Accumulation Of AGEs Research Articles

ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging

Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1G93A) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2′-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1WT). Transgenic mice carrying the hSOD1G93A gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1WT transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1G93A mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSODG93A transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.

Intra-articular site-specific distribution of advanced glycation end products in the shoulder of patients with diabetes mellitus having rotator cuff tears.

Advanced glycation end products (AGEs) are compounds formed due to aging and diabetes mellitus (DM). They activate NADPH oxidase (NOX) by binding to their receptors, thereby increasing the production of reactive oxygen species (ROS), which cause oxidative stress. In this study, we investigated the effects of AGEs on the tissues of the shoulder joint (such as rotator cuff synovium, and capsule) in patients with DM having rotator cuff tears. This study included eight patients with DM who underwent surgical treatment for rotator cuff tears with contracture. The rotator cuff, synovium, and joint capsule were harvested at the time of surgery and evaluated by hematoxylin-eosin staining. Furthermore, immunostaining was used for evaluating AGEs and receptor for AGEs (RAGE), cell activity, ROS, and apoptosis. Quantitative real-time polymerase chain reaction (qPCR) was employed for the cellular evaluation of NOX, interleukins, RAGE, and collagen. The AGEs and RAGE staining as well as the ratio of ROS and apoptosis were in the following order: rotator cuff > joint capsule > synovium. In contrast, the cellular activity was significantly higher in the synovium than in the other regions. The type I collagen expression (as shown by qPCR) as well as the RAGE and NOX expressions were as follows: rotator cuff > joint capsule > synovium. Conversely, the expression of inflammatory cytokines (i.e., IL-6 and IL-1β) was higher in the synovium than in the other regions. Our study is among the first to evaluate the effects of AGEs on each tissue of the shoulder joint in patients with DM having rotator cuff tears and contractures. The accumulation of AGEs in each tissue of the shoulder joint could reveal the locations affected by DM, which can lead to a better understanding of the pathophysiology of DM-related shoulder diseases.

Abstract 18522: Pyridoxamine (vitamin B6) Mitigation Of Structural Valve Degeneration Of Bioprosthetic Heart Valves

Introduction: Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde treated bovine pericardium (BP) have limited durability due to structural valve degeneration (SVD) resulting from both calcification and advanced glycation end product (AGE) deposition. Hypothesis: We investigated the hypothesis that PYR modification of BHV leaflets mitigates AGE-serum protein uptake, oxidation, and calcification mechanisms in model studies, both in vitro and in vivo. Methods: To model AGE accumulation in BHV, we used well-established in vitro and in vivo models. AGE and serum albumin (SA) uptake in BP were quantitated per immunohistochemistry (IHC) staining intensity. PYR uptake was quantified using a novel fluorescent assay. BP collagen was examined by second-harmonic generation (SHG) microscopy. Calcification studies investigated the activity of BP alkaline phosphatase (ALP), and BP calcium levels were quantitated using a colorimetric assay. In vivo studies used a juvenile rat subdermal BP implantation model with PYR oral administration or BP-PYR modification. Endpoints were calcification, SA, and AGE accumulation per IHC and ALP activity per enzyme histochemistry. Results: PYR modification of BP resulted in high-affinity binding of PYR with 2.0±0.2 μg/mg of PYR binding to BP that was stable for 28 days in physiological conditions. Modification had an inhibitory effect on SA uptake in vitro with 60±5% (p<0.001) reduction in IHC staining intensity; PYR modification of BP resulted in increased protection from oxidative damage in vitro with collagen structure preservation (by SHG) after ten days, while control tissues were degraded. After 28-day of in vivo subdermal BP implantation in rats, a significant 70±5% (p<0.001) decrease and 80±5% (p<0.001) decrease in SA IHC staining and AGE staining, respectively, as well as ALP activity was documented in BP-PYR. Quantitative analysis of calcium content demonstrated a reduction from 108±5 μg/mg in control to 77±5 μg/mg in BP-PYR explants (p<0.001). Conclusions: Our study demonstrated that PYR mitigates SVD mechanisms in vitro and in vivo, limiting both AGE-serum protein accumulation and calcification with associated inhibition of ALP.

AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review.

Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated. The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro- and macrovascular complications of diabetes mellitus. Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra- and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome. AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.

