Advanced Lipid Peroxidation End Products Research Articles

Long-term exposure to advanced lipid peroxidation end products impairs cognitive function through microbiota-gut-brain axis

The frequent intake of ultra-processed, heat-processed, and fat-enriched foods rich in dietary advanced lipoxidation end-products (ALEs) has been correlated with cognitive decline; however, the underlying mechanisms of action remain unexplored. This study investigated the impact of a 12-month dietary exposure to ALEs on learning, memory, and Aβ1–42 accumulation in mice, with a focus on the AMPK/SIRT1 signaling pathway and ADAM10 expression. The gut microbiota and metabolomic profiles revealed ALEs-induced gut dysbiosis and cognitive impairment, highlighting modulation through the microbiota-gut-brain axis. Key findings include increased pathogenic bacteria and decreased beneficial bacteria, linked to metabolite profile changes that affect neurotoxic Aβ1–42 peptide accumulation. This long-term comprehensive study underscores the need for dietary guidelines to reduce ALE intake and mitigate neurodegenerative disease risk, highlighting the intricate interplay between diet, gut microbiota, and cognitive health.

The Cutaneous Physiological Redox: Essential to Maintain but Difficult to Define.

Skin is a unique tissue, possessing extremely efficient protective and regulative mechanisms, similar only to the gut and lungs. These tissues serve as an interface with the environment and are exposed to stressors from both endogenous and exogenous sources. Interestingly, all these stressors lead downstream to a cellular production of reactive oxygen species (ROS) and other electrophiles, which, in turn could have deleterious outcomes for the living organism. Hence, such tissues should always maintain a “high-alert” condition in order to cope with these various insults. Nevertheless, a moderate production of ROS induced by stressors could actually be beneficial, although it is impossible to predict if and which exposure would lead to which outcome. Consequently, a parameter which would indicate the skin’s readiness to cope with continuously fluctuating conditions is required. It has been proposed that the redox status may serve as a suitable indicator. In this opinion manuscript, we argue that the redox status is a vague parameter that is difficult to characterized and quantify due to its extremely dynamic nature. The common convention that the redox status is composed solely of the balance between oxidants and reductants (ROS and antioxidants) is also thought-provoking. Since this parameter in vivo behaves in a dynamic and complex manner, it better fits the description of a process, rather than an individual parameter. We suggest that the homeostatic modulation of the physiological redox (PR) should be in focus, rather than the redox status parameter itself. It is further suggested that low molecular weight antioxidants (LMWA) are, in fact, rather insignificant concerning the PR maintenance, and that the major contributors to this delicate modulation are regulative, protein-based systems such as the protective phase II antioxidant enzymes. Moreover, we show that skin microbiome and cutaneous advanced lipid peroxidation end-products (ALEs) take part in sustaining the cutaneous PR homoeostasis via activation of the Nrf2–Keap1 protective pathway.

Can Medicinal Plants and Bioactive Compounds Combat Lipid Peroxidation Product 4-HNE-Induced Deleterious Effects?

The toxic reactive aldehyde 4-hydroxynonenal (4-HNE) belongs to the advanced lipid peroxidation end products. Accumulation of 4-HNE and formation of 4-HNE adducts induced by redox imbalance participate in several cytotoxic processes, which contribute to the pathogenesis and progression of oxidative stress-related human disorders. Medicinal plants and bioactive natural compounds are suggested to be attractive sources of potential agents to mitigate oxidative stress, but little is known about the therapeutic potentials especially on combating 4-HNE-induced deleterious effects. Of note, some investigations clarify the attenuation of medicinal plants and bioactive compounds on 4-HNE-induced disturbances, but strong evidence is needed that these plants and compounds serve as potent agents in the prevention and treatment of disorders driven by 4-HNE. Therefore, this review highlights the pharmacological basis of these medicinal plants and bioactive compounds to combat 4-HNE-induced deleterious effects in oxidative stress-related disorders, such as neurotoxicity and neurological disorder, eye damage, cardiovascular injury, liver injury, and energy metabolism disorder. In addition, this review briefly discusses with special attention to the strategies for developing potential therapies by future applications of these medicinal plants and bioactive compounds, which will help biological and pharmacological scientists to explore the new vistas of medicinal plants in combating 4-HNE-induced deleterious effects.

