Skeletal muscle is essential for maintaining body shape and supporting physiological processes. Musculoskeletal function is influenced by various factors, including nutrition, infection, injury or trauma, and advanced glycation end-products (AGEs), which are known to contribute in tissue degeneration, particularly in aging and diabetic populations. This study utilized a skeletal muscle-on-a-chip system to develop three-dimensional in vitro musculoskeletal tissue, enabling a detailed investigation of the effects of AGEs on muscle function and structure. AGEs-induced alterations on muscle were verified by assessments of musculoskeletal contractility, myotube growth, and apoptosis markers. Furthermore, metabolic changes such as modifications in collagen and NADH lifetime changes were observed using fluorescence-lifetime imaging microscopy (FLIM) in the AGEs-treated group. Our result demonstrated a significant reduction in musculoskeletal contractility and structural disruptions in response to AGEs exposure. Overall, these findings provide a robust in vitro model for elucidating the mechanisms by which AGEs impair muscle functionality and integrity, with potential implications for therapeutic strategies aimed at preserving muscle health and enhancing the quality of life in affected populations.

Chronic pain, a widespread condition impacting a large segment of the global population, involves persistent and diverse pain types including nociceptive, neuropathic, and the more recently defined nociplastic pain. This review explores the potential of Epigallocatechin gallate (EGCG), a key bioactive compound in green tea, known for its extensive biological activities that aid in pain management. Highlighting its anti-inflammatory, antioxidant, and neuroprotective effects, EGCG is posited as a promising alternative to conventional pain medications, which are often associated with significant side effects and dependency risks. Despite its therapeutic promise, EGCG's clinical application is hampered by poor bioavailability and stability. By outlining the current state of research and identifying gaps for future investigation, this review underscores the importance of integrating EGCG into a broader pain management paradigm. It advocates for extensive clinical trials to confirm EGCG's efficacy and safety in humans, aiming to establish it as a part of an integrative strategy for treating chronic pain, thus potentially reducing the reliance on conventional pharmacotherapy.

Diabetic neuropathy (DNP) is a common complication of diabetes that has a significant impact on the patient's quality of life. The primary objectives of clinical treatment for DNP these days are symptomatic pain management and glycemic control. Since there is currently no cure for nerve damage, the only objective is to alleviate discomfort and slow its progression. Pre-clinical research over the last decade has increasingly linked toll-like receptor 4 (TLR4)-mediated neuroinflammation as a major contributor to DNP development. The role of TLR4-mediated neuroinflammation in the pathophysiology of DNP is covered in this review, along with different therapeutic approaches that target TLR4-mediated neuroinflammation in DNP in pre-clinical research. Despite promising pre-clinical results, translating these findings into clinical practice remains a challenge, which we also discuss how to address and overcome in this review.

Diabetic retinopathy (DR), a complication of type 2 diabetes mellitus (T2DM), is typically asymptomatic in its early stages. Diagnosis typically relies on routine fundoscopy for the clinical detection of microvascular abnormalities. However, permanent retinal damage may occur well before clinical signs are appreciable. In the early stages of DR, the retina undergoes distinct epigenetic changes, including DNA methylation and histone modifications. Recent evidence supports unique epigenetic 'signatures' in patients with DR compared to non-diabetic controls. These DNA 'signature' sequences may be specific to the retina and may circulate in peripheral blood in the form of cell-free DNA (cfDNA). In this review, we explore the literature and clinical application of cfDNA sampling as an early, non-invasive, accessible assessment tool for early DR detection. First, we summarize the known epigenetic signatures of DR. Next, we review current sequencing technologies used for cfDNA detection, such as magnetic bead-based enrichment, next-generation sequencing, and bisulfite sequencing. Finally, we outline the current research limitations and emerging areas of study which aim to improve the clinical utility of cfDNA for DR evaluation.

In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.

Red cell distribution width (RDW) and glycated hemoglobin index (HGI) is considered an important tool for assessing the prognosis of sepsis patients, closely related to the risk of mortality associated with sepsis. This study investigates the association between the HGI combined with RDW and the risk of in-hospital mortality in patients with sepsis. We analyzed data from 13,726 sepsis patients who were admitted to the intensive care unit (ICU) for more than 24 h, sourced from the American Medical Information Mart for Intensive Care (MIMIC-IV) database. Kaplan-Meier survival curves and multivariable Cox regression analyses were employed to assess the impact of various variables on patient outcomes, stratified by quartiles of HGI and RDW. Additionally, restricted cubic spline (RCS) analysis was utilized to explore how changes in HGI and RDW might influence the studied outcomes. The results indicated that the highest quartile (Q4) of the combined metrics significantly increased in-hospital mortality compared to the lowest quartile (Q1) (p < 0.0001). Multivariable Cox regression analysis revealed that patients in Q4 faced the highest risk of in-hospital mortality (hazard ratio: 1.22, 95% confidence interval: [1.10-1.36], p < 0.001). RCS analysis demonstrated a nonlinear relationship between HGI-RDW and the risk of adverse outcomes. Further analysis identified significantly elevated risks in patients over 65 years old, those who were widowed, those receiving macrolide antibiotics, and those with congestive heart failure or severe liver disease. In conclusion, elevated levels of the combined HGI and RDW metrics are independent risk factors for adverse outcomes in critically ill patients with sepsis, associated with increased mortality.