Diyet ileri glikasyon son ürünleri (AGE) ve kadın infertilitesi

Advanced glycation end products (AGEs) are molecules formed by non-enzymatic reactions between reducing sugars and proteins, nucleic acids, or lipids. Advanced glycation end products may be formed endogenously under normal metabolic conditions or metabolic conditions such as diabetes and hyperglycemia, or exogenously during processing of foods at high temperatures and low humidity, including roasting, grilling, and frying. The accumulation of AGEs has a significant role in the development of disorders associated with infertility. Infertility is an increasingly common health problem in recent years. Dietary habits and nutrient intake are among the many factors affecting infertility in women. Receptor AGEs (RAGE) and AGEs have been observed in theca and granulosa cells of the ovaries. High levels of AGEs affect fertility through ovarian dysfunction, follicular growth, oocyte number, fertilization rate, embryo development, adverse effects on pregnancy rate, insulin resistance, apoptosis, endothelial dysfunction, increased inflammation, and reactive oxygen species (ROS). This review aims to investigate the pathophysiology of AGEs and their receptors, as well as their possible implications for female reproductive health.

Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway.

Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and connexin 40 (Cx40) in atrial myocytes, is an important cause of increased susceptibility of AF. The aim of our work is to investigate the mechanism of dysregulated Cx43 and Cx40 in atrial myocytes of diabetic rats. We established a type 1 diabetic rat model by intraperitoneal injection of streptozotocin. HL-1 cells and primary rat atrial myocytes were treated with AGEs in vitro. Using Western blotting, immunofluorescence staining, immunohistochemistry, and lucifer yellow diffusion measurements, we investigated dysregulation of Cx43 and Cx40 and its mechanism in atrial myocytes of diabetic rats. Accumulation of AGEs was found in diabetic rats. The expression of Cx43 and Cx40 was reduced in the atrium of diabetic rats, accompanied by the decrease of phosphorylated Adenosine 5'-monophosphate-activated protein kinase (p-AMPK). Similar results were found in cultured HL-1 cells and primary rat atrial myocytes, suggesting a role of AGEs on gap junction proteins. An AMPK agonist, 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), reversed the down-regulated Cx43 expression induced by AGEs stimulation. More importantly, lucifer yellow diffusion assay showed that AGEs significantly affected gap junctional function, and these changes were reversed by AICAR. Thus, we conclude that AGEs cause dysregulation of Cx43 and Cx40 in diabetic atria via the AMPK pathway, thereby leading to gap junction dysfunction, which may contribute to the increased AF susceptibility in diabetes.

Light-emitting diode-induced ellagic acid production in Drosera tokaiensis inhibits advanced glycation end-product formation

Drosera tokaiensis (DT) is an insectivorous plant that effectively inhibits advanced glycation end products (AGEs) generated from non-enzymatic reactions between reducing sugars and protein amino groups using phenolic compounds, including ellagic acid, myricitrin, and quercitrin. The accumulation of AGEs increases during the pathogenesis of non-communicable diseases, such as diabetes and nephropathy. Therefore, the extracts of Drosera species could have preventive effects against such diseases. The development of light-emitting diodes (LEDs) and their use in plant cultivation and tissue culture can enhance secondary metabolite production by controlling the wavelength of light in which plants are cultivated. We evaluated how LEDs affected the production of AGE-inhibitory compounds in extracts isolated from DT tissue cultures. DT was cultured for two months in different light wavelengths under unified photosynthetic photon flex density and the resulting extracts were used to examine changes in phenolic compound content and the inhibition of AGE formation. Cultivation in monochromatic light from LEDs had no significant effect on plant weight compared to conventional fluorescent cultivation, except for red LED light. Ellagic acid content increased regardless of LED coloration and the production and accumulation of myricitrin and quercitrin were inhibited. The extracts isolated from plantlets cultured under LEDs showed the same level of AGE inhibition as those cultured under fluorescent light. Therefore, for anti-glycation activity, DT can be grown stably and at a low cost using LED lights when compared to conventional culture methods.

Tetrahedral Framework Nucleic Acids Based Small Interfering RNA Targeting Receptor for Advanced Glycation End Products for Diabetic Complications Treatment.

