Modulation of the oxidative stress and lipid peroxidation by endocannabinoids and their lipid analogues

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts

Assessment of Exercise Stroke Volume and Its Prediction From Oxygen Pulse in Paralympic Athletes With Locomotor Impairments: Cardiac Long-Term Adaptations Are Possible

The determinants of cardiac output (CO) during exercise, i.e., stroke volume (SV) and heart rate (HR), could differ in Paralympic athletes (PAthl) with spinal cord injury (SCI) with respect to PAthl with locomotor impairments caused by different health conditions (HCs). The purposes of the present study were the comparisons of two groups of PAthl, one with SCI and the other with either amputation (AMP) or post poliomyelitis syndrome (PM), assessing the (1) peak cardiorespiratory responses and determinants (SV and HR) of CO during maximal and submaximal arm cranking exercise (ACE), respectively; (2) correlations between peak oxygen uptake (VO2peak) and the highest SV obtained during submaximal exercise; and (3) correlations between oxygen pulse (O-2 pulse, ratio between VO2 and HR) and both SV and O-2 arterio-venous difference [(a-v)O(2)diff]. Each athlete (19 PAthl with SCI, 9 with AMP, and 5 with PM) completed a continuous incremental cardiopulmonary ACE test to volitional fatigue to assess peak responses. In a different session, CO was indirectly measured through carbon dioxide (CO2) rebreathing method at sub-maximal exercise intensities approximating 30, 50, and 70% of the VO2peak. There were no significant differences between the PAthl groups in age, anthropometry, and VO2peak. However, peak HR was significantly lower, and peak O-2 pulse was significantly higher in PAthl with AMP/PM compared to those with SCI. During sub-maximal exercise, PAthl with AMP/PM displayed significantly higher SV values (154.8 +/- 17.60 ml) than PAthl with SCI (117.1 +/- 24.66 ml). SV correlated significantly with VO2peak in both PAthl with SCI (R-2 = 0.796) and AMP/PM (R-2 = 0.824). O-2 pulse correlated significantly with SV in both PAthl with SCI (R-2 = 0.888) and AMP/PM (R-2 = 0.932) and in the overall sample (R-2 = 0.896). No significant correlations were observed between O-2 pulse and (a-v)O(2)diff. It was concluded that in PAthl with different HCs: (1) significant differences, as a consequence of the different HC, exist in the determinants of CO at maximal and submaximal ACE; (2) SV is a significant determinant of VO2peak, suggesting cardiac adaptations possible also in PAthl with SCI; and (3) SV can be predicted from O-2 pulse measurements during submaximal exercise in both groups of PAthl

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4’-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC

Pharmacological targeting of CBP/p300 drives a redox/autophagy axis leading to senescence-induced growth arrest in non-small cell lung cancer cells

p300/CBP histone acetyltransferases (HAT) are critical transcription coactivators involved in multiple cellular activities. They act at multiple levels in non-small cell lung carcinoma (NSCLC) and appear, therefore, as promising druggable targets. Herein, we investigated the biological effects of A-485, the first selective (potent) drug-like HAT catalytic inhibitor of p300/CBP, in human NSCLC cell lines. A-485 treatment specifically reduced p300/CBP-mediated histone acetylation marks and caused growth arrest of lung cancer cells via activation of the autophagic pathway. Indeed, A-485 growth-arrested cells displayed phenotypic markers of cell senescence and failed to form colonies. Notably, disruption of autophagy by genetic and pharmacological approaches triggered apoptotic cell death. Mechanistically, A-485-induced senescence occurred through the accumulation of reactive oxygen species (ROS), which in turn resulted in DNA damage and activation of the autophagic pathway. Interestingly, ROS scavengers were able to revert senescence phenotype and restore cell viability, suggesting that ROS production had a key role in upstream events leading to growth arrest commitment. Altogether, our data provide new insights into the biological effects of the A-485 and uncover the importance of the autophagic/apoptotic response to design a new combinatorial anticancer strategy

Has COVID-19 Delayed the Diagnosis and Worsened the Presentation of Type 1 Diabetes in Children?

Objective: To evaluate whether the diagnosis of pediatric type 1 diabetes or its acute complications changed during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Italy. Research design and methods: This was a cross-sectional, Web-based survey of all Italian pediatric diabetes centers to collect diabetes, diabetic ketoacidosis (DKA), and COVID-19 data in patients presenting with new-onset or established type 1 diabetes between 20 February and 14 April in 2019 and 2020. Results: Fifty-three of 68 centers (77.9%) responded. There was a 23% reduction in new diabetes cases in 2020 compared with 2019. Among those newly diagnosed patient who presented in a state of DKA, the proportion with severe DKA was 44.3% in 2020 vs. 36.1% in 2019 (P = 0.03). There were no differences in acute complications. Eight patients with asymptomatic or mild COVID-19 had laboratory-confirmed severe acute respiratory syndrome coronavirus 2. Conclusions: The COVID-19 pandemic might have altered diabetes presentation and DKA severity. Preparing for any "second wave" requires strategies to educate and reassure parents about timely emergency department attendance for non-COVID-19 symptoms

Diabetic ketoacidosis at the onset of disease during a national awareness campaign: a 2-year observational study in children aged 0-18 years

After a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013-2014 in Italy, we aimed to verify a possible decline in the incidence of DKA at onset during a national prevention campaign

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements