Advanced Lipoxidation End Products Research Articles

Thermal-induced interactions between soy protein isolate and malondialdehyde: Effects on protein digestibility, structure, and formation of advanced lipoxidation end products

Thermally processed lipid- and protein-rich foods have sparked widespread concern since they may degrade food nutrition and even risk food safety. This study investigated soy protein isolate (SPI) alterations of digestibility and structure, as well as the formation of potentially hazardous chemicals, i.e., advanced lipoxidation end products (ALEs), after interacting with malondialdehyde (MDA, a lipid oxidation product) under high-temperature cooking conditions (100–180 °C, up to 60 min). In-vitro protein digestion of the SPI-MDA mixtures suggested that their room-temperature interactions damaged SPI digestibility, and increasing the temperature and the duration of the thermal treatment exacerbated the adverse effects. Protein oxidation, covalent aggregation of subunits, and changes in secondary and tertiary structures were revealed using thiol quantification, gel electrophoresis, fluorescence spectroscopy, and circular dichroism (CD) spectra, which could explain reduced protein digestibility. High-resolution mass spectrometry (HRMS) identified seven non-crosslinked ALEs and two crosslinked ALEs. Increased MDA concentrations promoted the generation of ALEs. Moreover, the acrolein-derived ALEs with reactive carbonyl groups were prone to further reacting into crosslinked ALEs, potentially responsible for the subunit aggregation.

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.

Prolonged Consumption of Dietary Advanced Lipoxidation End Products contributes to renal impairment in mice through Dysregulated Intestinal homeostasis

Prolonged Consumption of Dietary Advanced Lipoxidation End Products contributes to renal impairment in mice through Dysregulated Intestinal homeostasis

Effects of maternal advanced lipoxidation end products diet on the glycolipid metabolism and gut microbiota in offspring mice.

Dietary advanced lipoxidation end products (ALEs), which are abundant in heat-processed foods, could induce lipid metabolism disorders. However, limited studies have examined the relationship between maternal ALEs diet and offspring health. To investigate the transgenerational effects of ALEs, a cross-generation mouse model was developed. The C57BL/6J mice were fed with dietary ALEs during preconception, pregnancy and lactation. Then, the changes of glycolipid metabolism and gut microbiota of the offspring mice were analyzed. Maternal ALEs diet not only affected the metabolic homeostasis of dams, but also induced hepatic glycolipid accumulation, abnormal liver function, and disturbance of metabolism parameters in offspring. Furthermore, maternal ALEs diet significantly upregulated the expression of TLR4, TRIF and TNF-α proteins through the AMPK/mTOR/PPARα signaling pathway, leading to dysfunctional glycolipid metabolism in offspring. In addition, 16S rRNA analysis showed that maternal ALEs diet was capable of altered microbiota composition of offspring, and increased the Firmicutes/Bacteroidetes ratio. This study has for the first time demonstrated the transgenerational effects of maternal ALEs diet on the glycolipid metabolism and gut microbiota in offspring mice, and may help to better understand the adverse effects of dietary ALEs.

Aldehyde Dehydrogenase and Aldo-Keto Reductase Enzymes: Basic Concepts and Emerging Roles in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a complication of diabetes mellitus that can lead to vision loss and blindness. It is driven by various biochemical processes and molecular mechanisms, including lipid peroxidation and disrupted aldehyde metabolism, which contributes to retinal tissue damage and the progression of the disease. The elimination and processing of aldehydes in the retina rely on the crucial role played by aldehyde dehydrogenase (ALDH) and aldo-keto reductase (AKR) enzymes. This review article investigates the impact of oxidative stress, lipid-derived aldehydes, and advanced lipoxidation end products (ALEs) on the advancement of DR. It also provides an overview of the ALDH and AKR enzymes expressed in the retina, emphasizing their growing importance in DR. Understanding the relationship between aldehyde metabolism and DR could guide innovative therapeutic strategies to protect the retina and preserve vision in diabetic patients. This review, therefore, also explores various approaches, such as gene therapy and pharmacological compounds that have the potential to augment the expression and activity of ALDH and AKR enzymes, underscoring their potential as effective treatment options for DR.

