Changing to Impress: Testing a Mediation Model from Instagram Self-presentation to Cosmetic Surgery.

BACKGROUND: This study examined the relationship between false self-presentation on Instagram and consideration of cosmetic surgery through the mediating role of body image control in photos (BICP), photo manipulation, and body shame. We predicted that false self-presentation on Instagram was indirectly associated with cosmetic surgery intentions through the aforementioned constructs. METHODS: A total of 504 young Italian adults (28.2% males, 18-30 years) completed an online survey. They completed a questionnaire containing the Self-presentation on Instagram Questionnaire, the Body Image Control in Photos Questionnaire-revised, the Photo Manipulation Scale, the Objectified Body Consciousness Scale, and the Acceptance of Cosmetic Surgery Scale. The pattern of associations between the constructs was analyzed via path analysis. RESULTS: The results show that false self-presentation on Instagram was associated with photo manipulation, both directly and indirectly, through BICP. Furthermore, photo manipulation was linked to body shame, but neither of them was associated with cosmetic surgery intentions. Finally, false self-presentation on Instagram was associated with the consideration of cosmetic surgery only through the mediation of BICP. CONCLUSION: Findings indicate that self-presentation styles might affect Instagram photo behaviors and individuals' cosmetic surgery intentions, suggesting that surgeons should fully examine patients' motivations before providing them with services. Furthermore, intervention programs encouraging users to present a more authentic version of themselves online might reduce the risk of self-objectification and reduce the consideration of procedures aimed at modifying one's body for purely aesthetic reasons. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Delayed hypersensitivity reactions to iodinated contrast media: A diagnostic approach by skin tests.

BACKGROUND: Adverse drug reactions to iodinated contrast media (ICM) have risen due to their increasing use in x-ray-based imaging modalities. Delayed hypersensitivity reactions are mainly caused by nonionic monomeric compounds and represent an issue impacting the diagnostic-therapeutic pathways of cancer, cardiology and surgery patients. OBJECTIVES: To prospectively evaluate the usefulness of skin tests in delayed hypersensitivity reactions to ICM and to evaluate the tolerability of iobitridol, a monomeric nonionic low osmolality compound, as a possible safe alternative. METHODS: Patients with delayed hypersensitivity reactions to ICM referred to us from 2020 to 2022 were prospectively enrolled in the study. All patients underwent patch test and, if negative, intradermal test with the culprit ICM and iobitridol as alternative. RESULTS: A total of 37 patients (females 24, 64.9%) were enrolled in the study. Iodixanol and iomeprol were the most frequently involved ICM (48.5% and 35.2%, respectively); 62.2% of patients presented maculopapular eruption, while 37.8% reported delayed urticaria-like rash. Skin tests resulted positive to the culprit ICM in 19 patients (51.4%), 16 to patch test and 3 to intradermal test. Skin tests with iobitridol, tested as alternative, resulted positive in 3/19 patients (15.8%). All 16 patients with negative results to iobitridol were administered this ICM and tolerated it. CONCLUSIONS: In at least half of patients, delayed-type hypersensitivity was demonstrated by skin tests, particularly by patch test. This diagnostic approach resulted simple, cost-effective and safe, not only to confirm the culprit ICM but also to identify iobitridol as feasible alternative.

A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction.

Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.

There is a correlation between nutritional status, Self-Rated Health and Life Satisfaction? Evidence from 2018 Health Behaviour in School-aged Children cross sectional study in a sample of Italian adolescents living in Tuscany Region.

Background: Overweight has been associated with several social and phycological problems and is perceived as one of the major health care challenges to focus on in the future. The purpose of the study is to investigate the correlations among nutritional status, assessed by the Body Mass Index, the perception of one's own health status and Life Satisfaction, detected in Italian adolescents living in Tuscany Region, and to investigate the influence of gender on them. Methods: A statistically representative sample of 2760 Tuscan adolescents aged 11, 13 and 15 was involved in the 2018 Health Behaviours at School-aged Children survey. The participants were divided into three nutritional status class: underweight, normal weight and overweight (overweight + obese). Results: The results show that there is a statistically significant difference in all categories between boys and girls aged 13 and 15 years; in girls aged 11 and 13 years, the Life Satisfaction of the overweight group is statistically lower than that of normal and underweight groups; Self-Rated Health is statistically lower in all age groups for overweight individuals compared to normal weight children, except for 11-year-old females. Conclusions: Viewing the psychosocial problems related to overweight, more attention and care must be placed on adolescents to ensure their healthier development.

Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance.

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.

Risk Behaviors among Migrant Adolescents in Italy.

Adolescence is a critical period for engaging in health risk behaviors. Migrant adolescents may face unique challenges due to acculturation stress. This study aims to monitor substance use and problem gambling among migrant adolescents living in Italy. Data from the 2017/18 Health Behavior in School-Aged Children survey in Italy were analyzed. The 18,794 participants included 15-year-olds, categorized as native or migrants, with ethnic backgrounds from Western, Eastern European, or non-Western/non-European countries. Girls had higher smoking rates, while boys exhibited higher prevalence of alcohol-related risk behaviors, cannabis use, and gambling. Boys from Eastern European countries displayed a greater risk of drunkenness (OR: 1.58, 95% CI: 1.06-2.37), particularly in the first generation, while those from Western countries showed a higher risk of multiple substance use (OR: 1.44, 95% CI: 1.05-1.96). Girls from Eastern European and non-Western/non-European countries had a lower risk of alcohol consumption (OR: 0.50, 95% CI: 0.29-0.85; OR: 0.55, 95% CI: 0.33-0.91, respectively). Finally, boys, especially those from Eastern European and non-Western/non-European countries, had a significantly higher risk of problem gambling (OR: 1.83, 95% CI: 1.04-3.22; OR: 2.10, 95% CI: 1.29-3.42, respectively). This disparity was more pronounced in the first generation, possibly due to acculturation challenges and socio-economic factors. Risk behaviors in adolescents are influenced by complex interplays of gender, cultural factors, and migration generation. Preventive strategies should consider these factors to effectively address substance use and gambling in this heterogeneous population.

Metastasis: cancer cell's escape from oxidative stress.

According to a "canonical" view, reactive oxygen species (ROS) positively contribute, in different ways, to carcinogenesis and to malignant progression of tumor cells: they drive genomic damage and genetic instability, transduce, as signaling intermediates, mitogenic and survival inputs by growth factor receptors and adhesion molecules, promote cell motility and shape the tumor microenvironment by inducing inflammation/repair and angiogenesis. Chemopreventive and tumor-inhibitory effects of endogenous, diet-derived or supplemented antioxidants largely support this notion. However, emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance. This "heresy" has recently received important impulse from studies on the role of antioxidant capacity in cancer stem cells self-renewal and resistance to therapy; additionally, the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox-sensitive transcription factors, and results in an increase of cell resistance to oxidants. On the other hand, cytoskeleton rearrangement underlying cell motile and tumor-aggressive behavior use ROS as intermediates and are therefore facilitated by oxidative stress. Along this line of speculation, we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.

Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion.

Signal transduction by reactive oxygen species (ROS; "redox signaling") has recently come into focus in cellular biology studies. The signaling properties of ROS are largely due to the reversible oxidation of redox-sensitive target proteins, and especially of protein tyrosine phosphatases, whose activity is dependent on the redox state of a low pKa active site cysteine. A variety of mitogenic signals, including those released by receptor tyrosine kinase (RTKs) ligands and oncogenic H-Ras, involve as a critical downstream event the intracellular generation of ROS. Signaling by integrins is also essential for the growth of most cell types and is constantly integrated with growth factor signaling. We provide here evidence that intracellular ROS are generated after integrin engagement and that these oxidant intermediates are necessary for integrin signaling during fibroblast adhesion and spreading. Moreover, we propose a synergistic action of integrins and RTKs for redox signaling. Integrin-induced ROS are required to oxidize/inhibit the low molecular weight phosphotyrosine phosphatase, thereby preventing the enzyme from dephosphorylating and inactivating FAK. Accordingly, FAK phosphorylation and other downstream events, including MAPK phosphorylation, Src phosphorylation, focal adhesion formation, and cell spreading, are all significantly attenuated by inhibition of redox signaling. Hence, we have outlined a redox circuitry whereby, upon cell adhesion, oxidative inhibition of a protein tyrosine phosphatase promotes the phosphorylation/activation and the downstream signaling of FAK and, as a final event, cell adhesion and spreading onto fibronectin.

Role of the life span determinant P66(shcA) in ethanol-induced liver damage.

Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66(shcA)) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66+/+ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66-/- mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.

Bilirubin as an endogenous modulator of neurotrophin redox signaling.

