin-embedded (FFPE) tissues, has extended the application of chromatin studies to clinical patient samples. However, extensive crosslinking introduced during routine tissue fixa...
The p66ShcA protein controls cellular responses to oxidative stress, senescence and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotyp...
High-grade B cell lymphomas with concurrent activation of the MYC and BCL2 oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. MYC activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mo...
Aims:
Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc contributes to obesity-relat...
With the aim of developing miniaturized enzymatic biosensors suitable for in vitro diagnostic applications, such as monitoring of metabolites at single cell level, glucose and lactate biosensors were fabricated by immobilizing enzymes (glucose oxidase and lactate oxidase, respectively) on 10 μm Pt ultramicroelectrodes. These electrodes are meant to...
Genes involved in oxidative stress (OS) response play a role both in aging and development: reactive oxygen species (ROS) can trigger cell cycle arrest, a mechanism involved in aging, but, at physiological levels, act also as signalling molecules in development. The tumor suppressor p53, its short isoform p44, and p66Shc, whose deletion is associat...
Background and aims:
Anthracyclines are effective anticancer drugs that have improved prognosis of hundred thousand cancer patients worldwide and are currently the most common chemotherapeutic agents used for the treatment of blood, breast, ovarian and lung cancers. However, their use is limited because of a cumulative dose-dependent and irreversi...
Rationale:
In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin (cTn), functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients.
Objective:
To investigate the diagnostic accuracy for AMI and prognostic prediction of in-ho...
Dysfunctional mitochondria contribute to the development of many diseases and pathological conditions through the excessive production of reactive oxygen species (ROS), and where studied, ablation of p66Shc (p66) was beneficial. p66 translocates to the mitochondria and oxidizes cytochrome c to yield H2O2, which in turn initiates cell death. PKCβ-me...
Fig. S1 Representative FISH images of sections of different organs from G0, G3 and G5 TERC−/−P66SHC+/+ and TERC−/−p66SHC−/− mice, stained with the Cy3 conjugated TelC PNA probe (grayscale panels), the colored panels show Cy3 and DAPI fluorescence pattern in a stained section of WT liver as control.
Fig. S2 IHC analysis of testis slices from G3 and...
Maternal care is an essential early environment in mammals that ensures emotional regulation and adaptive fitness of progeny. Longevity and healthy aging are associated with favorable environmental factors including fitting social and behavioral features. In the present review, we discuss the findings that link rearing conditions and early maternal...
Mitochondrial alterations induced by oncogenes are known to be crucial for tumorigenesis. Ras oncogene leads to proliferative signals through a Raf-1/MEK/ERK kinase cascade, whose components have been found to be also associated with mitochondria. The mitochondrial pepdidyl-prolyl isomerase cyclophilin D (CypD) is an important regulator of the mito...
Oxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro‐oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down...
AMP-activated protein kinase (AMPK) activation is an established treatment for diabetes. Here the effects of anthocyanin extract from blood orange juice, i.e. cyanidin-3-O-β-glucoside (C3G) and its secondary metabolite protocatechuic acid (PCA), on AMPK signalling in murine hepatic cell line and in the liver of C57BL/6 mice were investigated. Resul...
Although reactive oxygen species (ROS) act as crucial factors in the onset and progression of a wide array of diseases, they are also involved in numerous signalling pathways related to cell metabolism, growth and survival. ROS are produced at various cellular sites, and it is generally agreed that mitochondria generate the largest amount, especial...
Introduction. There is increasing interest in therapeutic modulation of metabolic pathways in cancer. Tumor cells preferentially use aerobic glycolysis to meet their energetic demands. However, glycolysis inhibition alone is unable to bring durable responses because of limited therapeutic index and because of previously underappreciated metabolic a...
It is well known that aging and its associated diseases, including cancer, are triggered by oxidative damage to biological macromolecules. However, antioxidant compounds are still disappointingly distant from any clinical application, so that Jim Watson has declared that antioxidant supplementation may have caused more cancers than it has prevented...
Oxygen radicals generated by p66Shc drive adipogenesis, but contradictory data exist on the role of p66Shc in the development of obesity and the metabolic syndrome. We herein explored the relationships among p66Shc, adipose tissue remodelling and glucose metabolism using mouse models and human adipose tissue samples.
In wild-type (WT), leptin-defic...
Cancer cells show an abnormal balance of reduced/oxidised species and the detection of cancer redox balance can be exploited for diagnostic purposes. In particular, it is known that the expression of oncogenic Ras changes the intracellular oxidised/reduced glutathione balance. Electrochemical imaging of living cells is currently feasible by scannin...
