A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

A Bayesian multi-proxy contribution to the socioeconomic, political, and cultural history of late medieval Capitanata (southern Italy)

: Medieval southern Italy is typically viewed as a region where political, religious, and cultural systems coexisted and clashed. Written sources often focus on elites and give an image of a hierarchical feudal society supported by a farming economy. We undertook an interdisciplinary study combining historical and archaeological evidence with Bayesian modelling of multi-isotope data from human (n = 134) and faunal (n = 21) skeletal remains to inform on the socioeconomic organisation, cultural practices, and demographics of medieval communities in Capitanata (southern Italy). Isotopic results show significant dietary differences within local populations supportive of marked socioeconomic hierarchies. Bayesian dietary modelling suggested that cereal production, followed by animal management practices, was the economic basis of the region. However, minor consumption of marine fish, potentially associated with Christian practices, revealed intra-regional trade. At the site of Tertiveri, isotope-based clustering and Bayesian spatial modelling identified migrant individuals likely from the Alpine region plus one Muslim individual from the Mediterranean coastline. Our results align with the prevailing image of Medieval southern Italy but they also showcase how Bayesian methods and multi-isotope data can be used to directly inform on the history of local communities and of the legacy that these left

Respiratory and cardiovascular function at rest and during exercise testing in a healthy working population: effects of outdoor traffic air pollution

Background There is controversy regarding long-term adverse effects of urban pollutants in urban workers. Aim The aim of this study was to evaluate the effects of urban pollutants on respiratory and cardiovascular function in exposed traffic policemen compared to a control group. Methods Sixty-eight traffic policemen and 62 controls (all male) were investigated at rest and during symptom-limited incremental exercise test (performed with a cycle ergometer). The data were statistically evaluated. Results There were no significant differences in the mean values of resting ventilatory capacity, the forced spirometric test, or in blood gas parameters between the groups. The traffic exposed group demonstrated a number of significant changes in cardio respiratory measures on exercise testing. Twenty-six traffic policemen and none of the controls experienced exercise-induced ECG abnormalities, hypertension or oxyhaemoglobin desaturation; 80% of the 26 had resting PaO2 values <80 mmHg. Conclusion The findings suggest that chronic occupational exposure to urban pollutants reduces resistance to physical effort and increases the risk of cardiovascular and respiratory changes including slight hypoxemia

Identification of biochemical and molecular markers of early aging in childhood cancer survivors

Survival rates of childhood cancer patients have improved over the past four decades, although cancer treatments increase the risk of developing chronic diseases typical of aging. Thus, we aimed to identify molecular/metabolic cellular alterations responsible for early aging in childhood cancer survivors (CCS). Biochemical, proteomic, and molecular biology analyses were conducted on mononuclear cells (MNCs) isolated from peripheral blood of 196 CCS, the results being compared with those obtained on MNCs of 154 healthy subjects. CCS-MNCs showed inefficient oxidative phosphorylation associated with low energy status, and increased lipid peroxidation and lactate fermentation compared with age-matched normal controls. According to a mathematical model based on biochemical parameters, CCS-MNCs showed significantly higher metabolic ages than their real ages. The dysfunctional metabolism of CCS-MNCs is associated with lower expression levels of genes and proteins involved in mitochondrial biogenesis and metabolism regulation, such as CLUH, PGC1-alpha, and SIRT6 in CCS, not observed in the age-matched healthy or elderly subjects. In conclusion, our study identified some biochemical and molecular alterations possibly contributing to the pathophysiology of aging and metabolic deficiencies in CCS. These results identify new targets for pharmacological interventions to restore mitochondrial function, slowing down the aging-associated pathologies in CCS

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e., in high-fat-diet\u2013fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM