Publications by authors named "Francesca Castoldi"

54 Publications

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Neuroimaging and neurodevelopmental outcome after early fetal growth restriction: NEUROPROJECT-FGR.

Pediatr Res 2021 Jan 19. Epub 2021 Jan 19.

Department of Woman, Mother and Child, Buzzi Hospital, University of Milan, via Castelvetro 32, 20154, Milan, Italy.

Background: Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment.

Methods: Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years.

Results: TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005).

Conclusions: FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk.

Impact: Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions.
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http://dx.doi.org/10.1038/s41390-020-01333-1DOI Listing
January 2021

Autophagy-mediated metabolic effects of aspirin.

Cell Death Discov 2020 Nov 24;6(1):129. Epub 2020 Nov 24.

Karolinska Institute, Department of Bioscience and Nutrition, Huddinge, Sweden.

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b or Bcln1) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
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http://dx.doi.org/10.1038/s41420-020-00365-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687910PMC
November 2020

Caloric restriction mimetics for the treatment of cardiovascular diseases.

Cardiovasc Res 2021 05;117(6):1434-1449

Centre de Recherche des Cordeliers, Team "Metabolism, Cancer & Immunity", INSERM UMRS1138, Université de Paris, Sorbonne Université, 75006 Paris, France.

Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia-reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.
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http://dx.doi.org/10.1093/cvr/cvaa297DOI Listing
May 2021

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 Feb 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

Extending the mode of action of triethylenetetramine (trientine): Autophagy besides copper chelation.

J Hepatol 2020 10 16;73(4):970-972. Epub 2020 Jul 16.

Centre de Recherche des Cordeliers, INSERM U1138, Team "Metabolism, Cancer & Immunity", Sorbonne Université, Université de Paris, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.05.046DOI Listing
October 2020

Triethylenetetramine (trientine): a caloric restriction mimetic with a new mode of action.

Autophagy 2020 08 16;16(8):1534-1536. Epub 2020 Jun 16.

Centre de Recherche des Cordeliers, INSERM U1138, Team "Metabolism, Cancer & Immunity", Sorbonne Université, Université de Paris , Paris, France.

Caloric restriction mimetics (CRMs) are nontoxic macroautophagy/autophagy enhancers that act through the stimulation of cytoplasmic protein deacetylation reactions. Thus far, three functional classes of CRMs have been described: inhibitors of acetyltransferases (such as spermidine), inhibitors of acetyl coenzyme (AcCoA) synthesis (such as hydroxycitrate) and activators of deacetylases/sirtuins (such as resveratrol). Triethylenetetramine (also called trientine, abbreviated TETA) is a synthetic polyamine with resemblance in its structure to spermidine, a natural polyamine reputed for its pro-autophagic, anti-obesity and anti-aging effects. TETA, which is approved for the treatment of Wilson disease, has no effects on the longevity of mice, yet does induce autophagy and reduces weight gain in mice fed a high-fat diet (HFD). Mechanistically, these effects of TETA involve an increased activity of the TETA-metabolizing enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1). SAT1 overactivation ultimately results in the depletion of intracellular AcCoA with a consequent de-acetylation of cytoplasmic proteins and induction of autophagy. Accordingly, TETA fails to induce autophagy or to control HFD-induced weight gain in SAT1-deficient mice. Altogether, these findings indicate that TETA induces autophagy through a novel mode of action, namely, by the activation of an AcCoA-depleting enzyme.
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http://dx.doi.org/10.1080/15548627.2020.1778293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469548PMC
August 2020

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

Cell Death Differ 2020 10 6;27(10):2904-2920. Epub 2020 May 6.

Centre de Recherche des Cordeliers, INSERM U1138, Team "Metabolism, Cancer & Immunity", Sorbonne Université, Université de Paris, Paris, France.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.
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http://dx.doi.org/10.1038/s41418-020-0550-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494776PMC
October 2020

Monochorionic diamniotic twin pregnancy complicated by discordant premature closure of ductus arteriosus.

Clin Case Rep 2020 Apr 9;8(4):685-689. Epub 2020 Mar 9.

Fetal Therapy Unit 'Umberto Nicolini' V. Buzzi Children's Hospital University of Milan Milan Italy.

Prenatal DA closure due to early maternal intake of high-dose paracetamol and selective serotonin reuptake inhibitors. MC twin pregnancy uncomplicated by TTTS with discordant prenatal DA closure.
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http://dx.doi.org/10.1002/ccr3.2717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141735PMC
April 2020

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice.