Hydroxypyridinone-Diamine Hybrids as Potential Neuroprotective Agents in the PC12 Cell-Line Model of Alzheimer's Disease.

There is an urgent need to propose effective treatments for Alzheimer’s disease (AD). Although the origin of the disease is poorly understood, several therapeutic options have been proposed. The new therapeutic approaches targeting biometal-mediated neurodegenerative pathways appear to be interesting ones. As a continuation of our preceding studies, two novel series of advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) inhibitors have been developed as multifunctional scavengers. This extended work allowed us to highlight the new hydroxypyridinone-diamine hybrid IIa-3 bearing a C4 alkyl linker between the two pharmacophores. This derivative exhibited preserved potent capacities to trap reactive carbonyl species (vicinal diamine function) as well as reactive oxygen species and transition metals (hydroxypyridinone moiety) in comparison with previously described lead compound 1. In addition, its good predicted absorption, distribution, metabolism and excretion (ADME) properties were correlated with a better efficacy to inhibit in vitro methylglyoxal-induced apoptosis in neuronal-like PC12 cells. This new promising agent revealed improved druglikeness and ability to prevent biometal-mediated oxidative and carbonyl stress amplification involved in AD pathogenesis.

Intensification of serum albumin amyloidogenesis by a glycation-peroxidation loop (GPL)

The interaction of reducing sugars with proteins leads to the formation of advanced glycation end products (AGE) and reactive oxidative species (ROS). ROS peroxidise free or membrane included unsaturated fatty acids, leading to generate reactive aldehydes as advanced lipid peroxidation end products (ALE). Aldehydes from lipid peroxidation (LPO) react with proteins to cause alteration of protein structure to exacerbate complication of diseases. Here we studied serum albumin glycation in the presence and absence of liposomes as a bio-membrane model to investigate protein structural changes using various techniques including intrinsic and extrinsic fluorescence spectroscopies and electron microscopy analysis. Accordingly, serum albumin glycation and fibrillation were accelerated and intensified in the presence of liposomes through a hypothesized glycation-peroxidation loop (GPL). Together, our results shed light on the necessity of reconsidering diabetic protein glycation to make it close to physiological conditions mimicry, more importantly, proteins structural change due to diabetic glycation is intensified in the proximity of cell membranes which probably potentiates programmed cell death distinct from apoptosis.

Redox homeostasis in stomach medium by foods: The Postprandial Oxidative Stress Index (POSI) for balancing nutrition and human health

Red-meat lipid peroxidation in the stomach results in postprandial oxidative stress (POS) which is characterized by the generation of a variety of reactive cytotoxic aldehydes including malondialdehyde (MDA). MDA is absorbed in the blood system reacts with cell proteins to form adducts resulting in advanced lipid peroxidation end products (ALEs), producing dysfunctional proteins and cellular responses. The pathological consequences of ALEs tissue damage include inflammation and increased risk for many chronic diseases that are associated with a Western-type diet. In earlier studies we used the simulated gastric fluid (SGF) condition to show that the in vitro generation of MDA from red meat closely resembles that in human blood after consumption the same amount of meat. In vivo and in vitro MDA generations were similarly suppressed by polyphenol-rich beverages (red wine and coffee) consumed with the meal. The present study uses the in vitro SGF to assess the capacity of more than 50 foods of plant origin to suppress red meat peroxidation and formation of MDA. The results were calculated as reducing POS index (rPOSI) which represents the capacity in percent of 100g of the food used to inhibit lipid peroxidation of 200g red-meat a POSI enhancer (ePOSI). The index permitted to extrapolate the need of rPOSI from a food alone or in ensemble such Greek salad, to neutralize an ePOSI in stomach medium, (ePOS–rPOSI=0). The correlation between the rPOSI and polyphenols in the tested foods was R2=0.75. The Index was validated by comparison of the predicted rPOSI for a portion of Greek salad or red-wine to real inhibition of POS enhancers. The POS Index permit to better balancing nutrition for human health.