Digestibility of Malondialdehyde-Induced Dietary Advanced Lipoxidation End Products and Their Effects on Hepatic Lipid Accumulation in Mice.

Advanced lipoxidation end products (ALEs) are formed by modifying proteins with lipid oxidation products. The health effects of ALEs formed in vivo have been extensively studied. However, the digestibility, safety, and health risk of ALEs in heat-processed foods remain unclear. This investigation was performed to determine the structure, digestibility, and effect on the mice liver of dietary ALEs. The results showed that malondialdehyde (MDA) was able to alter the structure of myofibrillar proteins (MPs) to form linear, loop, and cross-linked types of Schiff bases and dihydropyridine derivatives under simulated heat processing, leading to the intra- and intermolecular aggregation of MPs and, thus, reducing the digestibility of MPs. In addition, dietary ALE intake resulted in abnormal liver function and lipid accumulation in mice. The core reason for these adverse effects was the destructive effect of ALEs on the intestinal barrier. Because the damage to the intestinal barrier leads to an increase in lipopolysaccharide levels in the liver, it induces liver damage by modulating hepatic lipid metabolism.

RAGE Inhibitors for Targeted Therapy of Cancer: A Comprehensive Review

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment.

Study of Albumin Oxidation in COVID-19 Pneumonia Patients: Possible Mechanisms and Consequences.

Oxidative stress induced by neutrophils and hypoxia in COVID-19 pneumonia leads to albumin modification. This may result in elevated levels of advanced oxidation protein products (AOPPs) and advanced lipoxidation end-products (ALEs) that trigger oxidative bursts of neutrophils and thus participate in cytokine storms, accelerating endothelial lung cell injury, leading to respiratory distress. In this study, sixty-six hospitalized COVID-19 patients with respiratory symptoms were studied. AOPPs-HSA was produced in vitro by treating human serum albumin (HSA) with chloramine T. The interaction of malondialdehyde with HSA was studied using time-resolved fluorescence spectroscopy. The findings revealed a significantly elevated level of AOPPs in COVID-19 pneumonia patients on admission to the hospital and one week later as long as they were in the acute phase of infection when compared with values recorded for the same patients 6- and 12-months post-infection. Significant negative correlations of albumin and positive correlations of AOPPs with, e.g., procalcitonin, D-dimers, lactate dehydrogenase, aspartate transaminase, and radiological scores of computed tomography (HRCT), were observed. The AOPPs/albumin ratio was found to be strongly correlated with D-dimers. We suggest that oxidized albumin could be involved in COVID-19 pathophysiology. Some possible clinical consequences of the modification of albumin are also discussed.

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease.

Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.

Do different lipid components accelerate the pathogenesis and severity of Diabetic Retinopathy?

BackgroundTo assess the association of lipid and lipid-derived toxic molecules in pathogenesis and severity of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM).MethodsThe present cross-sectional study included 14 healthy individuals (HC) without T2DM, 22 T2DM subjects without DR (DNR), 24 T2DM subjects with mild non-proliferative DR (MNPDR), and 24 T2DM subjects with high-risk proliferative DR (HRPDR). All subjects underwent plasma and vitreous analysis for estimation of total lipid (TL), free fatty acid (FFA), lipid peroxides (LPOs) like malondialdehyde (MDA), 4-Hydroxy-noneal (HNE), the advanced lipoxidation end product (ALE) like Hexanoyl-lysine (HLY) and vascular endothelial growth factor (VEGF) following standard spectrophotometric and enzyme-linked immunosorbent assay (ELISA) methods respectively.ResultsThe concentration of TL, FFA, markers of lipid peroxidation and lipoxidation as well as VEGF in plasma and vitreous were found to be significantly elevated stepwise inT2DM subjects (HRPDR > MNPDR > DNR) compared to healthy controls (HC).Further, plasma conventional lipid components like total cholesterol (TCH), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), FFA and TL showed their significant positive correlations with vitreous level of different LPOs, ALE and VEGF in the DR group.ConclusionTotal lipid and lipid-derived detrimental biomolecules ultimately result in increased secretion of VEGF and thus not only add as associated mediators in the pathogenesis of DR, these also accelerate the severity of microangiopathy in T2DM.

