Reactive aldehydes – second messengers of free radicals in diabetes mellitus

Jaganjac, Morana; Tirosh, Oren; Cohen, Guy; Sasson, Shlomo; Žarković, Neven

doi:10.3109/10715762.2013.789136

Cited by 111 publications

(94 citation statements)

References 93 publications

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“…Being saturated, PA is not subjected to peroxidation, yet it effectively augmented 4-HNE production in INS-1E cells by increasing the availability of AA and LA to peroxidation. We, and others, have reported that 4-hydroxyalkenals activate the PPARδ nuclear receptor in various cells, including beta cells [13,19,24,35,38]. The findings that 4-HNE scavenging with L-carnosine and PPARδ inhibition or its silencing attenuated PA-induced GSIS further support the role of the 4-HNE-PPARδ axis in beta cell function [13,39].…”

Section: Discussionsupporting

confidence: 59%

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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Aims/hypothesis Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucosestimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability. Methods INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly. Results PA was incorporated into membrane phospholipids in a concentration-and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death. Conclusions/interpretation These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.

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Section: Discussionsupporting

confidence: 59%

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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“…Hyperglycaemia generates ROS, which in turn causes damage to the cells in many ways. Damage to the cells ultimately results in secondary complications in diabetes mellitus (Hunt, Dean & Wolff 1988;Jaganjac et al 2013). Research data indicate that in diabetic patients, the gastric cells are subject to oxidative stress (Lomax, Sharkey & Furness 2010).…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic and anti-oxidant activities of the methanol leaf extract of <i>Vernonia amygdalina</i> in alloxan-induced diabetes in Wistar rats

Adeoye

Oyagbemi

Adedapo

et al. 2017

JOMPED

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The methanolic leaf extract of Vernonia amygdalina (MLVA) was assessed to evaluate its antidiabetic potential in rats. Diabetes was induced in male Wistar rats by the administration of alloxan monohydrate at 100 mg/kg of body weight. After 48 h, rats with fasting blood glucose levels of 200 mg/dL and above were considered diabetic and used for the study. The experimental animals were grouped into five groups (A–E) of 10 animals each. Group A rats were non-diabetic normal control, Group B consisted of diabetic control rats that received no treatment, groups C, D and E rats were diabetic rats but treated with glibenclamide, 200 and 400 mg/kg doses of MLVA respectively. Blood samples were collected at days 14 and 28 after induction for haematological and serum biochemical indices such as triglycerides, LDL, cholesterols etc. The intestine was collected and intestinal homogenate was prepared for the antioxidant studies. The extract at 200 mg/kg and 400 mg/kg doses significantly (p < 0.05) reduced blood glucose levels in extract-treated diabetic rats and also significantly increased weight gain in these rats. Most haematological parameters in treated rats experienced, while platelets and neutrophils were decreased. Biochemical indices measured were reduced in MLVA-treated groups compared with diabetic control. Treatment with MLVA also produced significant (p < 0.05) decrease in markers of oxidative stress but increased levels of enzymic and non-enzymic antioxidant markers in intestinal homogenates of treated groups compared with diabetic control. This study showed that V. amygdalina has antihyperglycaemic and in vivo antioxidant effects.

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“…The principles have mostly commonly been explored with linoleic acid and have focused on the formation of 4-hydroxy-2-nonenal (HNE), owing to the fact that it is one of the most abundantly formed lipid peroxidation products and has interesting biological effects [8,28,29]. The mechanisms are (i) reduction of hydroperoxide to an alkoxyl radical in the presence of a transition metal followed by β-scission; (ii) Hock rearrangement of a hydroperoxide and migration of a C-C to a C-O bond and cleavage; (iii) cyclization to form a dioxetane and subsequent cleavage.…”

Section: Aldehydes Are Fragmentation Products Of Oxidized Lipidsmentioning

confidence: 99%

“…Moreover, oxidized phospholipids are also bioactive, but in many cases have different effects to the corresponding free oxidized fatty acid, including both proinflammatory and anti-inflammatory effects. Lipid peroxidation has been associated with the physiopathology of several diseases, including atherosclerosis, cancer, diabetes and neurodegenerative disorders, as previously reviewed [8,9]. It is also important to bear in mind that non-radical lipid oxidation can also occur through the action of hypochlorous acid, which generates chlorinated products that have been reported to have bioactivity [10].…”

Section: Introductionmentioning

confidence: 99%

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Sousa

Pitt

Spickett

2017

Free Radical Biology and Medicine

138

105

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The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually D,β-unsaturated), γ-substituted alkenals and bis-aldehydes.Isolevuglandins are non-fragmented di-carbonyl compounds derived from H 2 -isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate D-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the D,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best Page | 2 known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule.However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research. AbbreviationsAcr-dG, 1,N2-propanodeoxyguanosine; AGEs, advanced glycation end-product; ALEs, advanced lipoxidation end product; ApoB100, apolipoprotein B100; ApoE, apolipoprotein E; ARP, aldehyde reactive probe; AspN, endoproteinase AspN (flavastacin); βLG, β-lactoglobulin; BHZ, biotin hydrazide; BN-PAGE, blue native polyacrylamide gel

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Reactive aldehydes – second messengers of free radicals in diabetes mellitus

Cited by 111 publications

References 93 publications

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Antidiabetic and anti-oxidant activities of the methanol leaf extract of <i>Vernonia amygdalina</i> in alloxan-induced diabetes in Wistar rats

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

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