Glyoxalase-1 overexpression attenuates arterial wall stiffening in diabetic mice.

Aims: Diabetes is a leading cause of mortality worldwide, primarily due to cardiovascular diseases (CVD). Arterial stiffness is a CVD predictor and is associated with increased mortality in diabetic individuals. In diabetes, the formation and accumulation of methylglyoxal (MGO), a highly reactive glycolysis by product and a major precursor in advanced glycation endproducts (AGEs) formation, has been implicated in CVD.

Fasting plasma methylglyoxal concentrations are associated with higher numbers of circulating intermediate and non-classical monocytes but with lower activation of intermediate monocytes: the Maastricht Study.

Purpose: Elevated methylglyoxal (MGO) levels and altered immune cell responses are observed in diabetes. MGO is thought to modulate immune cell activation. The current study investigated whether fasting or post-glucose-load plasma MGO concentrations are associated with circulating immune cell counts and activation in a large cohort study.

Sex differentially affects pro-inflammatory cell subsets in adipose tissue depots in a diet induced obesity model.

Obesity is a growing pandemic that increases the risk for cardiovascular diseases, type 2 diabetes, and particularly in women also the risk of cancer and neurodegenerative disorders such as dementia and multiple sclerosis. Preclinical studies on obesity focus on male mice as they gain bodyweight faster and show a clear pro-inflammatory phenotype. Here, using male and female mice, we induced obesity by feeding a high fat diet (HFD), and compared adipose tissue (AT) inflammation at the same adiposity stage (% AT/bodyweight) between both sexes.

Increased Levels of Circulating Methylglyoxal Have No Consequence for Cerebral Microvascular Integrity and Cognitive Function in Young Healthy Mice.

Diabetes and other age-related diseases are associated with an increased risk of cognitive impairment, but the underlying mechanisms remain poorly understood. Methylglyoxal (MGO), a by-product of glycolysis and a major precursor in the formation of advanced glycation end-products (AGEs), is increased in individuals with diabetes and other age-related diseases and is associated with microvascular dysfunction. We now investigated whether increased levels of circulating MGO can lead to cerebral microvascular dysfunction, blood-brain barrier (BBB) dysfunction, and cognitive impairment.

Glyoxalase 1 overexpression improves neurovascular coupling and limits development of mild cognitive impairment in a mouse model of type 1 diabetes.

Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO-detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment.

Methylglyoxal Mediates the Association Between 2-Hour Plasma Glucose and HbA1c With Inflammation: The Maastricht Study.

Context: Glucose excursions in persons with diabetes may drive chronic inflammation. Methylglyoxal (MGO) is formed from glucose, is elevated in persons with diabetes, and is a potent glycating agent linked with inflammation.

Objective: We investigated whether glucose excursions are associated with low-grade inflammation and whether MGO mediates this association.

The calcium-sensing-receptor (CaSR) in adipocytes contributes to sex-differences in the susceptibility to high fat diet induced obesity and atherosclerosis.

Background: Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR).

Pyridoxamine Alleviates Cardiac Fibrosis and Oxidative Stress in Western Diet-Induced Prediabetic Rats.

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk for heart failure, yet preventive cardiac care is suboptimal in this population. Pyridoxamine (PM), a vitamin B analog, has been shown to exert protective effects in metabolic and cardiovascular diseases. In this study, we aimed to investigate whether PM limits adverse cardiac remodeling and dysfunction in rats who develop T2DM.

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter.

Moderate-Intensity and High-Intensity Interval Exercise Training Offer Equal Cardioprotection, with Different Mechanisms, during the Development of Type 2 Diabetes in Rats.

Endurance exercise training is a promising cardioprotective strategy in type 2 diabetes mellitus (T2DM), but the impact of its intensity is not clear. We aimed to investigate whether and how isocaloric moderate-intensity exercise training (MIT) and high-intensity interval exercise training (HIIT) could prevent the adverse cardiac remodeling and dysfunction that develop T2DM in rats. Male rats received a Western diet (WD) to induce T2DM and underwent a sedentary lifestyle ( = 7), MIT ( = 7) or HIIT ( = 8).

Circulating and adipose tissue immune cells in tissue-specific insulin resistance in humans with overweight and obesity.