Targeting Scavenger Receptors in Inflammatory Disorders and Oxidative Stress.

Oxidative stress and inflammation cannot be considered as diseases themselves; however, they are major risk factors for the development and progression of the pathogenesis underlying many illnesses, such as cancer, neurological disorders (including Alzheimer’s disease and Parkinson’s disease), autoimmune and metabolic disorders, etc. According to the results obtained from extensive studies, oxidative stress–induced biomolecules, such as advanced oxidation protein products, advanced glycation end products, and advanced lipoxidation end products, are critical for an accelerated level of inflammation and oxidative stress–induced cellular damage, as reflected in their strong affinity to a wide range of scavenger receptors. Based on the limitations of antioxidative and anti-inflammatory molecules in practical applications, targeting such interactions between harmful molecules and their cellular receptors/signaling with advances in gene engineering technology, such as CRISPR or TALEN, may prove to be a safe and effective alternative. In this review, we summarize the findings of recent studies focused on the deletion of scavenger receptors under oxidative stress as a development in the therapeutic approaches against the diseases linked to inflammation and the contribution of advanced glycation end products (AGEs), advanced lipid peroxidation products (ALEs), and advanced oxidation protein products (AOPPs).

Absence of endogenous carnosine synthesis does not increase protein carbonylation and advanced lipoxidation end products in brain, kidney or muscle

Carnosine and other histidine-containing dipeptides are expected to be important anti-oxidants in vertebrates based on various in vitro and in vivo studies with exogenously administered carnosine or its precursor β-alanine. To examine a possible anti-oxidant role of endogenous carnosine, mice lacking carnosine synthase (Carns1−/−) had been generated and were examined further in the present study. Protein carbonylation increased significantly between old (18 months) and aged (24 months) mice in brain and kidney but this was independent of the Carns1 genotype. Lipoxidation end products were not increased in 18-month-old Carns1−/− mice compared to controls. We also found no evidence for compensatory increase of anti-oxidant enzymes in Carns1−/− mice. To explore the effect of carnosine deficiency in a mouse model known to suffer from increased oxidative stress, Carns1 also was deleted in the type II diabetes model Leprdb/db mouse. In line with previous studies, malondialdehyde adducts were elevated in Leprdb/db mouse kidney, but there was no further increase by additional deficiency in Carns1. Furthermore, Leprdb/db mice lacking Carns1 were indistinguishable from conventional Leprdb/db mice with respect to fasting blood glucose and insulin levels. Taken together, Carns1 deficiency appears not to reinforce oxidative stress in old mice and there was no evidence for a compensatory upregulation of anti-oxidant enzymes. We conclude that the significance of the anti-oxidant activity of endogenously synthesized HCDs is limited in mice, suggesting that other functions of HCDs play a more important role.

Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet.

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.

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress.

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.

Investigation of in vitro formation of advanced lipoxidation end products and advanced glycation end products precursors in high-fat processed meat products

The precursors glyoxal (GO) and methylglyoxal (MGO) of advanced glycation end products (AGEs) or advanced lipoxidation end products (ALEs) occur exogenously and endogenously. These α-dicarbonyl compounds, GO and MGO, can be formed from Maillard reactions during food processing as well as protein and lipid peroxidation. The purpose of the present study was to determine and evaluate the in vitro formation of AGEs and ALEs precursors, GO and MGO, in high-fat processed meat products. Before digestion, GO and MGO amounts in the samples ranged between 59.0 and 81.0 µg/100 g and between 11.7 and 47.0 µg/100 g, respectively. After in vitro digestion, GO and MGO formation ranged between 147.0 and 514.1% and 156.0 and 6912.3%, respectively. It is believed that prooxidant components, such as oxygen, enzymes, or heme-proteins, in the gastrointestinal tract promote lipid oxidation; therefore, GO and MGO can be formed. A higher rate of MGO increase was observed in starch containing meatball (chicken) and nugget samples in the gastrointestinal tract. It is thought that the carbohydrates in the meat samples may have contributed to the amount of GO and MGO formed. Thus, reducing fat and starch may produce low levels of GO and MGO formation in the foods during processing or digestion.