The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated.
The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) expression was also measured in islets from mice fed a high...
Heart rupture and heart failure are deleterious complications of myocardial infarction. The ShcA gene encodes for three protein isoforms, p46-, p52- and p66ShcA. p66ShcA induces oxidative stress. We studied the role of p66ShcA post-infarction. Expression of p66ShcA was analyzed in myocardium of patients with stable angina (n = 11), in explanted hea...
Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its delet...
Objective: The primary endpoint of this study is to determine whether short-term orange juice exposure is effective in increasing High Density Lipoproteins (HDL) cholesterol levels. Methods: This study was designed to include 74 women with a histological diagnosis of endocrine responsive early breast cancer. Patients will be randomized to a 12-wk o...
The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activa...
Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498–499InsTC mutation which causes t...
Metabolic stressful challenges during susceptible time windows, such as fetal life, can have important implications for health throughout life. Deletion of the p66(Shc) gene in mice leads to reduced oxidative stress (OS), resulting in a healthy and lean phenotype characterized by increased metabolic rate, resistance to high-fat diet (HFD)-induced o...
Aims:
The cellular prion protein, PrP(C), whose aberrant isoforms are related to prion diseases of humans and animals, has a still obscure physiological function. Having observed an increased expression of PrP(C) in two in vivo paradigms of heart remodelling, we focused on isolated mouse hearts to ascertain the capacity of PrP(C) to antagonize oxi...
Purpose: Heart failure is a growing problem worldwide. Cardiac remodeling, which features aseptic inflammation, metalloproteinase (MMP) activation and induction of matricellular proteins, contributes to heart failure progression after myocardial infarction (MI). The ShcA gene encodes three isoforms: p46-, p52- and p66ShcA, which are crucial for emb...
Growth factor receptors induce a transient increase in reactive oxygen species (ROS) levels upon receptor binding to promote signaling through oxidation of protein tyrosine phosphatases (PTPs). Most studies have focused on NADPH oxidases as the dominant source of ROS to induce PTP oxidation. A potential additional regulator of growth factor-induced...
Growth factor receptors induce a transient increase in Reactive Oxygen Species (ROS) levels upon receptor binding to promote signaling through oxidation of Protein Tyrosine Phosphatases (PTPs). Most studies have focused on NADPH Oxidases as the dominant source of ROS to induce PTP oxidation. A potential additional regulator of growth-factor-induced...
The signaling molecule p66Shc is often described as a longevity protein. This conclusion is based on a single life span study that used a small number of mice. The purpose of the present studies was to measure life span in a sufficient number of mice to determine if longevity is altered in mice with decreased Shc levels (ShcKO). Studies were comple...
Diabetes compromises the bone marrow (BM) microenvironment and reduces circulating CD34(+) cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system (SNS) is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after...
Several studies documented the key role of abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs) that are contributed also by mitochondrial dysfunction. The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mi...
Reactive oxygen species (ROS), mainly originated from mitochondrial respiration, are critical inducers of oxidative damage and involved in tissue dysfunction. It is not clear, however, whether oxidative stress is the result of an active gene program or it is the by-product of physiological processes. Recent findings demonstrate that ROS are produce...
Mitochondrial respiration produces both complete and partially reduced oxygen species that are involved in physiological and pathological processes. Indeed, unspecific oxidative damage induced by excessive mitochondrial reactive oxygen species (ROS) plays a role in aging and several diseases, whereas low amounts of ROS act in physiological signalin...
APC mutations causing Wnt activation are commonly found in colorectal cancer, but downstream pathways that facilitate tumorigenesis are unclear. In this issue of Cell Stem Cell, Myant et al. (2013) show that Rac1 activation is required for Wnt-driven Lgr5+ intestinal stem cell transformation through ROS production and NF-kB activation.
Oxidative stress is a determining factor of cellular senescence and aging, and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carryi...
Optimization of mesenchymal stem cells (MSC) culture conditions is of great importance for their more successful application in regenerative medicine. O(2) regulates various aspects of cellular biology and, in vivo, MSC are exposed to different O(2) concentrations spanning from very low tension in the bone marrow niche, to higher amounts in wounds....
Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitocho...
The mitochondrial reactive oxygen species (ROS) production is a crucial issue that has been involved in a variety of physio-pathological processes and aging. However, at the present measurements of mitochondrial ROS production is controversial. Indeed, the available tools are poorly specific and not direct. Now taking advantage of the progress in m...