Bilirubin is neurotoxic upon excess accumulation in the brain, but it also plays important physiological roles related to its antioxidant properties. Here we report that exposure of PC12 and primary rat cerebellar granule neurons to bilirubin (0.5-10 microM) drastically decreases nerve growth factor (NGF)/brain-derived neurotrophic factor signaling to Akt and extracellular signal-regulated kinases (ERKs), indicating a direct interference of the molecule with crucial prosurvival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, the latter being able to inhibit, in PC12 cells, accumulation of intracellular reactive oxygen species and phosphorylation of Akt and ERKs in response to extracellular hydrogen peroxide. Interestingly, in the absence of exogenous growth factor, bilirubin elicited the phosphorylation of ERKs and of the cAMP responsive element binding (CREB) transcription factor, a signature of NGF-dependent survival signaling. These growth factor-like signaling effects were paralleled by the induction of the neuronal nitric oxide synthase (nNOS) and generation of nitric oxide (NO). Pharmacological dissection of the signaling cascade triggered by bilirubin revealed that phosphorylation of ERKs requires NO signaling through soluble guanylyl cyclase, and, further upstream, influx of extracellular calcium is necessary for nNOS induction and NO release, likely through calcium-dependent phosphorylation of CREB. Importantly, the cascade elicited by bilirubin through NO and ERK is cytoprotective, as revealed by exacerbated bilirubin toxicity in cultures treated by either NOS or MEK inhibitors. Taken together, these observations indicate an important action of bilirubin on redox signaling by neurotrophins, with either inhibitory or agonistic effects based on growth factor availability.

Percutaneous ultrasound-guided ablation of BW7756-hepatoma using ethanol or acetic acid in a rat model.

BACKGROUND: To compare tumor necrosis in hepatoma induced in rats by a single percutaneous injection of ethanol (PEI) or acetic acid (PAI). METHODS: BW7756 hepatomas of 1 mm3 were implanted in the liver of 40 male healthy rats. After 14 days, the 36 surviving rats were treated, in a single session, by ultrasound-guided injection of 300 microl of 95% ethanol (n = 17) or 100 microl of 50% acetic acid (n = 19). They were sacrificed 14 days after treatment and explanted tumoral livers were examined. The same PAI procedure was repeated on 13 additional rats to exclude a suspected occurrence of technical failures during the experiment, due to a surprisingly high rate of deaths within 30 minutes after PAI. RESULTS: Four rats died within four days after tumor implantation; after PEI, 1/17 (6%) died, whereas after PAI 9/19 (47%) died. The remaining 26 rats, after 14 days post-percutaneous ablation, were sacrificed. Gross and microscopic examinations showed that the hepatoma's nodules treated with PEI had 45.3 +/- 19.4% tumor necrosis compared to 49 +/- 23.3% (P = NS) for those treated with PAI. Complete tumor necrosis was not found in any animal. Peritoneal invasion was present in 4/16 (25%) and 2/10 (20%) rats treated with PEI or PAI, respectively (P = NS). Autopsy was performed in the 5 additional rats that died within 30 minutes after PAI. CONCLUSION: Our results show that there is no significant difference in the percentage of tumor necrosis between two local ablation methods in spite of the different dosages used. However, mortality in the PAI-treated group was greater than in PEI-treated group, presumably due to greater acetic acid systemic diffusion and its metabolic side effects. In human subjects, HCC occurs in the setting of cirrhosis, where the non-tumoral tissue is firmer than the tumor structure, with consequent reduction of drug diffusion. This could be the reason why some human studies have concluded similar or even better safety and efficacy with PAI compared to PEI.

Repeated exposure to pyrrolidine-dithiocarbamate induces peripheral nerve alterations in rats.

Pyrrolidine-dithiocarbamate (PDTC), a synthetic compound widely used in cell biological investigations, recently attracted considerable interest as a putative anticancer agent. However, different dithiocarbamates have previously shown to cause neurological symptoms and morphological alterations in peripheral nerves. The purpose of the present study was to determine whether a 15-day oral administration with low doses of PDTC may produce adverse effects in peripheral nerves of rats. Female Wistar rats were assigned to receive PDTC [0.1, 0.5 or 1.0mmol/(kg body weight/day)] by gavage for 15 days. Reduced conduction velocity was observed by electrophysiological analysis in tibial nerves of treated animals, accompanied by a marked decrease in Shwann cell S100-protein expression determined by immunohistochemistry. Electron microscopy evaluation revealed marked myelin degeneration in the fibers of treated animals. In particular, both morphological and electrophysiological data suggested an impairment of large, fast conducting fibers, whereas the smallest and slowest ones remained intact. However, the activity of plasma and liver alkaline-phosphatase, an enzymic marker of hepatic dithiocarbamate toxicity, was not altered by the treatment. The total contents of the redox-active metal copper increased in tibial nerves of treated rats and was accompanied by raised levels of lipid peroxidation products. This finding suggests a role for oxidative stress in the development of PDTC-induced pathological and functional alterations of tibial nerves. The observation that a 15-day treatment with low doses of PDTC causes functional and morphological derangement of peripheral nerves advices against the possible use of this compound as a chemopreventive agent against cancer.