Objective: A proinflammatory adipose tissue (AT) microenvironment and systemic low-grade inflammation may differentially affect tissue-specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity.

Methods: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined.

Pyridoxamine prevents increased atherosclerosis by intermittent methylglyoxal spikes in the aortic arches of ApoE mice.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury.

Increased methylglyoxal formation in plasma and tissues during a glucose tolerance test is derived from exogenous glucose.

The dicarbonyl compound methylglyoxal (MGO) is a major precursor in the formation of advanced glycation endproducts (AGEs). MGO and AGEs are increased in subjects with diabetes and are associated with fatal and nonfatal cardiovascular disease. Previously, we have shown that plasma MGO concentrations rapidly increase in the postprandial phase, with a higher increase in individuals with type 2 diabetes.

Advanced glycation endproducts in diabetes-related macrovascular complications: focus on methylglyoxal.

Diabetes is associated with vascular injury and the onset of macrovascular complications. Advanced glycation endproducts (AGEs) and the AGE precursor methylglyoxal (MGO) have been identified as key players in establishing the relationship between diabetes and vascular injury. While most research has focused on the link between AGEs and vascular injury, less is known about the effects of MGO on vasculature.

Prolyl Carboxypeptidase Activity Is Present in Human Adipose Tissue and Is Elevated in Serum of Obese Men with Type 2 Diabetes.

Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue may suggest that adipose tissue is an important source of circulating PRCP.

Integrating multiplex immunofluorescent and mass spectrometry imaging to map myeloid heterogeneity in its metabolic and cellular context.

Cells often adopt different phenotypes, dictated by tissue-specific or local signals such as cell-cell and cell-matrix contacts or molecular micro-environment. This holds in extremis for macrophages with their high phenotypic plasticity. Their broad range of functions, some even opposing, reflects their heterogeneity, and a multitude of subsets has been described in different tissues and diseases.

Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?

The immune system plays an essential role in protecting the body against pathogens. Immune cells are activated during infections, resulting in a metabolic shift from oxidative phosphorylation to glycolysis. During glycolysis, methylglyoxal (MGO) can be formed as a by-product.

High-throughput single cell data analysis - A tutorial.

White blood cells protect the body against disease but may also cause chronic inflammation, auto-immune diseases or leukemia. There are many different white blood cell types whose identity and function can be studied by measuring their protein expression. Therefore, high-throughput analytical instruments were developed to measure multiple proteins on millions of single cells.

Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner.

The initiation and progression of autoimmune disorders such as multiple sclerosis (MS) is linked to aberrant cholesterol metabolism and overt inflammation. Liver X receptors (LXR) are nuclear receptors that function at the crossroads of cholesterol metabolism and immunity, and their activation is considered a promising therapeutic strategy to attenuate autoimmunity. However, despite clear functional heterogeneity and cell-specific expression profiles, the impact of the individual LXR isoforms on autoimmunity remains poorly understood.

Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems.

Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases.

Dietary advanced glycation endproducts (AGEs) increase their concentration in plasma and tissues, result in inflammation and modulate gut microbial composition in mice; evidence for reversibility.

Scope: Dietary advanced glycation endproducts (AGEs) are associated with negative biological effects, possibly due to accumulation in plasma and tissues and through modulation of inflammation and gut microbiota. Whether these biological consequences are reversible by limiting dietary AGE intake is unknown.

Methods And Results: Young healthy C57BL/6 mice were fed a standard chow (n = 10) or a baked chow high AGE-diet (n = 10) (~1.

Altered hepatic sphingolipid metabolism in insulin resistant mice: Role of advanced glycation endproducts.

High plasma levels of the sphingolipid intermediates ceramide (Cer) and sphingosine-1-phosphate (S1P) are suggested to be involved in the development of insulin resistance (IR). Recent evidence indicates that advanced glycation endproducts (AGEs) can alter the sphingolipids metabolism equilibrium. Since enzymes responsible for sphingolipid rheostat maintenance are highly expressed in liver, we thus investigated whether AGEs accumulation can affect hepatic sphingolipids metabolism in insulin resistant mice.

CERT reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease.

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains.

Associations of cells from both innate and adaptive immunity with lower nerve conduction velocity: the Maastricht Study.

Introduction: Distal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system.