Complications arising from diabetes can threaten multiple organs. Advanced glycation end products (AGEs) play a significant role in inducing these complications. Highly processed diets and hyperglycemia facilitate the accumulation of AGEs in the body. Interaction between AGEs and their main receptor (RAGE) initiates the transmission of intracellular inflammatory and cell death signals, which ultimately lead to complications. To counter AGEs-induced damage, we developed an siRNA-binding tetrahedral framework nucleic acids (TDN) system, termed Tsi, which combines the potent cell membrane penetrability and serum stability of TDN with the gene-targeting specificity of siRNA-RAGE. Tsi effectively and persistently downregulates the expression of RAGE, thereby suppressing inflammation by blocking the NF-κB pathway as well as exhibiting antioxidant functions. Furthermore, Tsi regulates the pyroptosis state of macrophages via the NLRP3/caspase-1 axis, which inhibits the spread of cell death signals and maintains homeostasis. This is of great significance for the synergistic treatment strategy for systemic complications in patients with refractory hyperglycemia. In summary, this study describes a nanomedicine that targets the RAGE and suppresses AGE-induced inflammation. This nucleic acid drug holds long-lasting efficacy and is independent of lowering hyperglycemia, which provides a strategy for the treatment of diabetic complications and age-related diseases.

Understanding the Association Between Obesity and Obstructive Sleep Apnea Syndrome: A Case-Control Study.

Introduction Obstructive sleep apnea (OSA) represents a sleep-related impairment linked to upper airway function. The question of whether OSA drives obesity or if shared underlying factors contribute to both conditions remains unresolved. Hence, this present study aims to understand the interplay between obstructive sleep apnea syndrome (OSAS) and obesity through in-depth analysis of anthropometric data within control subjects and OSA patients. Methodology A case-control study was conducted, which included 40 cases and 40 matched healthy controls. Study participants with reported symptoms of snoring, daytime drowsiness, or both were included in the study. All the study participants underwent comprehensive anthropometric assessments such as height, weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, waist-to-hip ratio, skin-fold thickness, and thickness measurements of biceps, triceps, suprailiac, and subscapular muscles. Results Within the OSA group, significant disparities emerged in mean age, waist circumference, waist-to-hip ratio, and diverse fat accumulations encompassing visceral, subcutaneous, trunk, and subcutaneous leg fat. Notably, skin-fold thickness at specific sites - biceps, triceps, subscapula, and suprailiac - demonstrated considerable augmentation relative to the control group. Furthermore, mean values associated with height, weight, BMI, neck circumference, fat percentage, subcutaneous arm fat, entire arm composition, and trunk skeletal muscle either equaled or exceeded those in the control group. However, statistical significance was not attained in these comparisons. Conclusion This investigation underscored a pronounced correlation between numerous endpoints characterizing OSA patients and markers of obesity. Consequently, addressing altered levels of obesity-linked anthropometric variables through pharmacological interventions might hold promise as a pivotal strategy for improving symptoms associated with OSA.

Advanced glycation end products promote intervertebral disc degeneration by transactivation of matrix metallopeptidase genes

Examine the mechanism by which advanced glycation end products (AGEs) induce intervertebral disc degeneration (IDD) in C57BL/6J mice. Matrix metallopeptidase (MMP) gene mRNA levels were assessed using RT-qPCR. Immunoprecipitation and co-immunoprecipitation were performed to identify the transcriptional complex regulating MMP expression due to AGEs. The preventive effects of inhibitors targeting this complex were tested in mice on high AGE diets. IDD and AGE accumulation were evident in mice on high-AGE diets (HAGEs), persisting across dietary shifts but absent in mice exclusively on low-AGE diets. Molecularly, HAGEs activated p21-activated kinase 1 (PAK1), prompting peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) phosphorylation. Ubiquitin-specific protease 12 (USP12) interacted with the phosphorylated PPRC1 (pPPRC1), safeguarding it from proteasomal degradation. This pPPRC1, in collaboration with two histone acetyltransferases p300/CREB-binding protein (CBP) and a transcription factor activator protein 1(AP1), enhanced the expression of 12 MMP genes (MMP1a/1b/3/7/9/10/12/13/16/19/23/28). In vitro AGE exposure on nucleus pulposus and annulus fibrosus cells replicated this gene activation pattern, driven by the PAK1/pPPRC1-p300/CBP-AP1 pathway. The application of PAK1, p300, and AP1 inhibitors reduced pPPRC1-p300/CBP-AP1 binding to MMP promoters, diminishing their expression. These inhibitors effectively thwarted IDD in HAGE mice. Our results revealed that HAGEs instigate IDD via the PAK1/pPPRC1-p300/CBP-AP1 signaling pathway. This insight can guide therapeutic strategies to slow IDD progression in prediabetic/diabetic patients.

