25 results on '"Bergamini, Ettore"'
Search Results
2. The Role of Autophagy in Aging.
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BERGAMINI, ETTORE, CAVALLINI, GABRIELLA, DONATI, ALESSIO, and GORI, ZINA
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PHYSIOLOGICAL aspects of aging , *AUTOPHAGY , *OXYGEN in the body , *FREE radicals , *CELLULAR aging , *AGING prevention , *LOW-calorie diet , *HUMAN life cycle , *GERONTOLOGY - Abstract
Aging denotes a postmaturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes of this deterioration may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and incomplete “housekeeping.” Caloric restriction is the most robust anti-aging intervention known so far. Similar beneficial effects on median and maximum life span were obtained by feeding animals a 40%-reduced diet or by every-other-day ad libitum feeding. In both instances, animals are forced to spend a great part of their time in a state of fasting and activated autophagy. Autophagy is a highly conserved process in eukaryotes, in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules. This process has an essential role in adaptation to fasting and changing environmental conditions, cellular remodeling during development, and accumulation of altered ROS-hypergenerating organelles in older cells. Several pieces of evidence show that autophagy is involved in aging and is an essential part of the anti-aging mechanism of caloric restriction. As an application, intensification of autophagy by the administration of an antilipolytic drug rescued older cells from accumulation of altered mtDNA in less than 6 hours. It is concluded that the pharmacologic intensification of autophagy (PISA treatment) has anti-aging effects and might prove to be a big step toward retardation of aging and prevention of age-associated diseases in humans. [ABSTRACT FROM AUTHOR]
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- 2007
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3. Molecular mechanisms of calorie restriction's protection against age-related sclerosis.
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Chiarpotto, Elena, Bergamini, Ettore, and Poli, Giuseppe
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LOW-calorie diet , *OXIDATIVE stress , *AGE factors in disease , *GROWTH factors , *CARDIOVASCULAR diseases - Abstract
The current knowledge on the molecular mechanisms of the protective effect of calorie restriction (CR) against age-related fibrosclerosis is tentatively reviewed with specific reference to the role of oxidative stress in aging. The effects of oxidative stress are often mediated by its own final products. Of these, 4-hydroxy-2,3-nonenal (HNE) induces the expression and synthesis of transforming growth factor β1 (TGFβ1) and activates nuclear binding of transcription factor activator protein 1 (AP-1) thus stimulating fibrogenesis. Several studies have shown that, as well as extending mean and maximum life span in a variety of species, CR delays the onset and slows the progression of a variety of age-associated diseases, including diabetes, cardiovascular diseases and neoplasia. However, the anti-aging mechanisms of CR are still not clearly understood. Of the numerous hypotheses put forward, one that still remains popular is protection against the age-associated increase of oxidative stress and consequent cell damage. CR protects the rat aorta from the age-related increase of both oxidative damage and fibrosis; as regards the possible mechanism/s of CR's protection against fibrosclerosis, it is conceivable that, by decreasing oxidative stress, CR reduces HNE levels and consequently TGFβ1 expression and collagen deposition, likely by down-regulating the activation of Jun-N terminal kinase and of AP-1. Through the modulation of reactive oxygen species and oxidative stress CR may also attenuate the age-associated increase in the inflammatory milieu, thus preserving vascular functional integrity by suppressing the age-associated increase in inflammatory enzyme activities and prostanoids. iubmb Life, 58: 695-702, 2006 [ABSTRACT FROM AUTHOR]
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- 2006
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4. Autophagy: A cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically
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Bergamini, Ettore
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AGING , *DEVELOPMENTAL biology , *NEURODEGENERATION , *OXIDATIVE stress - Abstract
Abstract: The process of ageing denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and not completed housekeeping, with an accumulation of altered ROS-hypergenerating organelles in older cells. It has been shown that autophagy is the only tier of defence against the accumulation of effete mitochondria and peroxisomes; that functioning of autophagy declines with increasing age and determinates cell and individual lifespan; that autophagy can be intensified by drugs; and that the pharmacological intensification of autophagy may be a big step towards retardation of ageing and prevention and therapy of age-associated diseases including neurodegeneration. [Copyright &y& Elsevier]
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- 2006
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5. In response to: "Is there an antiaging medicine?".