Oncoimmunology 2019;8(11):e1657375. Epub 2019 Sep 7.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8 T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.
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http://dx.doi.org/10.1080/2162402X.2019.1657375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791453PMC
September 2019

Comprehensive autophagy evaluation in cardiac disease models.

Cardiovasc Res 2020 03;116(3):483-504

Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Autophagy is a highly conserved recycling mechanism essential for maintaining cellular homeostasis. The pathophysiological role of autophagy has been explored since its discovery 50 years ago, but interest in autophagy has grown exponentially over the last years. Many researchers around the globe have found that autophagy is a critical pathway involved in the pathogenesis of cardiac diseases. Several groups have created novel and powerful tools for gaining deeper insights into the role of autophagy in the aetiology and development of pathologies affecting the heart. Here, we discuss how established and emerging methods to study autophagy can be used to unravel the precise function of this central recycling mechanism in the cardiac system.
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http://dx.doi.org/10.1093/cvr/cvz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064050PMC
March 2020

α-Ketoglutarate inhibits autophagy.

Aging (Albany NY) 2019 06;11(11):3418-3431

Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Descartes, Université Paris Diderot, "Metabolism, Cancer and Immunity", Paris 75006, France.

The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl -ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate α-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of α-ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular α-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect.
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http://dx.doi.org/10.18632/aging.102001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594794PMC
June 2019

Stress and feelings in mothers and fathers in NICU: identifying risk factors for early interventions.

Prim Health Care Res Dev 2019 06 7;20:e81. Epub 2019 Jun 7.

NICU, Ospedale dei Bambini V. Buzzi, ASST Fatebenefratelli-Sacco, Milano, Italy.

Aims: The aims of this study were to explore parents' stress levels and negative feelings after premature births and to identify the risk factors related to parents' stress and negative feelings during their children's neonatal intensive care unit (NICU) stay.

Background: Preterm birth is a multi-problematic event that may put the babies in danger for both their medical and neurophysiological conditions and could have a negative impact on both the mother-father relationship and the parent-child interactions.

Methods: The study involved 43 mothers and 38 fathers of preterm infants. All participants filled out the Parental Stressor Scale: Neonatal Intensive Care Unit and the Profile of Mood States.

Findings: The results revealed significant differences between mothers' and fathers' responses to preterm births in terms of both stress and negative feelings. We found that, for mothers, their own young age and the baby's need for respiratory support were significant predictors of stress; for fathers, their own young age and the baby's lower gestational age and worse condition at birth were significant predictors of stress and negative feelings. The NICU may be a stressful place both for mothers and fathers. Identifying which mothers and fathers are at risk immediately after their children are born could help to direct specific interventions that can reduce these parents' stress and prevent them from negative feelings.
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http://dx.doi.org/10.1017/S1463423619000021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567892PMC
June 2019

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Nat Commun 2019 02 19;10(1):651. Epub 2019 Feb 19.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
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http://dx.doi.org/10.1038/s41467-019-08555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180PMC
February 2019

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy.

Oncoimmunology 2019;8(1):e1498285. Epub 2018 Oct 1.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient ( or ) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, and mice, we observed an increase in the toxicity of MTX on mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.
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http://dx.doi.org/10.1080/2162402X.2018.1498285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287785PMC
October 2018

Spermidine reduces cancer-related mortality in humans.

Autophagy 2019 02 29;15(2):362-365. Epub 2018 Oct 29.

b INSERM, U1138 , Paris , France.

A recent prospective epidemiological study suggested that an increase in the nutritional uptake of the natural polyamine spermidine is associated with reduced overall and cancer-specific mortality. Here, we speculate through which mechanisms spermidine might exert such oncopreventive effects. ACLY, ATP citrate lyase; ATG, autophagy-related gene; CoA, coenzyme A; NSCLC, non-small cell lung cancer.
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http://dx.doi.org/10.1080/15548627.2018.1539592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333461PMC
February 2019

Mechanical Stretch of High Magnitude Provokes Axonal Injury, Elongation of Paranodal Junctions, and Signaling Alterations in Oligodendrocytes.

Mol Neurobiol 2019 Jun 8;56(6):4231-4248. Epub 2018 Oct 8.

INSERM UMR-S 1124, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, 45 rue des Saints-Pères, 75006, Paris, France.

Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination.
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http://dx.doi.org/10.1007/s12035-018-1372-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505516PMC
June 2019

Aspirin-another caloric-restriction mimetic.