Accumulation of advanced glycation end products promotes atrophic nonunion incidence in mice through a CtBP1/2-dependent mechanism

Atrophic nonunion (AN) is a complex and poorly understood pathological condition resulting from impaired fracture healing. Advanced glycation end products (AGEs) have been implicated in the pathogenesis of several bone disorders, including osteoporosis and osteoarthritis. However, the role of AGEs in the development of AN remains unclear. This study found that mice fed a high-AGE diet had a higher incidence of atrophic nonunion (AN) compared to mice fed a normal diet following tibial fractures. AGEs induced two C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, which were necessary for the development of AN in response to AGE accumulation. Feeding a high-AGE diet after fracture surgery in CtBP1/2−/− and RAGE−/− (receptor of AGE) mice did not result in a significant occurrence of AN. Molecular investigation revealed that CtBP1 and CtBP2 formed a heterodimer that was recruited by histone deacetylase 1 (HDAC1) and runt-related transcription factor 2 (Runx2) to assemble a complex. The CtBP1/2-HDAC1-Runx2 complex was responsible for the downregulation of two classes of bone development and differentiation genes, including bone morphogenic proteins (BMPs) and matrix metalloproteinases (MMPs). These findings demonstrate that AGE accumulation promotes the incidence of AN in a CtBP1/2-dependent manner, possibly by modulating genes related to bone development and fracture healing. These results provide new insights into the pathogenesis of AN and suggest new therapeutic targets for its prevention and treatment.

Evaluation of human skin response to solar-simulated radiation in an ex vivo model: Effects and photoprotection of L-Carnosine.

Sunlight, and more specifically the UV component, induces several skin damages, including sunburns, erythema and photoaging. The purpose of this work is to set up an ex vivo human skin model to assess the capacity of active principles in protecting skin from the deleterious effects of solar radiation. Ex vivo human skin biopsies were cultured in an air-liquid interface and exposed to solar-simulated radiation (SSR, 300-750 nm). L-Carnosine (0.2% and 2%) was applied topically to be tested as photoprotective compound. The effect on oxidative stress induction, photoaging and skin transcriptional profile was assessed by evaluating reactive oxygen species, advanced glycosylation end products formation and gene expression changes. In our model, SSR increases ROS production and AGE accumulation and affects the expression of genes related to oxidative stress, pigmentation, immunity, inflammation and photoaging. Among these pathways, 11 genes were selected as biomarkers to evaluate the skin solar radiation response. Results showed that L-Carnosine provides effective prevention against solar radiation damages reducing ROS, AGEs and mitigating the modulation of the selected biomarker genes. In conclusion, we report that our ex vivo skin model is a valuable system to assess the consequences of solar light exposure and the capacity of topically applied L-Carnosine to counteract them.

Advanced glycation end products induce nucleus pulposus cell apoptosis by upregulating TXNIP via inhibiting glycolysis pathway in intervertebral disc degeneration.

Accumulation of advanced glycation end products (AGEs) causes apoptosis in human nucleus pulposus cells (NPCs), contributing to intervertebral disc degeneration (IVDD). The purpose of this study was to determine the roles of thioredoxin-interacting protein (TXNIP) in the mechanisms underlying AGE-induced apoptosis of NPCs. TXNIP was silenced or overexpressed in HNPCs exposed to AGEs. Glycolysis was assessed using extracellular acidification rate (ECAR), ATP level, GLUT1, and GLUT4 measurements. AGEs, TXNIP, GLUT1, and GLUT4 levels in IVDD patients were measured as well. In NPCs, AGEs reduced cell viability, induced apoptosis, inhibited glycolysis, and increased TXNIP expression. Silencing TXNIP compromised the effects of AGEs on cell viability, apoptosis, and glycolysis in NPCs. Furthermore, TXNIP overexpression resulted in decreased cell viability, increased apoptotic cells, and glycolysis suppression. Furthermore, co-treatment with a glycolysis inhibitor improved TXNIP silencing's suppressive effects on AGE-induced cell injury in NPCs. In IVDD patients with Pfirrmann Grades II-V, increasing trends in AGEs and TXNIP were observed, while decreasing trends in GLUT1 and GLUT4. AGE levels had positive correlations with TXNIP levels. Both AGE and TXNIP levels correlated negatively with GLUT1 and GLUT4. Our study indicates that TXNIP plays a role in mediating AGE-induced cell injury through suppressing glycolysis. The accumulation of AGEs, the upregulation of TXNIP, and the downregulation of GLUT1 and GLUT4 are all linked to the progression of IVDD.

