Sirt3 and metabolic reprogramming mediate the antiproliferative effects of whey in human colon cancer cells

Emerging strategies to improve healthy aging include dietary interventions as a tool to promote health benefits and reduce the incidence of aging-related comorbidities. The health benefits of milk are also linked to its richness in betaines and short-chain acylcarnitines, which act synergisti-cally in conferring anticancer, anti-inflammatory, and antioxidant properties. Whey, despite being a dairy by-product, still has a considerable content of bioactive betaines and acylcarnitines. Here, we investigated the anticancer properties of whey from Mediterranean water buffalo (Bubalus bubalis) milk by testing its antiproliferative effects in colorectal cancer (CRC) cells HT-29, HCT 116, LoVo and SW480. Results indicated that treatment with whey for 72 h inhibited cell proliferation (p < 0.001), induced cell cycle arrest, and apoptosis via caspase-3 activation, and modulated cell metabolism by limiting glucose uptake and interfering with mitochondrial energy metabolism with the highest effects observed in HT-29 and HCT 116 cells. At molecular level, these effects were accompanied by upregulation of sirtuin 3 (SIRT3) (p < 0.01) and peroxisome proliferator-activated receptor (PPAR)-γ expression (p < 0.001), and downregulation of lactate dehydrogenase A (LDHA) (p < 0.01), sterol regulatory-element binding protein 1 (SREBP1) (p < 0.05), and PPAR-α (p < 0.01). Transient SIRT3 gene silencing blocked the effects of whey on the LDHA, PPAR-γ, and PPAR-α protein expressions (p < 0.01) suggesting that the whey capacity of perturbating the metabolic homeostasis in CRC cell lines is mediated by SIRT3

1-N6-Etheno-ADP-ribosylation of elongation factor-2 by diphtheria toxin

AbstractDiphtheria toxin fragment A is able to inhibit protein synthesis in the eukaryotic cell by ADP-ribosylating the diphthamide residue of elongation factor-2 (EF-2) [(1980) J. Biol. Chem. 255, 10710-10720]. The reaction requires NAD as ADP-ribose donor. This work reports on the capacity of an NAD analog, the nicotinamide 1-N6-ethenoadenine dinucleotide (ϵNAD), to be a substrate of diphtheria toxin fragment A in the transferring reaction of the fluorescent moiety, the ϵADP-ribose, to the EF-2. As a consequence of the transfer of the ϵADP-ribosyl moiety to the EF-2, there is an increase in the emission intensity of the fluorophore and a blue shift in its emission maximum. The ϵADP-ribosylated EF-2, like ADP-ribosylated EF-2, retains the capacity to bind GTP and ribosome. The utility of introducing a fluorescent probe in a well defined point of the EF-2 molecule for conformational or binding studies is discussed

Association between benzodiazepine prescriptions and potential risk factors of adverse drug reactions among elderly and very elderly: Findings from Friuli Venezia Giulia region, Italy

4noBackground: benzodiazepines (BDZs) highly increase the risk of adverse drug reactions (ADRs), especially in the elderly with certain medical conditions. Methods: point-prevalence study in December 2017; 2,456 patients ≥65 years were included from 14 regional public and private hospitals, 24 long-term chronic care facilities (LTCCFs) and 20 nursing homes (NHs). Data regarded BDZ prescriptions and comorbidities, co-prescriptions, or concurrent diseases, which could increase the risk of ADRs in BDZ users. Univariate and multivariate logistic regression analyses were used to assess associations between ADRs in BDZ users vs. non-users, as well as within users. Results: 671 patients were prescribed BDZ, whose half were in NHs. Being prescribed 10 or more drugs was twice more common among BDZ users compared to non-users. BDZs were prescribed for long-term to 80% of patients in NHs, while proportions were halved in hospitals and LTCCFs. In the analyses within BDZ users, patients in NHs and LTCCFs were at higher risk of dementia and concurrent use of opioid analgesic and antipsychotics compared to hospitalized patients. Conclusions: the use of BDZs in older patients is common in FVG. A great extent of comorbidities and concurrent medications at higher risk of ADRs was found. Analyses in different healthcare settings can allow to drive evidence-based interventions in order to discourage the use of BDZs and monitor the raise of ADRs.nonenoneCastelpietra G.; Balestrieri M.; Brusaferro S.; Arnoldo L.Castelpietra, G.; Balestrieri, M.; Brusaferro, S.; Arnoldo, L

SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

Emerging evidence indicates that defects in sirtuin signaling contribute to impaired glucose and lipid metabolism, resulting in insulin resistance (IR) and endothelial dysfunction. Here, we examined the effects of palmitic acid (PA) treatment on mitochondrial sirtuins (SIRT2, SIRT3, SIRT4, and SIRT5) and oxidative homeostasis in human endothelial cells (TeloHAEC). Results showed that treatment for 48 h with PA (0.5 mM) impaired cell viability, induced loss of insulin signaling, imbalanced the oxidative status (p &lt; 0.001), and caused negative modulation of sirtuin protein and mRNA expression, with a predominant effect on SIRT3 (p &lt; 0.001). Restoration of SIRT3 levels by mimic transfection (SIRT3+) suppressed the PA-induced autophagy (mimic NC+PA) (p &lt; 0.01), inflammation, and pyroptosis (p &lt; 0.01) mediated by the NLRP3/caspase-1 axis. Moreover, the unbalanced endothelial redox state induced by PA was counteracted by the antioxidant δ-valerobetaine (δVB), which was able to upregulate protein and mRNA expression of sirtuins, reduce reactive oxygen species (ROS) accumulation, and decrease cell death. Overall, results support the central role of SIRT3 in maintaining the endothelial redox homeostasis under IR and unveil the potential of the antioxidant δVB in enhancing the defense against IR-related injuries

Rx for addiction and medication safety: An evaluation of teen education for opioid misuse prevention

Background: Rhode Island (RI) ninth graders report lifetime nonmedical use of prescription opioids (NMUPO) of 8.9%. NMUPO is associated with transition to heroin use, opioid overdose, and death. Objectives: Measure changes in 9th grade students\u27 knowledge, confidence, perceptions of opioid use disorder prevention, overdose response with naloxone, treatment, and recovery, following the delivery of an interactive substance use disorder curriculum. Methods: Eight RI public high schools were recruited to participate. Freshman in each school were administered identical surveys that collected demographic data, substance use and misuse knowledge, students\u27 perceptions of substance misuse harm, reported drug use, and risk and protective behaviors before and after the curriculum. Results: Among 969 pre-intervention survey respondents, 19% reported use of marijuana, 3% heroin use, and 21% nonmedical use of prescription opioids. Between the pre-intervention to the post-intervention survey, significantly more students identified that addiction is a chronic brain disease (79%–83%, p = 0.05), drug users are not responsible for their addiction (81%–88%, p = 0.001), and that non-medical use of a prescription medication is use without a prescription (81%–88%, p = 0.001). Improved confidence was also reported in identifying opioid withdrawal symptoms (26%–45%, p \u3c 0.0001), identifying signs of an opioid overdose from 29% to 46% (p \u3c 0.0001), and knowing when to administer naloxone (17%–45%, p \u3c 0.0001). Confidence to refer someone to treatment improved from 31% to 45% (p \u3c 0.0001). Logistic regression showed associations between mental health, peer use, parental affection, and academic performance factors as related to NMUPO. Conclusions: Students reported significant NMUPO prevalence. Ninth grade students\u27 knowledge and confidence of opioid misuse, overdose response, and recovery resources increased following the delivery of a multi-modal interactive substance use disorder curriculum. Community, school, and student-level interventions are needed to reduce NMUPO

Psychometric properties and diagnostic accuracy of the short form of the geriatric anxiety scale (GAS-10)

Background: Anxious symptoms have a negative impact on different aspects of the elderly\u2019s quality of life, ranging from the adoption of unhealthy lifestyle behaviours to an increased functional impairment and a greater physical disability. Different brief assessment instruments have been developed as efficacy measures of geriatric anxiety in order to overcome psychometric weaknesses of its long form. Among these, the 10-item Geriatric Anxiety Scale (GAS-10) showed strong psychometric properties in community-dwelling samples. However, its diagnostic accuracy is still unexplored, as well as its discriminative power in clinical samples. Methods: In the present study, we explored the psychometric performance of the GAS-10 in the elderly through Item Response Theory in a sample of 1200 Italian community-dwelling middle-aged and elderly adults (53.8% males, mean age = 65.21 \ub1 9.19 years). Concurrent validity, as well as diagnostic accuracy, was examined in a non-clinical sample (N = 229; 46.72% males) and clinical sample composed of 35 elderly outpatients (74.28% females) with Generalized Anxiety Disorder (GAD). Results: The GAS-10 displayed good internal construct validity, with unidimensional structure and no local dependency, good accuracy, and no signs of Differential Item Functioning (DIF) or measurement bias due to gender, but negligible due to the age. Differences in concurrent validity and diagnostic accuracy among the long form version of the GAS and the GAS-10 were not found significant. The GAS-10 may be more useful than the longer versions in many clinical and research applications, when time constraints or fatigue are issues. Conclusion: Using the ROC curve, the GAS-10 showed good discriminant validity in categorizing outpatients with GAD disorder, and high anxiety symptoms as measured by the GAS-SF cut-off. The stable cut-off point provided could enhance the clinical usefulness of the GAS-10, which seems to be a promising valid and reliable tool for maximize diagnostic accuracy of geriatric anxiety symptoms

