Excessive Oxidative Stress Contributes to Increased Acute ER Stress Kidney Injury in Aged Mice.

The aged kidney is susceptible to acute injury due presumably to its decreased ability to handle additional challenges, such as endoplasmic reticulum (ER) stress. This was tested by giving tunicamycin, an ER stress inducer, to either old or young mice. Injection of high dose caused renal failure in old mice, not in young mice.

Pharmacologic control of oxidative stress and inflammation determines whether diabetic glomerulosclerosis progresses or decreases: A pilot study in sclerosis-prone mice.

Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic.

Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: a randomised controlled trial.

Aims/hypothesis: We previously reported that obese individuals with the metabolic syndrome (at risk), compared with obese individuals without the metabolic syndrome (healthy obese), have elevated serum AGEs that strongly correlate with insulin resistance, oxidative stress and inflammation. We hypothesised that a diet low in AGEs (L-AGE) would improve components of the metabolic syndrome in obese individuals, confirming high AGEs as a new risk factor for the metabolic syndrome.

Methods: A randomised 1 year trial was conducted in obese individuals with the metabolic syndrome in two parallel groups: L-AGE diet vs a regular diet, habitually high in AGEs (Reg-AGE).

Uremic Toxicity of Advanced Glycation End Products in CKD.

Advanced glycation end products (AGEs), a heterogeneous group of compounds formed by nonenzymatic glycation reactions between reducing sugars and amino acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in diseases associated with high levels of oxidative stress, such as CKD. In chronic renal failure, higher circulating AGE levels result from increased formation and decreased renal clearance. Interactions between AGEs and their receptors, including advanced glycation end product-specific receptor (RAGE), trigger various intracellular events, such as oxidative stress and inflammation, leading to cardiovascular complications.

Effects of sevelamer carbonate on advanced glycation end products and antioxidant/pro-oxidant status in patients with diabetic kidney disease.

Background And Objectives: The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.

Design, Setting, Participants, & Measurements: This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c >6.

Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?

Context: Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS.

Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice.

Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies.

Dietary consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-AARP Diet and Health Study.

Background: Advanced glycation end products (AGEs) are a heterogeneous group of compounds present in uncooked foods as well as in foods cooked at high temperatures. AGEs have been associated with insulin resistance, oxidative stress, and chronic inflammation in patients with diabetes. Dietary AGEs are an important contributor to the AGE pool in the body.

Dietary advanced glycation end products are associated with decline in memory in young elderly.

We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors).

Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans.

Age-associated dementia and Alzheimer's disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD.

Advanced glycation end products (AGE) and diabetes: cause, effect, or both?

Despite new and effective drug therapies, insulin resistance (IR), type 2 diabetes mellitus (T2D) and its complications remain major medical challenges. It is accepted that IR, often associated with over-nutrition and obesity, results from chronically elevated oxidant stress (OS) and chronic inflammation. Less acknowledged is that a major cause for this inflammation is excessive consumption of advanced glycation end products (AGEs) with the standard western diet.

Advanced glycation endproducts in diabetes and diabetic complications.

This review presents insights from studies of advanced glycation end products (AGEs) in humans and mice. Although the emphasis is on the effects of exogenous AGEs and the suppression of specific host defense mechanisms, AGEs are also formed intracellularly, where they may contribute to several normal intracellular functions. It is only when the overall levels of AGEs in the extracellular and the intracellular spaces exceeds the ability of the native antioxidant (and AGE) defenses that they pose a problem.

Combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes.

Objective: Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD) degeneration and back pain. Advanced-glycation-end-products (AGEs) increase reactive-oxygen-species (ROS) and inflammation, and are one cause for early development of diabetes mellitus.

Suppression of native defense mechanisms, SIRT1 and PPARγ, by dietary glycoxidants precedes disease in adult humans; relevance to lifestyle-engendered chronic diseases.

SIRT1 and PPARγ, host defenses regulating inflammation and metabolic functions, are suppressed under chronic high oxidant stress and inflammation (OS/Infl) conditions. In diabetes, dietary advanced glycation end products (dAGEs) cause OS/Infl and suppress SIRT1. Herein, we ask whether dAGEs also suppress host defense in adults without diabetes.

Increased circulating advanced glycation endproducts (AGEs) in acute trauma patients.

Background: Circulating levels of pro-inflammatory advanced glycation end products (AGEs) are increased in diabetes and other conditions characterized by chronically elevated oxidant stress (OS). OS also increases after acute trauma and is implicated in the development of complications such as multiple organ failure. Herein, we assess the effect of acute OS on circulating levels of AGEs in a cohort of acute trauma victims.

Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses.

Background: Pentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes.

Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1.

The epidemics of insulin resistance (IR) and type 2 diabetes (T2D) affect the first world as well as less-developed countries, and now affect children as well. Persistently elevated oxidative stress and inflammation (OS/Infl) precede these polygenic conditions. A hallmark of contemporary lifestyle is a preference for thermally processed nutrients, replete with pro-OS/Infl advanced glycation endproducts (AGEs), which enhance appetite and cause overnutrition.

Effect of dietary advanced glycation end products on mouse liver.

Unlabelled: The exact pathophysiology of non-alcoholic steatohepatitis (NASH) is not known. Previous studies suggest that dietary advanced glycation end products (AGEs) can cause oxidative stress in liver. We aim to study the effects of dietary AGEs on liver health and their possible role in the pathogenesis of NASH.

Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease.

Background And Objectives: Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Restricting food containing elevated AGEs improves these risk factors in diabetic CKD. Because diet adherence can be problematic, this study aimed to remove cytotoxic AGEs from food already ingested and to determine whether sevelamer carbonate sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities.

Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals.

Background: Advanced glycations end products increase oxidant stress, inflammation, and neurotoxicity. Serum levels are increased in diabetes and aging. We examined the relationship between serum methylglyoxal derivatives (sMG), and cognitive decline, in 267 non-demented elderly.

Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9.

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month.

Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice.

Inflammation has a key role in diabetic nephropathy (DN) progression. Pentosan polysulfate (PPS) has been shown to decreases interstitial inflammation and glomerulosclerosis in 5/6 nephrectomized rats. Since PPS has an excellent long-term safety profile in interstitial cystitis treatment, and we recently found that old diabetic C57B6 mice develop DN characterized by extensive tubulointerstitial inflammatory lesions that mimics human DN, we examined the effect of PPS on old diabetic mice.