Novel Redox Tests for Maillard Abuse-Induced Redox Imbalance: a Pilot Single Case Paradigm Analyzing Dietary Oxidized-Browned Foods and Their Instant-Influence on Oral-Intestinal, Extracellular, and Intracellular Systemic Oxidative and Reductive Stress and Eventual Association with COVID-19 Sepsis and Other Leading Causes of Morbidity and Mortality Globally

The public health hazards associated with Maillard end-products such as melanoidins and advanced lipoxidation end-products (ALEs) and advanced glycation end-products (AGEs), intermediary Maillard reaction creations, include most of the leading causes of morbidity and mortality globally. At the same time, only a few clinicians understand the intricacies linking redox biophysics and disease to humans and animals, explained here and in companion articles in simple to conceptualize terms. Maillard abuse causes increased systemic oxidative stress (SOS: pE-> pH+), an accelerant to the fatal vascular complications of type 1 diabetes. Maillard abuse-induced SOS (pE-> pH+) is also linked to type 2 diabetes, thyroid disorders, polycystic ovary syndrome, low testosterone, and osteoporosis. Many studies have shed light on exotic, intricate, and pricey markers to test extracellular and intracellular Maillard reaction-induced redox imbalance. And their corresponding influence on soluble and cell receptor signaling and the Maillard-induced redox-based diseases and deaths they cause. Inconclusive and pricey new markers for measuring extracellular and intracellular redox balance and imbalance cost thousands of US Dollars (USD) per in vivo assay. The author presents seven extracellular and intracellular redox markers costing less than 150 USD per in vivo assay, using standard laboratory tests available to medical centers worldwide. A PubMed search revealed no studies testing colas, pizza, burgers, and wings-specific intra-day Maillard-rich food binges on TSH, TG/HDL ratio (THR), VLDL/HDL ratio (VHR), LDL/HDL ratio (LHR), and urine pH+ extracellular redox markers, and neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) intracellular redox indicators. The objective of this pilot single case study is to test the feasibility of replication on a much larger scale. The second objective is to analyze the potential influence or lack of impact of Maillard intermediate and end-products on oral-intestine, corporal extracellular, and intracellular redox biophysics, soluble and cell receptor signaling, immunosuppression, inflammation, and risk for developing one or more of the leading causes of morbidity and mortality worldwide at three targeted intraday-pH+ points. The participant met inclusion criteria and drank acidic tide-inducing Maillard-rich colas to prompt an intra-oral-intestinal and the body’s extracellular systemic oxidative stress (SOS: pE-> pH+)-associated plasma acidic-tide. And had blood drawn for CBC with differential and platelet count, comprehensive metabolic panel, lipid panel, and TSH, and provided a sample for a routine urinalysis after an at-home confirmation of extracellular acidic-tide using ‘Just Fitter pH Test Strips pH 4.5 – pH 9.0.’ In a concerted attempt to reach an at-home urine pH+ strip value of 5.5, the top of the 4.5 to 5.5 urine and 7.35 to 7.38 blood systemic oxidative stress range (SOS: pE-> pH+). Before driving to the lab to give blood and urine samples for CBC with differential, comprehensive metabolic panel, lipid panel, TSH, and routine urinalysis. A similar procedure occurred to consuming mainly alkaline-botanical pizza, peanut butter shake, stronger alkaline tide-inducing acidic bacon double cheeseburgers and twelve fried chicken wings. The move from cola-associated urine pH+ 6 to pizza-associated pH+ 6.5 within the prime systemic energy PSE (pE- = pH+) urine pH+ range increased oral-intestinal, extracellular, and intracellular SOS by a factor of 50. The move from pizza-associated urine pH+ 6.5 to burgers and wings-associated pH+ 7.0 within the systemic reductive stress (SRS: pE-< pH+) urine pH+ range of 6.7 to 7.7, increased oral-intestinal, extracellular, and intracellular SOS (SOS: pE- > pH+) by a massive score of 556. This pilot study warrants reproduction on a larger scale with similarly healthy participants with elevated antioxidant tone. Such Maillard-intense trials require safe inclusionary criteria that limit initial subject sample pools to the equivalent of less than 25% of healthy females and males 8 to 80 years of age within or close to their ideal body mass indices and waist-to-height ratios.