Oxidative stress and antioxidant defenses in ethanol-induced cell injury.

Although in the past several mechanisms and factors have been proposed to be responsible for alcoholic liver disease (ALD), at present the involvement of oxygen free radicals and consequently of oxidative stress has acquired remarkable credit. In numerous experimental studies it has been shown the occurrence of alcohol-induced generation of oxygen- and ethanol-derived free radicals through different pathways and from different sources. Mitochondria appear to be both an important source of reactive oxygen species (ROS) and also a primary target of ethanol-induced damage. The consistent induction of the mitochondrial antioxidant enzyme manganese superoxide dismutase (Mn-SOD) observed in experimental animals after acute and chronic ethanol administration has all the characteristics of a "stress response" to an oxidative insult.

Mitochondrial superoxide dismutase: a promising target for new anticancer therapies.

Compelling experimental and epidemiological evidence involves oxygen radicals in carcinogenesis, acting reactive oxygen species both as endogenous genotoxins during cell initiation and as messenger molecules in mitogenesis and in tumor promotion. Moreover, oxidants stimulate neoangiogenesis, which is a prerequisite for tumor growth. However, while several natural as well as synthetic antioxidant compounds appear to be chemopreventive in mutagenicity assays, antioxidant-based treatments for the prevention or cure of cancer have led to non-conclusive if not disappointing results. This is likely due to the fact that oxygen radicals have also a major role in the natural defences against the propagation of cancer cells, i.e. tumor cell apoptosis and immune surveillance, and mediate the beneficial cytotoxic effect of both the chemo-and radio-therapy. In recent years, the mitochondrial antioxidant enzyme, Manganous Superoxide Dismutase (MnSOD), has received a growing attention as a negative modulator of cellular apoptosis and as a survival factor for cancer cells. In fact, while overexpression of this enzyme in cancer cells decreases proliferation and tumor incidence in transgenic models, it is clear that even small amounts of this enzyme are crucial for cell resistance to inflammatory stimuli and anticancer drugs, and prevent oncogene-induced apoptosis triggered by the tumor suppressor protein p53. A previously unexpected oncogenic potential of MnSOD is also suggested by the elevated levels of this enzyme in several classes of human neoplasms, in a fashion which often correlates with the degree of their malignancy. This review focuses on the debated issue of the pro- and/or anti-tumoral effect of MnSOD, with special emphasis on recent observations suggesting that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells and to circumvent their resistance to the commonly used anticancer treatments.

Radiofrequency ablation of hepatic tissue: a new experimental animal model.

BACKGROUND/AIMS: Experimental radiofrequency ablation has already been performed in healthy livers of porcine models, but not in less expensive and easy-to-manage rats, with devices capable of delivering radiofrequency ablation in the 20-30 g liver of such small animals being so far unavailable. METHODOLOGY: We experimented with a modified system of radiofrequency ablation of liver tissue in rat models developing a custom-made needle-microelectrode of very small dimensions (0.3x2 mm) and an electrode-tip cooling technique, based on saline solution infusion. We adjusted duration (seconds) and power (watts) of radiofrequency ablation letting them range between 5-50 seconds and 5-25 W, respectively, to obtain the greatest lesions with the least side effects. After sacrificing the animals, an accurate histological examination of the liver was made. RESULTS: It is possible to establish beforehand the diameter of thermal liver lesion on the basis of joules of applied energy. The greatest increase of liver thermal lesion diameter (8 mm) is obtained with a 250-joule (10 W for 25 seconds) thermal energy cooling the electrode-tissue interface. CONCLUSIONS: Experimental radiofrequency ablation in rat liver is an effective and cheap way to study its effects on healthy hepatic tissues. It might be the first step to treat experimentally caused liver tumors.