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Bergamini, Ettore
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AGING prevention , *GERONTOLOGY , *GERIATRICS , *AGING , *PERIODICALS , *AUTOPHAGY , *ANIMALS , *CONFERENCES & conventions - Abstract
Comments on the article 'Is There an Antiaging Medicine?,' which was published in the 2002 issue of 'The Journals of Gerontology.' Theme of the article; Background on autophagy; Description of the treatment developed by the Pharmacological Intensification of Suppression of Aging.
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- 2003
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6. Effects of aging, antiaging calorie restriction and in vivo stimulation of autophagy on the urinary excretion of 8OHdG in male Sprague-Dawley rats.
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Donati, Alessio, Cavallini, Gabriella, and Bergamini, Ettore
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SPRAGUE Dawley rats , *AUTOPHAGY , *AGING prevention , *MITOCHONDRIA , *DNA repair , *OXIDATIVE stress , *LOW-calorie diet , *LABORATORY rats - Abstract
8-Hydroxy-2-deoxyguanosine (8OHdG) excreted into the urine is considered a marker of oxidative stress effect on DNA, and it is reported to be mainly produced by the DNA repair system. In previous works, we showed that autophagy was also involved in 8OHdG disposal through the degradation of oxidatively altered mitochondria. Here, we show that aging in Sprague-Dawley male rats is associated with a decline in the in vitro function of liver autophagy and a slight and not significant decrease in the urinary excretion of 8OHdG. In addition, we demonstrate that anti-aging caloric restriction maintains levels of both liver autophagy and urinary excretion of 8OHdG at very high levels throughout life. Finally, we show the in vivo stimulation of autophagy by the administration of an antilipolytic agent or everolimus, which rescues rats from the accumulation of 8OHdG in the liver mtDNA, also causes a dramatic increase in the urinary excretion of 8OHdG. The intensification of autophagy by the administration of the antilipolytic drugs to fasting rats faded progressively with increasing age, together with a reduced increase in 8OHdG output into the urine. It is concluded that the process of autophagy may play a major role in the disposal of 8OHdG with urine, and that the assay of 8OHdG levels in the urine before and after the stimulation of autophagy may provide a novel, non-invasive and safe procedure to monitor the in vivo functioning of the process. [ABSTRACT FROM AUTHOR]
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- 2013
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7. Glycated plasma proteins in experimentally induced acute toxic renal failure by dichromate injection: evidence for loss with urine and decreased plasma levels.
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DE TATA, VINCENZO, BOMBARA, MARIA, NOVELLI, MICHELA, PINGITORE, RAFFAELE, BERGAMINI, ETTORE, and Bergamini, Ettore
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BLOOD proteins , *CHRONIC kidney failure - Abstract
In the rat, a single subcutaneous injection of sodium dichromate (20 mg/kg) causes acute renal injury and significant polyuria, proteinuria, and glycosuria (peaking 2–3 days after treatment, and returning to normal by day 5) without any changes in the plasma levels of protein, glucose, and glycated haemoglobin. Surprisingly, the percentage levels of glycated plasma total proteins and albumin (assayed by boronate affinity chromatography) transiently and significantly decrease during recovery from proteinuria (days 4 and 10 after treatment) and were found in the normal range of values by day 18. These changes are concomitant with a significant increase in the percentage level of glycated albumin in urine. Constancy of total plasma protein and the temporal pattern of levels of glycation suggest that changes in the percentage values of glycated proteins are secondary to a transient selective loss of glycated plasma proteins in urine. [ABSTRACT FROM AUTHOR]
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- 1998
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8. Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome.