Novel Redox Tests for Maillard Abuse-Induced Redox Imbalance: a Pilot Single Case Paradigm Analyzing Dietary Oxidized-Browned Foods and Their Instant-Influence on Oral-Intestinal, Extracellular, and Intracellular Systemic Oxidative and Reductive Stress and Eventual Association with COVID-19 Sepsis and Other Leading Causes of Morbidity and Mortality Globally

The public health hazards associated with Maillard end-products such as melanoidins and advanced lipoxidation end-products (ALEs) and advanced glycation end-products (AGEs), intermediary Maillard reaction creations, include most of the leading causes of morbidity and mortality globally. At the same time, only a few clinicians understand the intricacies linking redox biophysics and disease to humans and animals, explained here and in companion articles in simple to conceptualize terms. Maillard abuse causes increased systemic oxidative stress (SOS: pE-> pH+), an accelerant to the fatal vascular complications of type 1 diabetes. Maillard abuse-induced SOS (pE-> pH+) is also linked to type 2 diabetes, thyroid disorders, polycystic ovary syndrome, low testosterone, and osteoporosis. Many studies have shed light on exotic, intricate, and pricey markers to test extracellular and intracellular Maillard reaction-induced redox imbalance. And their corresponding influence on soluble and cell receptor signaling and the Maillard-induced redox-based diseases and deaths they cause. Inconclusive and pricey new markers for measuring extracellular and intracellular redox balance and imbalance cost thousands of US Dollars (USD) per in vivo assay. The author presents seven extracellular and intracellular redox markers costing less than 150 USD per in vivo assay, using standard laboratory tests available to medical centers worldwide. A PubMed search revealed no studies testing colas, pizza, burgers, and wings-specific intra-day Maillard-rich food binges on TSH, TG/HDL ratio (THR), VLDL/HDL ratio (VHR), LDL/HDL ratio (LHR), and urine pH+ extracellular redox markers, and neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) intracellular redox indicators. The objective of this pilot single case study is to test the feasibility of replication on a much larger scale. The second objective is to analyze the potential influence or lack of impact of Maillard intermediate and end-products on oral-intestine, corporal extracellular, and intracellular redox biophysics, soluble and cell receptor signaling, immunosuppression, inflammation, and risk for developing one or more of the leading causes of morbidity and mortality worldwide at three targeted intraday-pH+ points. The participant met inclusion criteria and drank acidic tide-inducing Maillard-rich colas to prompt an intra-oral-intestinal and the body’s extracellular systemic oxidative stress (SOS: pE-> pH+)-associated plasma acidic-tide. And had blood drawn for CBC with differential and platelet count, comprehensive metabolic panel, lipid panel, and TSH, and provided a sample for a routine urinalysis after an at-home confirmation of extracellular acidic-tide using ‘Just Fitter pH Test Strips pH 4.5 – pH 9.0.’ In a concerted attempt to reach an at-home urine pH+ strip value of 5.5, the top of the 4.5 to 5.5 urine and 7.35 to 7.38 blood systemic oxidative stress range (SOS: pE-> pH+). Before driving to the lab to give blood and urine samples for CBC with differential, comprehensive metabolic panel, lipid panel, TSH, and routine urinalysis. A similar procedure occurred to consuming mainly alkaline-botanical pizza, peanut butter shake, stronger alkaline tide-inducing acidic bacon double cheeseburgers and twelve fried chicken wings. The move from cola-associated urine pH+ 6 to pizza-associated pH+ 6.5 within the prime systemic energy PSE (pE- = pH+) urine pH+ range increased oral-intestinal, extracellular, and intracellular SOS by a factor of 50. The move from pizza-associated urine pH+ 6.5 to burgers and wings-associated pH+ 7.0 within the systemic reductive stress (SRS: pE-< pH+) urine pH+ range of 6.7 to 7.7, increased oral-intestinal, extracellular, and intracellular SOS (SOS: pE- > pH+) by a massive score of 556. This pilot study warrants reproduction on a larger scale with similarly healthy participants with elevated antioxidant tone. Such Maillard-intense trials require safe inclusionary criteria that limit initial subject sample pools to the equivalent of less than 25% of healthy females and males 8 to 80 years of age within or close to their ideal body mass indices and waist-to-height ratios.