Validation of the Italian version of the Revised Prenatal Coping Inventory (NuPCI) and its correlations with pregnancy-specific stress

Background: Pregnancy is a period of happiness but also of physical and psychological changes that can lead to distress. Functional coping strategies can reduce the pregnancy specific-stress. This study aimed to assess the psychometric properties of the Revised Prenatal Coping Inventory (NuPCI) in an Italian sample and to investigate how coping strategies were associated with pregnancy-specific stress. Methods: In this cross-sectional study, low-risk pregnant women (N = 211) were assessed with NuPCI, NuPDQ (Revised-Prenatal Distress Questionnaire), Brief-COPE (Coping Orientation to the Problems Experienced), and STAI (State-Trait Anxiety Inventory). The reliability of NuPCI was evaluated by assessing its internal consistency and factor structure (with a Confirmatory Factor Analysis, CFA). The concurrent validity between NuPCI and Brief-COPE and NuPDQ and STAI was investigated. Lastly, the relationship between NuPCI and NuPDQ was analyzed, as well as the ability of these scales to predict Apgar score at birth. Results: Internal consistency of NuPCI scales was good for Planning-Preparation (\u251C=0.84) and Spiritual-Positive Coping (\u251C=0.81) scales, acceptable for Avoidance (\u251C=0.76) scale. Moreover, the original three-factor structure was confirmed using a CFA with 29 of the 32 items (\u3c72374 = 618.06; RMSEA = 0.056, 95% confidence interval: [0.048, 0.063]); CFI = 0.920; and TLI = 0.913). Statistically significant correlations between NuPCI scales and Brief-COPE subscales ranged between r = + 0.217 and r = + 0.624; also, NuPDQ score was positively correlated with STAI scales (State scale: r = + 0.539; Trait scale: r = + 0.462). Concurrent validity was confirmed reporting that NuPDQ score was predicted by NuPCI scores (R2 = 0.423, p < 0.001), positively by Avoidance (\u3b2=+0.572) and Planning-Preparation (\u3b2=+0.215) and negatively by Spiritual-Positive Coping (\u3b2=-0.132). Finally, considering the stress, the effect of the Avoidance and Spiritual-Positive Coping scores respectively in decreasing (+ 155%) and increasing (+ 16%) the Apgar score became stronger. Conclusions: Italian NuPCI has sound psychometric properties and it is a useful coping measure. NuPDQ showed also a good validity. Our results may suggest a significant role for coping strategies, particularly in modulating the condition of the newborn at birth

New perspectives on an “old” technique: Lipari obsidian and Neolithic communities investigated by Fission Track Dating

“Lipari obsidian and Neolithic human communities in the Aeolian islands” is a project aimed at studying the connection between obsidian flows on the island of Lipari and Neolithic populations on the Aeolian archipelago, in Italy. As it is well known, obsidian is of particular interest to trace prehistorical trading patterns; indeed, Lipari obsidian has the widest distribution and has been found in southern France, Dalmazia, Sicily and mainland Italy. The project outputs will give a general vision of both archaeological and volcanological aspects through thestratigraphic and radiometric dating of eruptions which produced obsidian, in relationship with the first phases of the human settlements and row material exploitation. To reach this goal, we are considering both raw materials (geological samples) from different flows and artifacts from Neolithic settlements (archaeological samples) on the Aeolian islands, and performing fission track dating to get the age of obsidian sources and artefacts. Obtained results are expected to shed some new light on the raw material procurement and on the ability of the Neolithic populations to move from their locations, with particular attention to the consequences of environmental features on the first human settlements on the Aeolian islands