Rhein alleviates advanced glycation end products (AGEs)-induced inflammatory injury of diabetic cardiomyopathy in vitro and in vivo models.

In diabetic patients, diabetic cardiomyopathy (DCM) is one of the most common causes of death. The inflammatory response is essential in the pathogenesis of DCM. Rhein, an anthraquinone compound, is extracted from the herb rhubarb, demonstrating various biological activities. However, it is unclear whether rhein has an anti-inflammatory effect in treating DCM. In our research, we investigated the anti-inflammatory properties as well as its possible mechanism. According to the findings in vitro, rhein could to exert an anti-inflammatory effect by reducing the production of NO, TNF-α, PGE2, iNOS, and COX-2 in RAW264.7 cells that had been stimulated with advanced glycosylation end products (AGEs). In addition, rhein alleviated H9C2 cells inflammation injury stimulated by AGEs/macrophage conditioned medium (CM). In vivo have depicted that continuous gavage of rhein could improve cardiac function and pathological changes. Moreover, it could inhibit the accumulation of AGEs and infiltration of inflammatory factors inside the heart of rats having DCM. Mechanism study showed rhein could suppress IKKβ and IκB phosphorylation via down-regulating TRAF6 expression to inhibit NF-κB pathway in AGEs/CM-induced H9C2 cells. Moreover, the anti-inflammation effect of rhein was realized through down-regulation phosphorylation of JNK MAPK. Furthermore, we found JNK MAPK could crosstalk with NF-κB pathway by regulating IκB phosphorylation without affecting IKKβ activity. And hence, the protective mechanism of rhein may involve the inhibiting of the TRAF6-NF/κB pathway, the JNK MAPK pathway, and the crosstalk between the two pathways. These results suggested that rhein may be a promising drug candidate in anti-inflammation and inflammation-related DCM therapy.

Age-related changes in scalp biophysical parameters: A comparative analysis of the 20s and 50s age groups.

Age-related changes in scalp parameters affect hair quality and scalp condition. However, detailed data on biophysical parameters of the scalp across age groups remain scarce. We aimed to investigate the differences in scalp parameters between individuals in their 20s and 50s and analyze their sex-specific variations. Two hundred participants (160 women and 40 men) were equally divided into 20s and 50s age groups. Biophysical parameters of the scalp, including elasticity, pH, trans-epidermal water loss (TEWL), sebum production, desquamation, firmness, redness, and yellowness, were measured in the vertex, occipital, and temporal regions. Hair density and thickness were measured in the temporal region. The accumulation of advanced glycation end products (AGEs) in the skin was noninvasively measured in a subset of 60 women. Skin firmness and redness increased with age in women, whereas yellowness increased with age in both sexes. Sebum production and pH levels were significantly lower in the 50s age group than in the 20s age group, particularly in women. TEWL was lower in men in their 50s than in those in their 20s, particularly in the occipital region. A significant reduction in hair density was observed in the 50s age group in both sexes. AGE accumulation in the skin increased with age and was correlated with scalp skin yellowness. Age-related changes in scalp parameters have important implications for hair health and scalp condition. These findings emphasize the importance of considering age and sex when developing hair care strategies.

Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimer’s disease

Objective. Electrical stimulation has had a profound impact on our current understanding of nervous system physiology and provided viable clinical options for addressing neurological dysfunction within the brain. Unfortunately, the brain’s immune suppression of indwelling microelectrodes currently presents a major roadblock in the long-term application of neural recording and stimulating devices. In some ways, brain trauma induced by penetrating microelectrodes produces similar neuropathology as debilitating brain diseases, such as Alzheimer’s disease (AD), while also suffering from end-stage neuron loss and tissue degeneration. The goal of the present study was to understand whether there may be any parallel mechanisms at play between brain injury from chronic microelectrode implantation and those of neurodegenerative disorder. Approach. We used two-photon microscopy to visualize the accumulation, if any, of age- and disease-associated factors around chronically implanted electrodes in both young and aged mouse models of AD. Main results. We determined that electrode injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in wild-type and AD mice alike. Furthermore, we reveal that chronic microelectrode implantation reduces the growth of pre-existing Alzheimer’s plaques while simultaneously elevating amyloid burden at the electrode-tissue interface. Lastly, we uncover novel spatial and temporal patterns of glial reactivity, axonal and myelin pathology, and neurodegeneration related to neurodegenerative disease around chronically implanted microelectrodes. Significance. This study offers multiple novel perspectives on the possible neurodegenerative mechanisms afflicting chronic brain implants, spurring new potential avenues of neuroscience investigation and design of more targeted therapies for improving neural device biocompatibility and treatment of degenerative brain disease.

Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho

Aging is a natural process of gradual decrease in physical and mental capacity. Biological age (accumulation of changes and damage) and chronological age (years lived) may differ. Biological age reflects the risk of various types of disease and death from any cause. We selected potential biomarkers of aging - telomerase, AGEs, GDF11 and 15 (growth differentiation factor 11/15), sirtuin 1, NAD+ (nicotinamide adenine dinucleotide), inflammasome NLRP3, DNA/RNA damage, and klotho to investigate changes in their levels depending on age and sex. We included 169 healthy volunteers and divided them into groups according to age (under 35; 35–50; over 50) and sex (male, female; male and female under 35; 35–50, over 50). Markers were analyzed using commercial ELISA kits. We found differences in values depending on age and gender. GDF15 increased with age (under 30 and 35–50 p < 0.002; 35–50 and over 50; p < 0.001; under 35 and over 50; p < 0.001) as well as GDF11 (35–50 and over 50; p < 0.03; under 35 and over 50; p < 0.02), AGEs (under 30 and 35–50; p < 0.005), NLRP3 (under 35 over 50; p < 0.03), sirtuin 1 (35–50 and over 50; p < 0.0001; under 35 and over 50; p < 0.004). AGEs and GDF11 differed between males and females. Correlations were identified between individual markers, markers and age, and markers and sex. Markers that reflect the progression of biological aging vary with age (GDF15, GDF11, AGEs, NLRP3, sirtuin) and sex (AGEs, GDF11). Their levels could be used in clinical practice, determining biological age, risk of age-related diseases and death of all-causes, and initiating or contraindicating a therapy in the elderly based on the patient’s health status.

The Effect of Treatment With Aminoguanidine, an Advanced Glycation End Product Inhibitor, on Streptozotocin-Induced Diabetic Rats and Its Effects on Physiological and Renal Functions.

Diabetes is a multifactorial syndrome that affects the functioning of the renin-angiotensin system (RAS). The role of advanced glycation end products (AGEs) in diabetes is well known. In the present study, we hypothesized that the prevention of AGE accumulation or abrogation of AGE synthesis using an AGE inhibitor, aminoguanidine (AG), in streptozotocin (STZ)-induced diabetic animal modelswould affect the progression of diabetes and its related complications. We determined the effects of aminoguanidine (AG), an AGE inhibitor, in STZ-induced diabetic rats by determining various indices of RAS and renal functions. Additionally, we also investigated the effect of the drug, AG, on various hemodynamic and physiological functions in the body of the animals. Male Sprague Dawley rats weighing 200-250 g were assigned to four groups (n = 4-6): Vehicle, Vehicle+AG, STZ-induced, and STZ-induced+AG rats. Type 1 diabetes was induced by a single intraperitoneal (IP) injection of streptozotocin (55 mg/kg) dissolved in sodium citrate buffer. The control groups (Vehicle) were injected with buffer. The blood glucose levels were measured after 48 hours, and animals with blood glucose levels > 300 mg/dL were included in the study. Blood glucose levels in the vehicle rats were also determined to ensure non-diabetic conditions. After confirmation, AG was administrated at a dose of 1 g/L in drinking water for two weeks. Urine was collected to measure the glomerular filtration rate (GFR), and the immune reactivity for AT1 and AT2 proteins was analyzed by immunoblotting. Data were expressed as mean ± standard error of the mean(SEM), and a p-value < 0.05 was considered statistically significant. Diabetic rats had a significant drop in body weight, accompanied by increased food and water consumption. The diabetic rats exhibited significantly increased urine flow and GFR. These phenotypes were significantly or considerately reversed by AG treatment in the STZ+AG-treated diabetic rats. Aminoguanidineprevented the increase in blood sugar levels compared to STZ-induced diabetic rats alone (295.9 ± 50.69 versus 462.3 ± 18.6 mg/dL (p < 0.05)). However, it did not affect the glomerular filtration rate (GFR) and glomerular damage, as assessed by the renal histopathological studies. The STZ-induced diabetic rats had an increased sodium excretion (3.24 ± 0.40 mmol) and significantly increased expression of the AT2 receptor and that of the AT1 receptor, which was slightly reversed by the treatment with AG. Treatment with AG decreased sodium excretion (2.12 ± 0.63, as compared to the diabetic rats). These rats also had modestly decreased expression of the AT2 receptor (0.99 ± 0.07 versus 1.12 ± 0.08, as compared to the STZ-induced diabetic rats), while theAT1 receptors showed a slight increase in the STZ+AG-treated rats compared to the STZ-induced diabetic rats (1.1 ± 0.19 versus 1.08 ± 0.12). This study highlights the action of the drugAG in not exacerbating any damage in diabetic rats. Employing AG as a pharmacological intervention to prevent an increase in blood sugar adds a new dimension to controlling increased blood sugar and preventing diabetic complications. The employability and pharmacological intervention of the drug AG, in diabetes, therefore, need a renewed and further investigation.