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Montecucco, Fabrizio, Bertolotto, Maria, Vuilleumier, Nicolas, Franciosi, Ulisse, Puddu, Alessandra, Minetti, Silvia, Delrio, Andrea, Quercioli, Alessandra, Bergamini, Ettore, Ottonello, Luciano, Pende, Aldo, Lenglet, Sébastien, Pelli, Graziano, Mach, François, Dallegri, Franco, and Viviani, Giorgio Luciano
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INSULIN resistance , *NEUTROPHILS , *CARDIOVASCULAR diseases , *ATHEROSCLEROSIS , *METABOLIC disorders , *CHEMOKINES , *MONOCYTES - Abstract
Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients (n = 11) or healthy controls (n = 8). Serum and plasma was collected before acipimox administration (time 0) as well as 2-5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophi I and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time o and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum-induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNKI/2 phosphorylation. Although mRNA expression of acipimox receptor (GPRIO9) was shown in human neutrophils, 5-500 μM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin. [ABSTRACT FROM AUTHOR]
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- 2011
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9. Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation
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Castello, Laura, Froio, Teresa, Maina, Marco, Cavallini, Gabriella, Biasi, Fiorella, Leonarduzzi, Gabriella, Donati, Alessio, Bergamini, Ettore, Poli, Giuseppe, and Chiarpotto, Elena
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LABORATORY rats , *ANIMAL models of inflammation , *FIBROSIS , *OXIDATIVE stress , *LOW-calorie diet , *EXTRACELLULAR matrix , *REACTIVE oxygen species , *TRANSFORMING growth factors - Abstract
Abstract: The free radical theory of aging is currently one of the most popular. In parallel, many studies have demonstrated the association of fibrosis and increased oxidative stress in the pathogenesis of some chronic human diseases, and fibrosis is often characteristic of aging tissues. One of the few interventions that effectively slow aging is calorie restriction and the protection against the age-associated increase of oxidative stress remains one of the foremost hypotheses to explain this action. As an alternative to traditional calorie restriction, another dietary regimen, termed alternate-day fasting, has also been tested, whose antiaging mechanisms have not been explored so much extensively. We thus studied the effects of alternate-day fasting, started at 2 months of age, on oxidative stress and fibrosis in the heart during aging. In the left ventricle of the heart of elderly (aged 24 months) versus young (aged 6 months) male rats we found a significant increase in oxidative stress paralleled by increased fibrosis. In parallel there was a significant increase in inflammatory cytokine levels and in NF-kB DNA binding activity with advancing age. Alternate-day fasting protected against all these age-related phenomena. These data support the hypothesis that this kind of dietary restriction protects against age-related fibrosis, at least in part by reducing inflammation and oxidative damage, and this protection can thus be considered a factor in the prevention of age-related diseases with sclerotic evolution. [Copyright &y& Elsevier]
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- 2010
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10. Age-Related Changes in Endothelin-1 Receptor Subtypes in Rat Heart.
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Del Ry, Silvia, Maltinti, Maristella, Giannessi, Daniela, Cavallini, Gabriella, and Bergamini, Ettore
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ENDOTHELINS , *BINDING sites , *BIOCHEMISTRY , *HEART , *LABORATORY rats , *TISSUES - Abstract
Density, affinity, and subtype distribution of endothelin-1 (ET-1) binding sites were determined in rat cardiac tissue as a function of age in order to evaluate the association of alterations in the endothelin receptor system and aging in the heart. A significant decrease in the receptor subtype ET-A, which represents 70% to 80% of the total receptor population in cardiac tissue of 3- and 12-month-old rats, was observed in 24-month-old rats with respect to the younger groups. These findings indicate an alteration in ET-1 cardiac receptors associated with aging, mainly due to a variation in the receptor subtype distribution. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Effect of Aging and Anti-Aging Caloric Restriction on the Endocrine Regulation of Rat Liver Autophagy.