S-allylcysteine inhibits chondrocyte inflammation to reduce human osteoarthritis via targeting RAGE, TLR4, JNK, and Nrf2 signaling: comparison with colchicine.

The discovery of new pharmacological agents is needed to control the progression of osteoarthritis (OA), characterized by joint cartilage damage. Human OA chondrocyte (OAC) cultures were either applied to S-allylcysteine (SAC), a sulfur-containing amino acid derivative, or colchicine, an ancient anti-inflammatory therapeutic, for 24 h. SAC or colchicine did not change viability at 1 nM-10 µM but inhibited p-JNK/pan-JNK. While SAC seems to be more effective, both agents inhibited reactive oxygen species (ROS), 3-nitrotyrosine (3-NT), lipid hydroperoxides (LPO), advanced lipoxidation end-products (ALEs as 4-hydroxy-2-nonenal, HNE), advanced glycation end-products (AGEs), and increased glutathione peroxidase (GPx) and type-II-collagen (COL2). IL-1β, IL-6, and osteopontin (OPN) were more strongly inhibited by SAC than by colchicine. In contrast, TNF-α was inhibited only by SAC, and COX2 was only inhibited by colchicine. Casp-1/ICE, GM-CSF, receptor for advanced glycation end-products (RAGE), and toll-like receptors (TLR4) were inhibited by both agents, but bone morphogenetic protein 7 (BMP7) was partially inhibited by SAC and induced by colchicine. Nuclear factor erythroid 2-related factor 2 (Nrf2) was induced by SAC; in contrast, it was inhibited by colchicine. Although they exert opposite effects on TNF-α, COX2, BMP7, and Nrf2, SAC and colchicine exhibit anti-osteoarthritic properties in OAC by modulating redox-sensitive inflammatory signaling.

In-Depth AGE and ALE Profiling of Human Albumin in Heart Failure: Ex Vivo Studies.

Advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), particularly carboxymethyl-lysine (CML), have been largely proposed as factors involved in the establishment and progression of heart failure (HF). Despite this evidence, the current literature lacks the comprehensive identification and characterization of the plasma AGEs/ALEs involved in HF (untargeted approach). This work provides the first ex vivo high-resolution mass spectrometry (HR-MS) profiling of AGEs/ALEs occurring in human serum albumin (HSA), the most abundant protein in plasma, characterized by several nucleophilic sites and thus representing the main protein substrate for AGE/ALE formation. A set of AGE/ALE adducts in pooled HF-HSA samples was defined, and a semi-quantitative analysis was carried out in order to finally select those presenting in increased amounts in the HF samples with respect to the control condition. These adducts were statistically confirmed by monitoring their content in individual HF samples by applying a targeted approach. Selected AGEs/ALEs proved to be mostly CML derivatives on Lys residues (i.e., CML-Lys12, CML-Lys378, CML-Lys402), and one deoxy-fructosyl derivative on the Lys 389 (DFK-Lys 389). The nature of CML adducts was finally confirmed using immunological methods and in vitro production of such adducts further confirmed by mass spectrometry.

The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy.

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.