The prevalence of Dupuytren’s disease in patients with diabetes mellitus

BackgroundDupuytren’s disease (DD) is a fibroproliferative hand disorder associated with various medical conditions, including diabetes mellitus (DM). The reported prevalence of DM among DD patients varies widely, primarily due to small sample sizes in previous studies.MethodsThis was a retrospective cohort study using data from the TriNetX Research Database. We analyzed the overall prevalence of DD between 2010 and 2020, comparing the DM, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) cohorts. Within the DM group, patients were further categorized based on hemoglobin A1c (HbA1c) values and prescribed anti-diabetic agents (insulin or metformin). We compared the prevalence of DD diagnosis in each group using prevalence ratios and differences.ResultsThere is a higher prevalence of DD in patients with T2DM than in patients with T1DM (relative risk [RR]: 1.641; 95% confidence interval [CI]: [1.356, 1.986]). Among patients with diabetes, there is a higher prevalence of DD in those taking insulin compared to those taking metformin (RR: 0.801, 95% CI: [0.774, 0.83]). The prevalence of DD varies depending on HbA1c levels, with a prevalence of 0.463% in patients having levels within the diabetic range, while lower prevalences of 0.392% and 0.416% are found in patients with prediabetes or uncontrolled diabetes, respectively.ConclusionsThis study provides further insight into the relationship between DM and DD. These findings may be attributed to the increased accumulation of advanced glycosylated end products (AGEs) in patients with diabetes. Future research exploring the connection between AGE accumulation and DD development may enhance our understanding of the relationship between DD and DM.

Age-related advanced glycation end-product accumulation impairs mitochondrial regulation after vitrification†.

Vitrification is an important assisted reproductive technology, although it induces mitochondrial dysfunction in embryos. Herein, we aimed to investigate whether age-associated accumulation of advanced glycation end-products (AGEs) in oocytes impairs the recovery of embryos from cryopreservation-induced mitochondrial dysfunction/damage. Mouse eight-cell stage embryos developed in vitro were vitrified and warmed and incubated up to the blastocyst stage. AGE levels in oocytes were higher in both aged mice and AGE accumulation mouse models (MGO-mice) than those in young and control mice. In addition, the level of SIRT1 upregulation was lower for embryos of aged and MGO-mice than that for embryos of young and control mice. The highest mitochondrial DNA (mtDNA) content was detected in blastocysts derived from vitrified embryos of aged and MGO-mice. The spent culture medium of blastocysts derived from both aged and MGO-mice contained higher mtDNA content than that of the blastocysts derived from young and control mice. EX527 increased mtDNA content in the spent culture medium of vitrified embryos derived from young mice. In addition, p62 aggregate levels were higher in vitrified embryos of control mice than those in vitrified embryos of MGO-mice. The SIRT1 activator, resveratrol, increased p62 aggregation levels in vitrified embryos derived from young and aged mice, whereas vitrification did not affect p62 aggregation levels in embryos from aged mice. Therefore, age-associated AGE accumulation induces decreased responsive SIRT1 upregulation following vitrified-warmed treatment and impairs mitochondrial quality control activity in vitrified embryos.