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Donati, Alessio, Recchia, Gianluca, Cavallini, Gabriella, and Bergamini, Ettore
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LOW-calorie diet , *AGING prevention , *INSULIN , *RATS , *HORMONES , *GLUCAGON - Abstract
Autophagy is a process that sequesters and degrades altered organelles and macromolecular cytoplasmic constituents for cellular restructuring and repair, and as a source of nutrients for metabolic use in early starvation it may be involved in anti-aging mechanisms of caloric restriction. The effects of 40% daily dietary restriction (DR) and intermittent feeding (EOD) on the age-related changes in the endocrine regulation of autophagic proteolysis were studied by monitoring the rate of valine release from isolated rat liver cells. Results show that in ad libitum-fed rats sensitivity of autophagy to glucagon and insulin declines by one order of magnitude in older rats. Both DR and EOD maintain the sensitivity to glucagon at juvenile levels, whereas only EOD can fully maintain response to insulin. It is concluded that changes in the sensitivity to glucagon may have a role in the aging process. [ABSTRACT FROM AUTHOR]
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- 2008
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12. In vivo effect of an antilipolytic drug (3,5′-dimethylpyrazole) on autophagic proteolysis and autophagy-related gene expression in rat liver
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Donati, Alessio, Ventruti, Annamaria, Cavallini, Gabriella, Masini, Matilde, Vittorini, Simona, Chantret, Isabelle, Codogno, Patrice, and Bergamini, Ettore
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GENE expression , *GENETIC regulation , *FATTY acids , *SUGARS - Abstract
Abstract: Autophagy is an intracellular pathway induced by starvation, inhibited by nutrients, that is responsible for degradation of long-lived proteins and altered cell organelles. This process is involved in cell maintenance could be induced by antilipolytic drugs and may have anti-aging effects [A. Donati, The involvement of macroautophagy in aging and anti-aging interventions, Mol. Aspects Med. 27 (2006) 455–470]. We analyzed the effect of an intraperitoneal injection of an antilipolytic agent (3,5′-dimethylpyrazole, DMP, 12mg/kg b.w.), that mimics nutrient shortage on autophagy and expression of autophagic genes in the liver of male 3-month-old Sprague–Dawley albino rats. Autophagy was evaluated by observing electron micrographs of the liver autophagosomal compartment and by monitoring protein degradation assessed by the release of valine into the bloodstream. LC3 gene expression, whose product is one of the best known markers of autophagy, was also monitored. As expected, DMP decreased the plasma levels of free fatty acids, glucose, and insulin and increased autophagic vacuoles and proteolysis. DMP treatment caused an increase in the expression of the LC3 gene although this occurred later than the induction of authophagic proteolysis caused by DMP. Glucose treatment rescued the effects caused by DMP on glucose and insulin plasma levels and negatively affected the rate of autophagic proteolysis, but did not suppress the positive regulatory effect on LC3 mRNA levels. In conclusion, antilipolytic drugs may induce both autophagic proteolysis and higher expression of an autophagy-related gene and the effect on autophagy gene expression might not be secondary to the stimulation of autophagic proteolysis. [Copyright &y& Elsevier]
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- 2008
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13. Effects of oxidative stress on the Dolichol content of isolated rat liver cells.
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Guarini, Monica, Stabile, Angela, Cavallini, Gabriella, Donati, Alessio, and Bergamini, Ettore
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OXIDATIVE stress , *LIVER cells , *ISOPENTENOIDS , *TISSUES , *CELL membranes , *FREE radicals - Abstract
Dolichol, a long-chain polyisoprenoid broadly distributed in all tissues and cellular membranes with unknown function(s), might have a role in free radical metabolism [it accumulates in older tissues and decreases after CCl4 (in liver) or phenylhydrazine (in spleen and liver) administration]. The effects of the NADPH-ADP-Fe system on Dolichol levels in isolated hepatocytes were explored and the time-course of changes was compared with the release of MDA in the incubation medium and the decrease in CoQ 9 and 10 and Vitamin E levels. Results showed that the system increased lipid peroxidation and decreased Dolichol and CoQ levels in_parallel fashions and lowered Vitamin E levels with shorter latency. Meanwhile, no increase in dead cells and no Dolichol release in the medium were detected. In conclusion, an increase in oxidative stress possibly caused a rapid degradation of dolichol by the same (unknown) mechanism responsible for the breakdown of_Ubiquinone isoprenoid chains. [ABSTRACT FROM AUTHOR]
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- 2007
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14. Effect of a caloric restriction regimen on the angiogenic capacity of aorta and on the expression of endothelin-1 during ageing
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Facchetti, Floriana, Monzani, Elena, Cavallini, Gabriella, Bergamini, Ettore, and La Porta, Caterina A.M.
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LOW-calorie diet , *MURIDAE , *CYTOKINES , *MESSENGER RNA - Abstract
Abstract: Ageing is accompanied by impaired angiogenesis, as well as by a deficient expression of several angiogenic growth factors and the alteration of endothelial functions. Caloric restriction (CR) is the only intervention that can extend lifespan and retard age-related-decline functions in mammals by reducing the rate of ageing and the progression of the associated diseases. Herein, we have investigated the effects of ageing and of a caloric restriction regimen (mild or severe) on the angiogenic response and on the expression of endothelin-1 (ET-1) in the aorta of male 3-, 12- or 24-month-old Sprague–Dawley rats fed ad libitum (AL), fed ad libitum and fasted 1 day a week (mild CR) or fasted every other in alternate days (severe CR). Our findings, using the rat aorta ring assay, show that the angiogenic capacity of aorta decreases with ageing in the oldest rats only. Furthermore, caloric restriction counteracts the age-related changes caloric restrictions actually give raise to a similar recovery. Interestingly, the mRNA ET-1 levels as well as ET-1 expression in aorta sprouting decreases both in middle and in aged animals. Mild and severe caloric restriction regimens prevents ET-1 changes. [Copyright &y& Elsevier]
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- 2007
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15. Antagonistic Effects of Oxidized Low Density Lipoprotein and α-Tocopherol on CD36 Scavenger Receptor Expression in Monocytes.
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Munteanu, Adelina, Taddei, Michele, Tamburini, Ilaria, Bergamini, Ettore, Azzi, Angelo, and Zingg, Jean-Marc
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LOW density lipoproteins , *VITAMIN E , *MONOCYTES , *PROTEIN kinase C , *PROTEIN kinases , *CHEMICAL reactions - Abstract
Vitamin E deficiency increases expression of the CD36 scavenger receptor, suggesting specific molecular mechanisms and signaling pathways modulated by α-tocopherol. We show here that α-tocopherol down-regulated CD36 expression (mRNA and protein) in oxidized low density lipoprotein (oxLDL)-stimulated THP-1 monocytes, but not in unstimulated cells. Furthermore, α-tocopherol treatment of monocytes led to reduction of fluorescent oxLDL-3,3′-dioctadecyloxacarbocyanine perchlorate binding and uptake. Protein kinase C (PKC) appears not to be involved because neither activation of PKC by phorbol 12-myristate 13-acetate nor inhibition by PKC412 was affected by α-tocopherol. However, α-tocopherol could partially prevent CD36 induction after stimulation with a specific agonist of peroxisome proliferator-activated receptor-γ (PPARγ; troglitazone), indicating that this pathway is susceptible to α-tocopherol action. Phosphorylation of protein kinase B (PKB) at Set473 was increased by oxLDL, and α-tocopherol could prevent this event. Expression of PKB stimulated the CD36 promoter as well as a PPARγ element-driven reporter gene, whereas an inactive PKB mutant had no effect. Moreover, coexpression of PPARγ and PKB led to additive induction of CD36 expression. Altogether, our results support the existence of PKB/PPARγ signaling pathways that mediate CD36 expression in response to oxLDL. The activation of CD36 expression by PKB suggests that both lipid biosynthesis and fatty acid uptake are stimulated by PKB. [ABSTRACT FROM AUTHOR]
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- 2006
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16. Peripheral lymphocyte 8-OHdG levels correlate with age-associated increase of tissue oxidative DNA damage in Sprague–Dawley rats. Protective effects of caloric restriction
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Wolf, Federica I., Fasanella, Silvia, Tedesco, Beatrice, Cavallini, Gabriella, Donati, Alessio, Bergamini, Ettore, and Cittadini, Achille
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DNA damage , *BIOCHEMICAL genetics , *LYMPHOCYTES , *AGING - Abstract
Abstract: 8-Hydroxy-deoxyguanosine adducts (8-OHdG), indices of oxidative DNA damage, were measured by immunohystochemistry with diaminobenzidine detection in the brain, skeletal muscle, heart, liver, tenuum mucosa and lymphocytes from young (4 months) and aged (24 months) Sprague–Dawley rats fed ad libitum or held on two different caloric restriction diets (alternate day ad libitum feeding or daily feeding with 40% reduced calories). In the absence of caloric restriction the levels of oxidative DNA damage increased as a function of age in all tissues examined, with a maximum ∼3-fold increase being detected in the peripheral lymphocytes and the heart and a minimum ∼2-fold increase being detected in the liver and brain tissues. Caloric restriction regimens effectively reduced age-dependent increase of oxidative DNA damage in all tissues examined; in particular, the brain and small intestine did not exhibit any age-related increase of oxidative DNA damage. We propose that the levels of 8-OHdG in peripheral lymphocytes may serve a biochemical index of age-related whole organism oxidative DNA damage. Immunohistochemistry might be exploited as a rapid and simple techniques for measuring lymphocytes oxidative DNA damage in large scale studies. [Copyright &y& Elsevier]
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- 2005
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17. Accumulation of dolichol in older tissues satisfies the proposed criteria to be qualified a biomarker of aging.
