Carla Iacobini

The adaptor protein p66Shc regulates oxidative stress and aging, but its role in renal aging is unclear. We investigated the effects of p66Shc deletion on age-related kidney changes, focusing on G protein-coupled receptor 124 (GPR124) and cellular senescence. Using kidney and urine samples from p66Shc^−/− and wild-type mice aged 5–24 months, we found that p66Shc deficiency slows renal aging. Compared to wild-type mice, p66Shc^−/− mice showed better kidney function and reduced glomerular sclerosis and mesangial expansion from 18 months, alongside attenuated fibrosis, oxidative stress, and podocyte loss. Age-related declines in GPR124 were also smaller in p66Shc^−/− mice, correlating with lower p16^INK4a levels in glomeruli and cultured podocytes. These findings suggest that p66Shc deletion provides kidney protection by limiting oxidative stress and senescence, potentially through the preservation of GPR124. This study links p66Shc to natural kidney aging and identifies GPR124 as a mediator of p66Shc-driven senescence, suggesting potential targets for interventions in age-related renal decline.

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor’s involvement in renal damage of different origins.

Aims: To investigate the relationship between changes in physical fitness and cardiovascular risk factors and scores in patients with type 2 diabetes receiving either a behavioural counselling intervention to increase moderate‐to‐vigorous‐intensity physical activity (MVPA) and decrease sedentary‐time (SED‐time) or standard care.Materials and Methods: This is a pre‐specified ancillary analysis of the Italian Diabetes and Exercise Study_2, a 3‐year randomized clinical trial in which 300 physically inactive and sedentary patients were randomized 1:1 to receive either a one‐month theoretical and practical counselling each year or standard care. Mean changes from baseline throughout the 3‐year period in MVPA, SED‐time, cardiorespiratory fitness (VO_2max), muscle strength, flexibility, cardiovascular risk factors and scores were calculated for study completers (n = 267) and considered irrespective of study arm.Results: Haemoglobin (Hb) A_1c and coronary heart disease (CHD) risk scores decreased with quartiles of VO_2max and lower body muscle strength changes. Multivariable linear regression analysis showed that increases in VO_2max independently predicted decreases in HbA_1c, blood glucose, diastolic blood pressure (BP), CHD and total stroke 10‐year risk and increases in HDL cholesterol, whereas increases in lower body muscle strength independently predicted decreases in body mass index (BMI), waist circumference, triglycerides, systolic BP, CHD and fatal stroke 10‐year risk. These associations remained after including changes in BMI, waist circumference, fat mass and fat‐free mass, or MVPA and SED‐time as covariates.Conclusions: Improvement in physical fitness predicts favourable changes in cardiometabolic risk profile, independent of changes not only in (central) adiposity or body composition but also in MVPA and SED‐time.Trial Registration: ClinicalTrials.gov; NCT01600937; URL https://clinicaltrials.gov/ct2/show/NCT01600937.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.

Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today’s unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.

Background and Purpose: The advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy (DN) by promoting renal inflammation and injury. L‐carnosine acts as a quencher of the AGE precursors reactive carbonyl species (RCS), but is rapidly inactivated by carnosinase. In this study, we evaluated the effect of FL‐926‐16, a carnosinase‐resistant and bioavailable carnosine derivative, on the onset and progression of DN in db/db mice.Experimental Approach: Adult male db/db mice and coeval db/m controls were left untreated or treated with FL‐926‐16 (30 mg·kg⁻¹ body weight) from weeks 6 to 20 (prevention protocol) or from weeks 20 to 34 (regression protocol).Key Results: In the prevention protocol, FL‐926‐16 significantly attenuated increases in creatinine (−80%), albuminuria (−77%), proteinuria (−75%), mean glomerular area (−34%), fractional (−40%) and mean (−42%) mesangial area in db/db mice. This protective effect was associated with a reduction in glomerular matrix protein expression and cell apoptosis, circulating and tissue oxidative and carbonyl stress, and renal inflammatory markers, including the NLRP3 inflammasome. In the regression protocol, the progression of DN was completely blocked, although not reversed, by FL‐926‐16. In cultured mesangial cells, FL‐926‐16 prevented NLRP3 expression induced by RCS but not by the AGE N^ε‐carboxymethyllysine.Conclusion and Implications: FL‐926‐16 is effective at preventing the onset of DN and halting its progression in db/db mice by quenching RCS, thereby reducing the accumulation of their protein adducts and the consequent inflammatory response. In a future perspective, this novel compound may represent a promising AGE‐reducing approach for DN therapy.

Galectin-3 is expressed in various tissues, including the bone, where it is considered a marker of chondrogenic and osteogenic cell lineages. Galectin-3 protein was found to be increased in the differentiated chondrocytes of the metaphyseal plate cartilage, where it favors chondrocyte survival and cartilage matrix mineralization. It was also shown to be highly expressed in differentiating osteoblasts and osteoclasts, in concomitance with expression of osteogenic markers and Runt-related transcription factor 2 and with the appearance of a mature phenotype. Galectin-3 is expressed also by osteocytes, though its function in these cells has not been fully elucidated. The effects of galectin-3 on bone cells were also investigated in galectin-3 null mice, further supporting its role in all stages of bone biology, from development to remodeling. Galectin-3 was also shown to act as a receptor for advanced glycation endproducts, which have been implicated in age-dependent and diabetes-associated bone fragility. Moreover, its regulatory role in inflammatory bone and joint disorders entitles galectin-3 as a possible therapeutic target. Finally, galectin-3 capacity to commit mesenchymal stem cells to the osteoblastic lineage and to favor transdifferentiation of vascular smooth muscle cells into an osteoblast-like phenotype open a new area of interest in bone and vascular pathologies.