Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity

The coming age of flavonoids in the treatment of diabetic complications

Diabetes mellitus (DM), and its micro and macrovascular complications, is one of the biggest challenges for world public health. Despite overall improvement in prevention, diagnosis and treatment, its incidence is expected to continue increasing over the next years. Nowadays, finding therapies to prevent or retard the progression of diabetic complications remains an unmet need due to the complexity of mechanisms involved, which include inflammation, oxidative stress and angiogenesis, among others. Flavonoids are natural antioxidant compounds that have been shown to possess anti-diabetic properties. Moreover, increasing scientific evidence has demonstrated their potential anti-inflammatory and anti-oxidant effects. Consequently, the use of these compounds as anti-diabetic drugs has generated growing interest, as is reflected in the numerous in vitro and in vivo studies related to this field. Therefore, the aim of this review is to assess the recent pre-clinical and clinical research about the potential effect of flavonoids in the amelioration of diabetic complications. In brief, we provide updated information concerning the discrepancy between the numerous experimental studies supporting the eficacy of flavonoids on diabetic complications and the lack of appropriate and well-designed clinical trials. Due to the well-described beneficial effects on different mechanisms involved in diabetic complications, the excellent tolerability and low cost, future randomized controlled studies with compounds that have adequate bioavailability should be evaluated as add-on therapy on well-established anti-diabetic drugsThis paper was not funded. The authors work has been supported by FEDER-ISCIII Funds (PI17/00130, PI17/01495), Spanish Ministry of Economy and Competitiveness (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN) and Spanish Society of Atherosclerosis (SEA). TCO is an employee of FAES Pharma. The authors (except JAM) have an ongoing research project in common with FAES Pharma on Flavonoids in diabetic complications under the auspices of the joint-RETOS Collaborations Project 2017 (RTC-2017-6089-1), program supported by Spanish Ministry of Economy and Competitiveness

Hemodynamic Tolerance of Virtual Reality Intradialysis Exercise Performed during the Last 30 Minutes versus the Beginning of the Hemodialysis Session

[EN] Background: Exercise improves the physical function of people suffering from chronic kidney disease on hemodialysis (HD). Virtual reality is a new type of intradialysis exercise that has a positive impact on physical function. Intradialysis exercise is recommended during the first 2 h, but its safety in the last part of the dialysis session is unknown. Methods: This was a pilot sub-study of a clinical trial. Several hemodynamic control variables were recorded, including blood pressure, heart rate, and intradialytic hypotensive events. These variables were recorded during three different HD sessions, one HD session at rest, another HD session with exercise during the first two hours, and one HD session with exercise during the last 30 min of dialysis. The intradialysis virtual reality exercise was performed for a maximum of 30 min. Results: During exercise sessions, there was a significant increase in heart rate (6.65 (4.92, 8.39) bpm; p < 0.001) and systolic blood pressure (6.25 (0.04,12.47) mmHg; p < 0.05). There was no difference in hemodynamic control between the sessions with exercise during the first two hours and the sessions with exercise during the last 30 min. There was no association between intra-dialytic hypotensive events at rest (five events) or exercise at any point (two vs. one event(s), respectively). Conclusion: performing exercise with virtual reality at the end of a hemodialysis session is not associated with hemodynamic instability.Funding included a research project (PID2019-108814RA-I00) supported by the Spanish Government 'Ministerio de Ciencia e Innovacion', a research prize awarded by the nonprofit organization Fundacion Renal Tomas de Osma, as well as from a research grant (IDOC 17-19 and PPC14/2017) awarded by the Universidad Cardenal Herrera CEU.García-Testal, A.; Martínez-Olmos, FJ.; Gil-Gómez, J.; López-Tercero, V.; Lahoz-Cano, L.; Hervás-Marín, D.; Cana-Poyatos, A.... (2023). Hemodynamic Tolerance of Virtual Reality Intradialysis Exercise Performed during the Last 30 Minutes versus the Beginning of the Hemodialysis Session. Healthcare. 11(1). https://doi.org/10.3390/healthcare1101007911

Neurotoxicity of prion peptides mimicking the central domain of the cellular prion protein

The physiological functions of PrP(C) remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrP(C) are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown

Dative constructions in Romance and beyond

This book offers a comprehensive account of dative structures across languages –with an important, though not exclusive, focus on the Romance family. As is well-known, datives play a central role in a variety of structures, ranging from ditransitive constructions to cliticization of indirect objects and differentially marked direct objects, and including also psychological predicates, possessor or causative constructions, among many others. As interest in all these topics has increased significantly over the past three decades, this volume provides an overdue update on the state of the art. Accordingly, the chapters in this volume account for both widely discussed patterns of dative constructions as well as those that are relatively unknown