Association of the OCTN1/1672T variant with increased risk for colorectal cancer in young individuals and ulcerative colitis patients.

BACKGROUND: Ulcerative colitis (UC) is associated with colorectal cancer. Chronic inflammation may also play a role in the pathogenesis of sporadic colorectal cancer (SCC), particularly in younger patients (<55 years). We evaluated whether single nucleotide polymorphisms of the OCTN1 and OCTN2 genes are associated with UC, SCC, and with UC cases with cancer progression (UCCP). METHODS: We evaluated the OCTN1 and OCTN2 polymorphisms in 200 patients with UC, 59 patients with UCCP, 200 patients with SCC, and 200 controls (HC). IL-8 expression was also assessed by real-time polymerase chain reaction (PCR). Additionally, we transfected human colon carcinoma Caco2 cells, homozygous for OCTN1/1672T variant, with the OCTN1/1672C allele and NF-κB activity was evaluated by luciferase based reporter assay and IL-8 mRNA expression by real-time PCR. RESULTS: OCTN2 polymorphisms did not present a significant association with any group of patients compared to normal controls. Conversely, homozygosity for the OCTN1/1672T variant was significantly associated with UC (P = 0.047 vs. HC), with UCCP (UCCP vs. HC, P < 0.001), and with SCC developing in early age (<55 years) (P = 0.021 vs. HC). Importantly, IL-8 mRNA expression was higher in UC and UCCP patients homozygous for the OCTN1 1672T variant compared to the other genotypes. Moreover, in Caco2 cells transfection of the OCTN1/1672C variant reduced the activity of the proinflammatory factor NF-κB. CONCLUSION: Our data demonstrate that OCTN1 could have a role in modulating the severity of chronic inflammation associated with SCC in early age and in UC patients, and that its polymorphisms may help to predict malignant progression of IBD.

Role of MnSOD and p66shc in mitochondrial response to p53.

Control of intracellular redox balance has emerged as a primary function of the p53 network, with crucial implications for tumor suppression, aging, and cell metabolism. Mitochondria are central to redox homeostasis, produce energy, and trigger apoptosis and senescence: not surprisingly, many "old" and "new" functions of p53 appear to be based in mitochondria. Genetic and biomolecular evidence indicates that generation of reactive oxygen species (ROS) in mitochondria can be a deliberate and finely regulated cell response on which signaling by environmental stressors, oncogenes, and nutrients converge. p53 orchestrates mitochondrial redox signaling by the coordinated control of at least two key effectors: the superoxide scavenger MnSOD, and the ROS generator p66shc. This review presents recent evidence and emerging questions regarding the p53-MnSOD-p66shc connection, and discusses how dissection of a circuitry comprising a tumor suppressor, an antioxidant, and a molecule regulating cell survival and mammalian lifespan can provide a framework to address important aspects related to the intricate connection between metabolism, aging, and cancer.

Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage.

Deregulated nutrient signaling plays pivotal roles in body ageing and in diabetic complications; biochemical cascades linking energy dysmetabolism to cell damage and loss are still incompletely clarified, and novel molecular paradigms and pharmacological targets critically needed. We provide evidence that in the retrovirus-packaging cell line HEK293-T Phoenix, massive cell death in serum-free medium is remarkably prevented or attenuated by either glucose or aminoacid withdrawal, and by the glycolysis inhibitor 2-deoxy-glucose. A similar protection was also elicited by interference with mitochondrial function, clearly suggesting involvement of energy metabolism in increased cell survival. Oxidative stress did not account for nutrient toxicity on serum-starved cells. Instead, nutrient restriction was associated with reduced activity of the mTOR/S6 Kinase cascade. Moreover, pharmacological and genetic manipulation of the mTOR pathway modulated in an opposite fashion signaling to S6K/S6 and cell viability in nutrient-repleted medium. Additionally, stimulation of the AMP-activated Protein Kinase concomitantly inhibited mTOR signaling and cell death, while neither event was affected by overexpression of the NAD+ dependent deacetylase Sirt-1, another cellular sensor of nutrient scarcity. Finally, blockade of the mTOR cascade reduced hyperglycemic damage also in a more pathophysiologically relevant model, i.e. in human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemia. Taken together these findings point to a key role of the mTOR/S6K cascade in cell damage by excess nutrients and scarcity of growth-factors, a condition shared by diabetes and other ageing-related pathologies.