Dietary interventions to contrast the onset and progression of diabetic nephropathy. a critical survey of new data

This article is a critical overview of recent contributions on the dietary corrections and the foods that have been claimed to delay or hinder the onset of diabetic nephropathy (DN) and its progression to end-stage renal disease. Innovative dietary and behavioral approaches to the prevention and therapy of DN appear the more captivating in consideration of the rather well established protocols for glucose and blood pressure control in use. In addition to restricted caloric intake to contrast obesity and the metabolic syndrome, adjustments in the patient's macronutrients intake, and in particular some degree of reduction in protein, have been long considered in the prevention of DN progression. More recently, the focus has shifted to the source of proteins and the content of glycotoxins in the diet as well as to the role of specific micronutrients. Few clinical trials have specifically addressed the role of those micronutrients associated with diet proteins that show the most protective effect against DN. Research on clinical outcome and mechanisms of action of such micronutrients appears the most promising in order to develop both effective intervention on nutritional education of the patient and selection of functional foods capable of contrasting the onset and progression of DN

Role of galectin-3 in bone cell differentiation, bone pathophysiology and vascular osteogenesis

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

Synthesis of 1,2-diamines using nitrogen-containing heterocyclic templates

This thesis describes the development of new methods for the synthesis of 1,2- diamines. Chapter one reviews current methods for the synthesis of 1,2- diamines, and their importance in chemistry. Chapter two highlights attempts to synthesise 1,2-diamines using two nitrogen-containing heterocycles, namely 3- phenyl-1,3,5-triazabicyclo[3.2.0]hept-6-ene-2,4-dione and imidazolin-2-one, which both contain an endocyclic double bond. It includes the synthesis of a novel 1,2-diazetine as well as the functionalisation of imidazolin-2-one via a palladium-catalysed cross-coupling reaction with phenyl iodide. Subsequent hydrogenation and hydrolysis was then utilised to afford 1-phenylethane-1,2- diamine dihydrochloride. Chapter three describes the synthesis and functionalisation of a range of 3-methylene-1,2-diazetidines that were subsequently hydrogenated in an asymmetric fashion, with [Rh(NBD)2]BF4 and ligand Mandyphos M004-1, to yield 1,2-diazetidines with up to 89% ee. Reduction with LiDBB allowed for the synthesis of two carbamate-protected 1,2-diamines in three steps. The first examples of epoxidation, reaction with tetracyanoethylene and 1,3-dipolar cycloadditions of 3-methylene-1,2- diazetidines are reported. Chapter four details the experimental procedures and characterisation data for the novel compounds produced

Deficiency of the purinergic receptor 2X7 attenuates nonalcoholic steatohepatitis induced by high-fat diet. possible role of the NLRP3 Inflammasome

Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH), a critical step in the progression of nonalcoholic fatty liver disease (NAFLD) to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7), through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7 −/−) and coeval wild-type (WT) mice were fed a high-fat diet (HFD) or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7 −/− than WT mice, and only 1/7 Pr2x7 −/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7 −/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets

Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

PMCID: PMC3579848This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The inflammasome in chronic complications of diabetes and related metabolic disorders

Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications

The "sweet" path to cancer. focus on cellular glucose metabolism

The hypoxia-inducible factor-1α (HIF-1α), a key player in the adaptive regulation of energy metabolism, and the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), a critical regulator of glucose consumption, are the main drivers of the metabolic rewiring in cancer cells. The use of glycolysis rather than oxidative phosphorylation, even in the presence of oxygen (i.e., Warburg effect or aerobic glycolysis), is a major metabolic hallmark of cancer. Aerobic glycolysis is also important for the immune system, which is involved in both metabolic disorders development and tumorigenesis. More recently, metabolic changes resembling the Warburg effect have been described in diabetes mellitus (DM). Scientists from different disciplines are looking for ways to interfere with these cellular metabolic rearrangements and reverse the pathological processes underlying their disease of interest. As cancer is overtaking cardiovascular disease as the leading cause of excess death in DM, and biological links between DM and cancer are incompletely understood, cellular glucose metabolism may be a promising field to explore in search of connections between cardiometabolic and cancer diseases. In this mini-review, we present the state-of-the-art on the role of the Warburg effect, HIF-1α, and PKM2 in cancer, inflammation, and DM to encourage multidisciplinary research to advance fundamental understanding in biology and pathways implicated in the link between DM and cancer

The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis

Vascular calcification correlates with inflammation and plaque instability in a dual manner, depending on the spotty/granular (micro) or sheet-like/lamellated (macro) pattern of calcification. Modified lipoproteins trigger both inflammation and calcification via receptors for advanced lipoxidation/glycation endproducts (ALEs/AGEs). This study compared the roles of galectin-3 and receptor for AGEs (RAGE), two ALEs/AGEs-receptors with diverging effects on inflammation and bone metabolism, in the process of vascular calcification. We evaluated galectin-3 and RAGE expression/localization in 62 human carotid plaques and its relation to calcification pattern, plaque phenotype, and markers of inflammation and vascular osteogenesis; and the effect of galectin-3 ablation and/or exposure to an ALE/AGE on vascular smooth muscle cell (VSMC) osteogenic differentiation. While RAGE co-localized with inflammatory cells in unstable regions with microcalcification, galectin-3 was expressed also by VSMCs, especially in macrocalcified areas, where it co-localized with alkaline phosphatase. Expression of galectin-3 and osteogenic markers was higher in macrocalcified plaques, whereas the opposite occurred for RAGE and inflammatory markers. Galectin-3-deficient VSMCs exhibited defective osteogenic differentiation, as shown by altered expression of osteogenic transcription factors and proteins, blunted activation of pro-osteoblastogenic Wnt/β-catenin signalling and proliferation, enhanced apoptosis, and disorganized mineralization. These abnormalities were associated with RAGE up-regulation, but were only in part prevented by RAGE silencing, and were partially mimicked or exacerbated by treatment with an AGE/ALE. These data indicate a novel molecular mechanism by which galectin-3 and RAGE modulate in divergent ways, not only inflammation, but also vascular osteogenesis, by modulating Wnt/β-catenin signalling, and independently of ALEs/AGEs

Diabetes and pancreatic cancer-a dangerous liaison relying on carbonyl stress

Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals

Diabetic complications and oxidative stress: A 20‐year voyage back in time and back to the future

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