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Parentini, Ilaria, Cavallini, Gabriella, Donati, Alessio, Gori, Zina, and Bergamini, Ettore
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BIOMARKERS , *AGING , *DIGOXIN , *LIFE spans , *TRISOMY - Abstract
Criteria for defining biomarkers have been suggested. Accumulation of dolichol in tissues of older animals meets the following criteria: (a) levels of dolichol exhibit a quantitative correlation with age in all tissues and are not altered by several age-dependent diseases in the same direction as that of aging; (b) accumulation is not secondary to metabolic changes of aging and is altered appropriately by factors that modulate the aging rate like caloric restriction and physical exercise; (c) biomarker is applicable to different tissues across mammalian species, including humans, and to trisomy 21 and its hypothalamic digoxin-mediated model. Reliable changes in tissue dolichol levels are seen in relatively short intervals of time compared to over a life span, and levels can be tested on a small amount of tissue without causing death of the animal. In this article, we show applications to the study of host-graft interaction and detection of gender-related differences in biological age, and we discuss mechanism(s) of accumulation. [ABSTRACT FROM AUTHOR]
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- 2005
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18. Effects of life-long exercise on circulating free fatty acids and muscle triglyceride content in ageing rats
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Novelli, Michela, Pocai, Alessandro, Skalicky, Monika, Viidik, Andrus, Bergamini, Ettore, and Masiello, Pellegrino
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DEVELOPMENTAL biology , *TRIGLYCERIDES , *TREADMILLS , *ADVERTISING - Abstract
Regular physical exercise has emerged, together with dietary restriction, as an effective intervention in delaying degenerative diseases and augmenting life span in rodents. The mechanisms involved remain largely unknown, although a beneficial influence on the age-related alteration of insulin sensitivity has been hypothesized. As muscle triglyceride (TG) accumulation is considered a reliable index of muscle insulin resistance, in this study we explored muscle TG content in 23-month-old male Sprague–Dawley rats subjected to life-long training. Plasma glucose, insulin, free fatty acid (FFA) and leptin levels were also measured. Both voluntary running in wheels (RW) and forced training in treadmill (TM) were studied. As RW rats weighed less than controls, a cohort of untrained animals, fed to pair weight (PW) with RW, was added to discriminate the effect of exercise from that of food restriction. Sedentary ad libitum fed rats served as controls. In 23-month-old RW rats, muscle TG content was reduced by 50% with respect to age-matched sedentary controls, while in TM group this reduction was smaller but still highly significant, and occurred independently on the changes in body fat mass. In both the trained rat groups, there was a significant decrease in circulating FFA levels and a trend to reduced insulin levels. In PW rats, muscle TG levels decreased similarly to RW rats, while plasma parameters were less modified. In particular, RW training was more effective than PW in preventing the age-related increase in circulating leptin levels. Our results suggest that voluntary exercise effectively counteracts the development of insulin resistance in the muscles of ageing rats as well as other related changes such as hyperlipacidaemia and compensatory hyperleptinaemia. Forced training or moderate food restriction appear slightly less effective than voluntary exercise in preventing age-dependent alterations in nutrient distribution and/or utilization. [Copyright &y& Elsevier]
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- 2004
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19. Anti-aging effects of anti-lipolytic drugs
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Donati, Alessio, Cavallini, Gabriella, Carresi, Cristiano, Gori, Zina, Parentini, Ilaria, and Bergamini, Ettore
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INSULIN shock , *RATS , *DRUGS , *RESEARCH - Abstract
Genetic disruption of insulin and insulin-like signaling pathways may extend lifespan. Hyperinsulinemia and insulin resistance may accelerate aging. The hypothesis was tested that a once-a-week life-long inhibition of insulin secretion by the administration of anti-lipolytic drugs might have anti-aging effects. Groups of 3-month-old male Sprague-Dawley rats were (a) given standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted 1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by the gastric tube. The AL, FW and EOD groups received saline intragastrically. Treatment with ACIPIMOX transiently decreased plasma free fatty acids, glucose and insulin and increased valine plasma levels, and had no long-term effect on food consumption and body weight. By age 6, 12 and 24 months subgroups were taken and the age-related changes in liver dolichol and autophagic proteolysis—which are correlated with life-expectancy—were measured. Liver dolichol levels increased and autophagic proteolysis decreased in mature and older AL rats; EOD and FWA fully counteracted these changes; FW rats had significant but smaller beneficial effects. It is concluded that life-long weekly-repeated transient inhibition of insulin secretion by antilipolytic drugs may have an anti-aging effect, additive to the anti-aging effect of a milder caloric restriction. Speculation is that transiently lower plasma insulin levels might stimulate the anti-aging cell-repair mechanism autophagy, which has longer lasting effects on cell housekeeping. [Copyright &y& Elsevier]