Synthesis and incorporation of an advanced lipid peroxidation end-product building block into collagen mimetic peptides.

Advanced lipid peroxidation end-products (ALEs) accumulate with ageing and oxidative stress-related diseases. Despite their potential therapeutic value, there are no suitably protected ALE building blocks reported in the literature to enable their site-specific incorporation into synthetic peptides. The synthesis of an Fmoc-protected ALE building block, N∈-(3-methylpyridinium)lysine (MP-lysine) and its incorporation into collagen model peptides is reported.

Multifunctional diamine AGE/ALE inhibitors with potential therapeutical properties against Alzheimer's disease

An important part of pathogenesis of Alzheimer's disease (AD) is attributed to the contribution of AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts). In order to attenuate the progression of AD, we designed a new type of molecules that consist of two trapping parts for reactive carbonyl species (RCS) and reactive oxygen species (ROS), precursors of AGE and ALE, respectively. These molecules also chelate transition metals, the promoters of ROS formation. In this paper, synthesis of the new AGE/ALE inhibitors and evaluation of their physicochemical and biological properties (carbonyl trapping capacity, antioxidant activity, Cu2+-chelating capacity, cytotoxicity and protective effect against in vitro MGO-induced apoptosis in the model AD cell-line PC12) are described. It is found that compounds 40b and 51e possess promising therapeutic potentials for treating AD.

Elastin aging and lipid oxidation products in human aorta

Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development.

Quantitative analysis of phospholipids containing arachidonate and docosahexaenoate chains in microdissected regions of mouse brain

Phospholipids containing polyunsaturated fatty acyl chains are prevalent among brain lipids, and regional differences in acyl chain distribution appear to have both functional and pathological significance. A method is described in which the combined application of GC and multiple reaction monitoring (MRM) MS yielded precise relative quantitation and approximate absolute quantitation of lipid species containing a particular fatty acyl chain in milligram-sized tissue samples. The method uses targeted MRM to identify specific molecular species of glycerophosphocholine lipids, glycerophospho-ethanolamine lipids, glycerophosphoinositol lipids, glycerophosphoserine lipids, glycero-phosphoglycerol lipids, and phosphatidic acids that contain esterified arachidonate (AA) and docosahexaenoate (DHA) separated during normal phase LC/MS/MS analysis. Quantitative analysis of the AA and DHA in the LC fractions is carried out using negative ion chemical ionization GC/MS and stable isotope dilution strategies. The method has been applied to assess the glycerophospholipid molecular species containing AA and DHA in microdissected samples of murine cerebral cortex and hippocampus. Results demonstrate the potential of this approach to identify regional differences in phospholipid concentration and reveal differences in specific phospholipid species between cortex and hippocampus. These differences may be related to the differential susceptibility of different brain regions to neurodegenerative disorders.

An Azido-Biotin Reagent for Use in the Isolation of Protein Adducts of Lipid-derived Electrophiles by Streptavidin Catch and Photorelease

HNE (4-hydroxynonenal), a byproduct of lipid peroxidation, reacts with nucleophilic centers on proteins. A terminal alkynyl analog of HNE (alkynyl HNE, aHNE) serves as a surrogate for HNE itself, both compounds reacting with protein amine and thiol functional groups by similar chemistry. Proteins modified with aHNE undergo reaction with a click reagent that bears azido and biotin groups separated by a photocleavable linker. Peptides and proteins modified in this way are affinity purified on streptavidin beads. Photolysis of the beads with a low intensity UV light releases bound biotinylated proteins or peptides, i.e. proteins or peptides modified by aHNE. Two strategies, (a) protein catch and photorelease and (b) peptide catch and photorelease, are employed to enrich adducted proteins or peptide mixtures highly enriched in adducts. Proteomics analysis of the streptavidin-purified peptides by LC-MS/MS permits identification of the adduction site. Identification of 30 separate peptides from human serum albumin by peptide catch and photorelease reveals 18 different aHNE adduction sites on the protein. Protein catch and photorelease shows that both HSA and ApoA1 in human plasma undergo significant modification by aHNE.

Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors

Reactive carbonyl compounds (RCCs) formed during lipid peroxidation and sugar glycoxidation, namely Advanced lipid peroxidation end products (ALEs) and Advanced Glycation end products (AGEs), accumulate with ageing and oxidative stress-related diseases, such as atherosclerosis, diabetes or neurodegenerative diseases. RCCs induce the 'carbonyl stress' characterized by the formation of adducts and cross-links on proteins, which progressively leads to impaired protein function and damages in all tissues, and pathological consequences including cell dysfunction, inflammatory response and apoptosis. The prevention of carbonyl stress involves the use of free radical scavengers and antioxidants that prevent the generation of lipid peroxidation products, but are inefficient on pre-formed RCCs. Conversely, carbonyl scavengers prevent carbonyl stress by inhibiting the formation of protein cross-links. While a large variety of AGE inhibitors has been developed, only few carbonyl scavengers have been tested on ALE-mediated effects. This review summarizes the signalling properties of ALEs and ALE-precursors, their role in the pathogenesis of oxidative stress-associated diseases, and the different agents efficient in neutralizing ALEs effects in vitro and in vivo. The generation of drugs sharing both antioxidant and carbonyl scavenger properties represents a new therapeutic challenge in the treatment of carbonyl stress-associated diseases.

Advanced lipid peroxidation end-products in Alexander's disease

Rosenthal fibers (RF), intra-astrocytic hyaline inclusions, accumulate in various pathological conditions and are the histological hallmark of Alexander's disease. While the major protein components of RF have been identified, the factors accounting for their pathogenesis, accumulation, and insolubility are largely unknown. In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. In all the cases of Alexander's disease examined, strong immunolabeling of RF by the antibodies to 4-hydroxy-2-nonenal pyrrole adducts were noted. By contrast, age-matched control cases showed no immunoreactivity. These results indicate that modification of protein by lipid peroxidation adducts may play an important role in the formation of RF as well as in the pathogenesis of Alexander's disease. Furthermore, taken together with our previous data indicating advanced Maillard reaction end products in RF, it seems that post-translational modification of RF, initiated by oxidative stress, is critical for both the accumulation and the insolubility of RF, and therefore, by inference, in the pathogenesis of Alexander's disease.

4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease.

Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine-derived pyrrole adducts formed by lipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age-matched control patients. HNE-pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid-beta deposits were unlabeled. Age-matched controls showed only background HNE-pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress-related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.

Immunochemical evidence supporting 2-pentylpyrrole formation on proteins exposed to 4-hydroxy-2-nonenal.

Previous model studies suggested the formation of lysine-based 2-pentylpyrroles as novel late adduction products formed upon exposure of proteins to the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). Two 2-pentylpyrrole immunogens were prepared, one by treating keyhole limpet hemocyanin (KLH) directly with 4-oxononanal and the other by preformation of 6-(2-pentylpyrrol-1-yl)hexanoic acid from 6-aminocaproic acid and 4-oxononanal, followed by carbodiimide coupling to KLH. Pyrrole content and lysine modification in KLH were assayed independently. Following immunization of rabbits, antibody titer increased and plateaued over a 4 month period. The structural specificity of the IgG fractions of the antisera was evaluated through comprehensive competitive ELISA studies. These antibodies were used to verify the time-dependent appearance of the 2-pentylpyrrole epitope in protein exposed to HNE. Potential advantages of antibodies recognizing "advanced lipid peroxidation end products" over those recognizing "early" HNE adduction products are discussed.