Both dietary and endogenous reactive carbonyl species, such as methylglyoxal (MGO) and glyoxal (GO), react with proteins to generate advanced glycation end products (AGEs), which contribute to metabolic diseases. However, accurately determining individual AGEs in biological samples remains challenging due to the lack of standardized methods. In this study, we optimized and detailed procedures for AGE digestion using enzyme cocktails and separation and detection via high-resolution LC-MS/MS. For the first time, we observed that enzyme backgrounds contained higher levels of methylglyoxal-derived hydroimidazolone 1 (MG-H1) and glucosepane than mouse plasma by 1.4-3 times (e.g., 1512.55 ± 18.89 nM in enzymes vs 496.95 ± 90.91 nM in plasma for MG-H1). Using this optimized method, we quantified fructosyl-lysine and nine AGEs in the plasma, kidneys, and urine of mice. MGO-derived AGEs increased significantly in the plasma and kidneys after MGO treatment. Additionally, both MGO- and GO-derived AGEs were elevated in high-fat-diet (HF)-fed mice compared to low-fat-diet (LF)-fed controls, with further increases in HF-fed mice supplemented with MGO (HFM). This optimized method provides accurate AGE quantification, enabling insights into their role as biomarkers for metabolic syndrome and advancing the understanding of dietary and metabolic contributions to AGE formation.

Periodontitis and diabetes mellitus are two highly prevalent chronic conditions that share a bidirectional relationship, significantly impacting public health. Periodontitis, a gum inflammation caused by microbial dysbiosis, aggravates glycemic control in diabetics, while uncontrolled diabetes heightens periodontitis severity. These conditions create a vicious cycle, where inflammation and microbial dysbiosis mutually drive disease progression, exacerbating systemic health. The underlying mechanisms involve inflammation, immune dysfunction, and microbial dysbiosis, with both diseases contributing to a chain of chronic inflammation that exacerbates systemic health. This relationship is significant because managing one condition can significantly impact the other. In diabetic individuals, interventions such as periodontal therapy have shown effectiveness in improving glycemic control, underscoring the potential of integrated strategies for managing these conditions simultaneously. In this review, we highlight the importance of a deeper understanding of the molecular and immunological interactions between these diseases is essential for developing integrated therapeutic approaches, with the potential to enhance the quality of life of the patient significantly.

Methylglyoxal (MGO), a glycolysis by-product and precursor to advanced glycation endproducts (AGEs), is associated with glucose intolerance, type 2 diabetes, and vascular dysfunction. This study examined the long-term effects of elevated MGO on blood pressure, insulin sensitivity, and vascular function in healthy mice. Male C57Bl/6J mice were assigned to control (n = 16) or MGO-treated groups (50 mM in drinking water for 13 weeks, n = 16). Measurements included body weight, fasting plasma glucose, water consumption, blood pressure, and analysis of plasma/tissue for MGO, AGEs, glyoxalase activity, and inflammation markers. Endothelial function was assessed using wire myography, and the response of human placental arteries to MGO-modified insulin was evaluated. MGO treatment significantly increased plasma MGO (123.3%, p < 0.001), AGEs MG-H1 (208.6%, p < 0.001) and CEL (64.3%, p < 0.001), and AGEs in the heart, kidney, and liver, along with body weight (+ 6.4%, p = 0.032) and blood pressure (systolic + 5.0%, p = 0.046; diastolic + 6.5%, p = 0.043). Glucose sensitivity and endothelial function remained unaffected. CRP levels rose, and MGO-modified insulin enhanced vascular contraction. In conclusion, chronic MGO exposure increased plasma MGO to diabetic-like levels, raised body weight and blood pressure, and did not alter glucose sensitivity or endothelial function. Modification of insulin by MGO may contribute to MGO-related changes in blood pressure.

Since the arrival of continuous glucose monitoring (CGM), the relationship between the glucose management indicator (GMI) and HbA1c has been a topic of considerable interest in diabetes research. This study aims to explore the association between the GMI/HbA1c ratio and the presence of preclinical carotid atherosclerosis in type 1 diabetes (T1D).