Autophagy 2018 18;14(7):1162-1163. Epub 2018 Jul 18.

a Gustave Roussy Cancer Campus , Villejuif , France.

The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode . In sum, aspirin acts as a CRM.
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http://dx.doi.org/10.1080/15548627.2018.1454810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103658PMC
June 2019

Aspirin induces autophagy inhibition of the acetyltransferase EP300.

Oncotarget 2018 May 15;9(37):24574-24575. Epub 2018 May 15.

Guido Kroemer: Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre & Marie Curie, Paris, France; Université Paris-Sud/Paris XI, Faculté de Médecine, Kremlin-Bicêtre, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.18632/oncotarget.25364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973857PMC
May 2018

Premature birth: complexities and difficulties in building the mother-child relationship.

J Reprod Infant Psychol 2017 Nov 6;35(5):509-523. Epub 2017 Oct 6.

c Neurologia Pediatrica, Ospedale dei Bambini Vittore Buzzi, ICP , Milano , Italy.

Aim: This paper aims to investigate if the dyadic interactive behaviours were influenced by parental stress and feelings both in preterm and full-term mother-child dyads.

Methods: 45 mothers (age = 35.29 ± 5.38) and fathers (age = 36.77 ± 6.89) of preterm infants (GA = 30.25 ± 2.95; BW = 1288.02 ± 488.76), and 36 mothers (age = 32.60 ± 4.56) and fathers (age = 35.54 ± 5.16) of full-term (GA = 39.88 ± 1.38; BW = 3156.39 ± 493.81) were involved. Parents filled out the Impact of Event Scale Revised (IES-R), Profile of Mood States (POMS) and Parenting Stress Index Short Form (PSI-SF) and interactive behaviours (Global Rating Scale) was videotaped after 3 months.

Results: Mothers of preterm children showed higher level of Intrusiveness (M = 4.07 ± .74, M = 4.39 ± .51, t = 2.22, p = .029) and Remoteness (M = 4.45 ± .83, M = 4.79 ± .34, t = 2.51, p = .015) than mothers of term children. In preterm mothers' lower levels of Sensitivity, higher levels of Intrusiveness, Remoteness and Depression are associated with the presence of negative feelings and parental stress in both parents. Moreover, higher children Distress is associated to parental negative feelings, paternal stress and post-traumatic symptoms. A higher score of parental negative feelings and parental stress predicted lower scores in Global RatingScale dimensions.

Conclusions: Our results underline that preterm birth could be a risk factor for the co-construction of interactive exchanges between mother and premature baby. This study could help practitioners to better consider parental roles and to carry out specific supportive interventions for both parents and children.
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http://dx.doi.org/10.1080/02646838.2017.1383977DOI Listing
November 2017

Functional nutrients in infants born by vaginal delivery or Cesarean section.

Pediatr Med Chir 2017 Dec 22;39(4):184. Epub 2017 Dec 22.

UOC Neonatologia, Patologia Neonatale e Terapia Intensiva Neonatale, Ospedale dei Bambini V. Buzzi, ASST FBF - Sacco - Buzzi, Milano.

The development of a proper neonatal microbiota is of great importance, especially for the effects that dysbiosis has in acute and chronic diseases' onset. The microbiota, particularly the intestinal one, plays a crucial role in maintaining the health of the host, preventing colonization by pathogenic bacteria and significantly influencing the development and maturation of a normal gastrointestinal mucosal immunity. Several factors may interfere with the physiological development of microbiota, such as diseases during pregnancy, type of delivery, maternal nutrition, type of neonatal feeding, use of antibiotics, exposition to hospital environment (e.g., neonatal intensive care unit) and genetic factors. Thanks to a proper maternal and neonatal supplementation with specific functional nutrients, it is now possible to correct dysbiosis, thus reducing the risks for the newborn's health. In this review of the literature, we give an overview of the studies highlighting the composition of the maternal, fetal and neonatal microbiota, the factors potentially responsible for dysbiosis and the use of functional nutrients to prevent diseases' onset.
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http://dx.doi.org/10.4081/pmc.2017.184DOI Listing
December 2017

Aspirin Recapitulates Features of Caloric Restriction.

Cell Rep 2018 02;22(9):2395-2407

Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Université Pierre et Marie Curie, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.
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http://dx.doi.org/10.1016/j.celrep.2018.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848858PMC
February 2018

Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens.

Cell Death Dis 2017 08 3;8(8):e2970. Epub 2017 Aug 3.

Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.