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- 2004
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20. Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis
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Del Roso, Alessandra, Vittorini, Simona, Cavallini, Gabriella, Donati, Alessio, Gori, Zina, Masini, Matilde, Pollera, Maria, and Bergamini, Ettore
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LIVER , *LABORATORY rats , *PROTEOLYSIS - Abstract
Autophagy is a universal, highly regulated mechanism responsible for the degradation of long-lived proteins, cytomembranes and organelles during fasting and may be the cell repair mechanism that mediates the anti-ageing effects of calorie restriction (). The function of autophagy was studied in vivo on male Sprague Dawley rats fed ad libitum or 40% food restricted. Autophagy was induced in overnight fasted rats by the injection of an anti-lipolytic agent and was investigated by electron microscopy. Changes in regulatory plasma nutrients and hormones were assessed and rate of proteolysis was calculated from the release of 14C6-valine from pre-labelled resident proteins. Results in rats fed ad libitum showed that autophagic-proteolytic response to antilypolitic agents was paramount in one month-old rats; was high but delayed in 2 month-old rats, decreased remarkably in 6 month-old rats and almost negligible at older age. Parallel ageing-related changes were observed in the effects of treatment lowering glucose and insulin plasma levels. Calorie restriction prevented all changes. In view of the known suppressive effects of insulin, it may be concluded that the age-changes of autophagy are secondary to the ageing-related alteration in glucose metabolism and hormone levels, whose appearance is delayed by calorie restriction. Data may support the hypothesis that ad libitum feeding accelerates the rate of ageing by raising insulin plasma levels and suppressing autophagy and membrane maintenance, and that calorie restriction may break this vicious circle. [Copyright &y& Elsevier]
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- 2003
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21. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated.
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Lupi, Roberto, Dotta, Francesco, Marselli, Lorella, Guerra, Silvia Del, Masini, Matilde, Santangelo, Carmela, Patané, Giovanni, Boggi, Ugo, Piro, Salvatore, Anello, Marcello, Bergamini, Ettore, Mosca, Franco, Mario, Umberto Di, Prato, Stefano Del, Marchetti, Piero, Del Guerra, Silvia, Patané, Giovanni, Di Mario, Umberto, and Del Prato, Stefano
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FATTY acids , *ISLANDS of Langerhans , *LIPID metabolism , *PROTEIN metabolism , *GLUCOSE metabolism , *APOPTOSIS , *CELL physiology , *COMPARATIVE studies , *INSULIN , *RESEARCH methodology , *MEDICAL cooperation , *TYPE 2 diabetes , *PROTEOLYTIC enzymes , *RESEARCH , *TRIGLYCERIDES , *EVALUATION research , *IN vitro studies - Abstract
In an effort to better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of beta-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated. [ABSTRACT FROM AUTHOR]
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- 2002
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22. Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism.
- Author
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Marchetti, Piero, Lupi, Roberto, Federici, Massimo, Marselli, Lorella, Masini, Matilde, Boggi, Ugo, Del Guerra, Silvia, Patanè, Giovanni, Piro, Salvatore, Anello, Marcello, Bergamini, Ettore, Purrello, Francesco, Lauro, Renato, Mosca, Franco, Sesti, Giorgio, Del Prato, Stefano, and Patanè, Giovanni
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ISLANDS of Langerhans , *AMINO acids - Abstract
Type 2 (non-insulin-dependent) diabetes results from decreased insulin action in peripheral target tissues (insulin resistance) and impaired pancreatic beta-cell function. These defects reflect both genetic components and environmental risk factors. Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. Insulin content was lower in variant than control islets (94 +/- 47 vs. 133 +/- 56 microU/islet; P < 0.05). Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. Glucose utilization and oxidation did not differ in variant and wild-type islets at both low and high glucose levels. Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. These alterations may account for the increased predisposition to type 2 diabetes in individuals carrying the Gly(972)-->Arg amino acid polymorphism of IRS-1. [ABSTRACT FROM AUTHOR]
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- 2002
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23. Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions.