In the last years, autophagy has been revealed as an essential pathway for multiple biological processes and physiological functions. As a catabolic route, autophagy regulation by nutrient availability has been evolutionarily conserved from yeast to mammals. On one hand, autophagy induction by starvation is associated with a significant loss in body weight in mice. Here, we demonstrate that both genetic and pharmacological inhibition of the autophagy process compromise weight loss induced by starvation. Moreover, autophagic potential also impacts on weight gain induced by distinct hypercaloric regimens. Atg4b-deficient mice, which show limited autophagic competence, exhibit a major increase in body weight in response to distinct obesity-associated metabolic challenges. This response is characterized by the presence of larger adipocytes in visceral fat tissue, increased hepatic steatosis, as well as reduced glucose tolerance and attenuated insulin responses. Similarly, autophagy-deficient mice are more vulnerable to experimentally induced type-I diabetes, showing an increased susceptibility to acute streptozotocin administration. Notably, pharmacological stimulation of autophagy in wild-type mice by spermidine reduced both weight gain and obesity-associated alterations upon hypercaloric regimens. Altogether, these results indicate that systemic autophagic activity influences the resilience of the organism to weight gain induced by high-calorie diets, as well as to the obesity-associated features of both type-1 and type-2 diabetes.
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http://dx.doi.org/10.1038/cddis.2017.373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596561PMC
August 2017

Effects of Breathing and Apnoea during Sustained Inflations in Resuscitation of Preterm Infants.

Neonatology 2017 25;111(4):360-366. Epub 2017 Jan 25.

Ospedale dei Bambini "V. Buzzi," ASST-FBF-Sacco, Milan, Italy.

Background: A sustained inflation (SI) at birth in preterm babies may be ineffective unless the infants breathe. Gain in lung volume is associated with breathing during delivery room non-invasive management.

Objective: To describe the breathing patterns of preterm infants during an SI and correlate to a calculated gain in lung volume.

Methods: Retrospective observational study. Data collected from a respiratory function monitor during SI (25 cmH2O for 15 s then PEEP at 5 cmH2O) through a face mask in preterm infants (gestational age [GA] ≤31 weeks). Spontaneous breaths, inspiratory time (TI), inspiratory/expiratory tidal volume (Vti/Vte), and gain in lung volume were determined.

Results: 30 SIs in 20 infants (mean GA 27 weeks; birth weight 825 g) were analysed and stratified in 2 groups according to spontaneous breathing: SIs without spontaneous breaths (apnoea: n = 11) and SIs with spontaneous breaths (breathing: n = 19). Mean GA was lower in the apnoea group versus the breathing group (25 vs. 27+5 weeks; p = 0.01). Mean birth weight was lower in the apnoea group versus the breathing group (683 vs. 860 g; p = ns). In the breathing group, the mean number of spontaneous breaths was 4 with a mean TI of 0.52 min, the mean Vti/kg was 5.9 mL/kg, and the mean Vte was 2.7 mL/kg. The calculated mean gain in lung volume was 7.5 mL/kg in the apnoea group and 17.8 mL/kg in the breathing group (p = 0.039).

Conclusions: Actively breathing infants during an SI at birth showed a gain in lung volume higher than apnoeic infants. Spontaneous breathing during SI seems to be related to GA.
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http://dx.doi.org/10.1159/000454799DOI Listing
March 2018

Metabolic effects of fasting on human and mouse blood in vivo.

Autophagy 2017 Mar 6;13(3):567-578. Epub 2017 Jan 6.

a Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138 , Paris , France.

Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status.
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http://dx.doi.org/10.1080/15548627.2016.1271513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361613PMC
March 2017

Mothers and Fathers in NICU: The Impact of Preterm Birth on Parental Distress.

Eur J Psychol 2016 Nov 18;12(4):604-621. Epub 2016 Nov 18.

Neonatal Intensive Care Unit (NICU), V. Buzzi-Ospedale dei Bambini, ICP, Milan, Italy.

Preterm birth is a stressful event for families. In particular, the unexpectedly early delivery may cause negative feelings in mothers and fathers. The aim of this study was to examine the relationship between preterm birth, parental stress and negative feelings, and the environmental setting of NICU. 21 mothers (age = 36.00 ± 6.85) and 19 fathers (age = 34.92 ± 4.58) of preterm infants (GA = 30.96 ± 2.97) and 20 mothers (age = 40.08 ± 4.76) and 20 fathers (age = 40.32 ± 6.77) of full-term infants (GA = 39.19 ± 1.42) were involved. All parents filled out the Parental Stressor Scale: Neonatal Intensive Care Unit, the Impact of Event Scale Revised, Profile of Mood States, the Multidimensional Scale of Perceived Social Support and the Post-Partum Bonding Questionnaire. Our data showed differences in emotional reactions between preterm and full-term parents. Results also revealed significant differences between mothers and fathers' responses to preterm birth in terms of stress, negative feelings, and perceptions of social support. A correlation between negative conditions at birth (e.g., birth weight and Neonatal Intensive Care Unit stay) and higher scores in some scales of Impact of Event Scale Revised, Profile of Mood States and Post-Partum Bonding Questionnaire were found. Neonatal Intensive Care Unit may be a stressful place both for mothers and fathers. It might be useful to plan, as soon as possible, interventions to help parents through the experience of the premature birth of their child and to begin an immediately adaptive mode of care.
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http://dx.doi.org/10.5964/ejop.v12i4.1093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114875PMC
November 2016

Velocity time integral for right upper pulmonary vein in VLBW infants with patent ductus arteriosus.

Clinics (Sao Paulo) 2016 Oct 1;71(10):580-585. Epub 2016 Oct 1.

University of Milan, IRCCS "Ca' Granda-Ospedale Maggiore Policlinico", Neonatal Intensive Care Unit, Milan, Italy.

Objective:: Early diagnosis of significant patent ductus arteriosus reduces the risk of clinical worsening in very low birth weight infants. Echocardiographic patent ductus arteriosus shunt flow pattern can be used to predict significant patent ductus arteriosus. Pulmonary venous flow, expressed as vein velocity time integral, is correlated to ductus arteriosus closure. The aim of this study is to investigate the relationship between significant reductions in vein velocity time integral and non-significant patent ductus arteriosus in the first week of life.

Methods:: A multicenter, prospective, observational study was conducted to evaluate very low birth weight infants (<1500 g) on respiratory support. Echocardiography was used to evaluate vein velocity time integral on days 1 and 4 of life. The relationship between vein velocity time integral and other parameters was studied.

Results:: In total, 98 very low birth weight infants on respiratory support were studied. On day 1 of life, vein velocity time integral was similar in patients with open or closed ductus. The mean vein velocity time integral significantly reduced in the first four days of life. On the fourth day of life, there was less of a reduction in patients with patent ductus compared to those with closed patent ductus arteriosus and the difference was significant.

Conclusions:: A significant reduction in vein velocity time integral in the first days of life is associated with ductus closure. This parameter correlates well with other echocardiographic parameters and may aid in the diagnosis and management of patent ductus arteriosus.
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http://dx.doi.org/10.6061/clinics/2016(10)05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054770PMC
October 2016

Autophagy induction for the treatment of cancer.

Autophagy 2016 10 17;12(10):1962-1964. Epub 2016 Aug 17.

a Gustave Roussy Cancer Campus , Villejuif , France.

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8 T lymphocyte-dependent anticancer immune responses.
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http://dx.doi.org/10.1080/15548627.2016.1214778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079541PMC
October 2016

Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance.

Cancer Cell 2016 07;30(1):147-160

Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM, U1138, 75006 Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address:

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.
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http://dx.doi.org/10.1016/j.ccell.2016.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715805PMC
July 2016

Sustained Inflation and Its Role in the Delivery Room Management of Preterm Infants.

Neonatology 2016 3;109(4):366-8. Epub 2016 Jun 3.

NICU-Ospedale dei Bambini x2018;V. Buzzi' - ASST Fatebenefratelli/Sacco, Milan, Italy.

A noninvasive approach in the delivery room in place of intubation and mechanical ventilation can reduce rates of bronchopulmonary dysplasia and death. Nevertheless, the rate of nasal continuous positive airway pressure failure still remains high. In order to prevent lung injury and to enhance the success of continuous positive airway pressure, sustained inflation (administration by face mask or nasopharyngeal tube of a high peak pressure of 20-25 cm H2O, maintained for 10-15 s) has been recently proposed to establish an early and efficient functional residual capacity in the delivery room. Sustained inflation is an intriguing therapy, although the results of clinical trials are controversial in terms of respiratory outcomes. A critical role in the success of sustained inflation could be the presence of open or closed glottis and the contribution of spontaneous breathing that allows air to enter the lungs during the maneuver. Recent neonatal resuscitation guidelines suggest that sustained inflation may be considered in individual clinical circumstances or research settings.
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http://dx.doi.org/10.1159/000444899DOI Listing
November 2017
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