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Donati, Alessio, Cavallini, Gabriella, Paradiso, Cristina, Vittorini, Simona, Pollera, Maria, Gori, Zina, Bergamini, Ettore, Donati, A, Cavallini, G, Paradiso, C, Vittorini, S, Pollera, M, Gori, Z, and Bergamini, E
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AGING & nutrition , *PROTEIN metabolism , *LIVER cells - Abstract
Autophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair and as a source of nutrients for metabolic use in early starvation. The effects of two antiaging dietary regimens (initiated in rats at the age of 2 months), namely, 40% dietary restriction (DR) and every-other-day ad-libitum feeding, that exhibited different effects on metabolism and similar effects on longevity on the age-related changes in the regulation of autophagic proteolysis were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells of male albino Sprague-Dawley rats aged 2, 6, 12, 18, 24, and 27 months. (The liver cells were incubated in vitro with added amino acids and 10(-7) M insulin or glucagon.) Age-matched male albino Sprague-Dawley rats fed ad libitum served as a control. Results show that in ad-libitum-fed rats, after a transient increase by age 6 months, autophagic proteolysis and regulation by amino acid exhibit a dramatic age-related decline, and that the age-related changes are prevented by dietary antiaging intervention. A comparison shows that the protective effects of DR and every-other-day ad-libitum feeding are partially different in 24-month-old rats (but the beneficial effects of the two diets on regulation of autophagic proteolysis are always similar). With regard to endocrine regulation, results confirm that the liver cell response to glucagon (but not to insulin) declines with increasing age, and they show that antiaging DRs significantly improve the effects of glucagon (and have no effect on the response to insulin). The interactions of age by diet, glucagon (and in older rats, insulin), and amino acids are significant. It is concluded that DR significantly improves the susceptibility of liver cells to lysosomal degradation, and it prevents decline with increasing age. It is suggested that improved liver autophagy and lysosomal degradation might be part of the antiaging mechanisms of DR. [ABSTRACT FROM AUTHOR]
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- 2001
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24. Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes.
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Donati, Alessio, Cavallini, Gabriella, Paradiso, Cristina, Vittorini, Simona, Pollera, Maria, Gori, Zina, Bergamini, Ettore, Donati, A, Cavallini, G, Paradiso, C, Vittorini, S, Pollera, M, Gori, Z, and Bergamini, E
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AUTOPHAGY , *LIVER cells , *RATS - Abstract
During intervals between meals, autophagy is a major source of nutrients and may remove damaged organelles and membranes. Age-related changes in the regulation of autophagic proteolysis were studied by monitoring the rate of valine release from liver cells of 2-, 6-, 12-, 18-, and 24-month-old male Sprague-Dawley rats fed ad libitum, and incubated in vitro with added amino acids and 10(-7) M of insulin or glucagon. The maximum rate of proteolysis and its maximum inhibition by amino acids were reached at 6 months and declined thereafter. In contrast, the rate of protein degradation in the presence of high concentrations of amino acids was not affected by aging. The inhibitor effect of insulin was additive to that of amino acids and was not altered significantly by age. The conclusion is that altered regulation of autophagic proteolysis decreases susceptibility of older cells to lysosomal degradation, and it may lead to the accumulation of altered organelles and membranes. [ABSTRACT FROM AUTHOR]
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- 2001
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25. Calorie restriction protects against age-related rat aorta sclerosis.
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Castello, Laura, Froio, Teresa, Cavallini, Gabriella, Biasi, Fiorella, Sapino, Anna, Leonarduzzi, Gabriella, Bergamini, Ettore, Poli, Giuseppe, and Chiarpotto, Elena
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LOW-calorie diet , *FIBROSIS , *COLLAGEN diseases , *AORTA , *ARTERIES , *TISSUES , *PROTEIN kinases , *LABORATORY rats - Abstract
Investigates whether calorie restriction (CR) might down-regulate fibrosis by preventing oxidant-dependent signaling and consequent fibrogenic stimulus. Effect of CR on age-related increase of oxidative damage and fibrosis in rat aorta; Protection offered by CR against tissue sclerosis through down-regulation of mitogen-activated protein kinases.
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- 2005
- Full Text
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