Individuals with T1D and no prior history of cardiovascular disease were recruited from two centers. Carotid ultrasonography was performed using a standardized protocol and carotid plaques were defined as intima-media thickness ≥ 1.5 mm. CGM-derived data were collected from a 14-day report. A GMI/HbA1c ratio < 0.90 was selected to identify "fast-glycator" phenotype.

A total of 584 participants were included (319 women, 54.6%), with a mean age of 48.8 ± 10.7 years and a mean diabetes duration of 27.5 ± 11.4 years. Carotid plaques were present in 231 subjects (39.6%). Approximately 43.7% and 13.4% of participants showed absolute differences of ≥ 0.5 and ≥ 1.0 between 14-day GMI and HbA1c, respectively. Among patients ≥ 48 years, the fast-glycator phenotype was independently associated with presence of plaques (OR 2.27, 95%CI: 1.06-4.87), even after adjusting for non-specific and T1D-specific risk factors and statin treatment. No significant association was observed in younger subjects (p for interaction < 0.05).

Fast-glycator phenotype is independently associated with atherosclerosis in T1D individuals aged ≥ 48 years, suggesting an age-related increase in the glycation risk. These findings highlight the potential of the GMI/HbA1c ratio for cardiovascular risk stratification in this population.

Background/Objectives: Poor metabolic control is associated with increased levels of advanced glycation end products (AGEs), which in turn may lead to increased arterial stiffness. The aim of this study was to estimate the association between glycated haemoglobin A1c (HbA1c) and aortic pulse wave velocity (a-PWV) in healthy subjects and to analyse the mediating effect of AGEs measured by skin autofluorescence (SAF) on this association. Methods: HbA1c, a-PWV and SAF were analysed in 390 healthy Spanish subjects from the EVasCu study (42.02 ± 13.14 years, 63.08% females). A directed acyclic graph (DAG) was generated to define the covariates to be included, and the model was confirmed via multiple linear regression analysis. Descriptive and exploratory analyses were performed to investigate the associations between variables. Finally, adjusted and unadjusted mediation analyses were performed to verify the influence of SAF on the main association between HbA1c and a-PWV. Results: Multiple linear regression analyses for a-PWV supported the validity of the structure in the DAG. Descriptive and exploratory analyses revealed that when the models were adjusted to include all covariates, the statistical significance of the main association disappeared. Mediation analysis revealed that SAF mediated 35.77% of the effect of HbA1c on a-PWV in the unadjusted model and 42.18% after adjusting for covariates. Conclusions: Our study suggests that increases in HbA1c levels are associated with increases in a-PWV and that this relationship is mediated by the SAF score in healthy adults.

Protein glycation leads to the generation of advanced glycation end products (AGE). AGEs are implicated in the pathogenesis of chronic diabetic complications and age-related disorders. Some AGEs lead to protein cross-linking, affecting the protein function irreversibly. Long-lived predominantly found proteins such as collagen are primarily affected due to glycation-induced damage. Assessment of the antiglycation potential of substances requires costly equipment. A simple procedure is established to monitor glycation-induced protein cross-linking inhibitory potential of medicinal plants using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). SDS-PAGE separates proteins according to their molecular size. As the cross-linked products formed due to glycation-induced damage are stable under denaturing conditions and are of high molecular weight, such products can be separated and detected using SDS-PAGE. As the degree of high molecular weight products observed is proportionate to the extent of glycation-induced damage, SDS-PAGE can be used to monitor the potential of medicinal plants to inhibit glycation-induced protein cross-linking.

Carboxymethyllysine(CML) is one of advanced glycation end products(AGEs), which is associated with the occurrence and development of chronic diseases such as diabetes, cardiovascular disease, Alzheimer's disease, etc. This study focused on assessing the CML formation pattern in walnut cookies and the related impact of food additives on the CML content and sensory characteristics. The results showed that the baking conditions significantly affected the CML content in the walnut cookies, which exhibited a significant positive correlation with the sensory evaluation scores. Three food additives, namely propyl gallate (PG), theaflavins (TF), and tea polyphenols (TP), were selected based on their high CML inhibition rates. They were combined using mixture optimal design, and the optimal compounding ratios were obtained, which were X1 = 0.236, X2 = 0.400, and X3 = 0.364. These ratios were converted to the additive ratios in the walnut cookies, with PG at 0.0236 ‰, TF at 0.160 ‰, and TP at 0.146 ‰. The CML inhibition rate reached a maximum value of 40.98 %, with the sensory evaluation score also higher.

Increasing data suggest a crucial relationship between glycolipid metabolic disorder and neuropsychiatric injury. The aim of this study is to investigate the behavioral performance changes and neuropathological injuries in mice challenged with high-fat diet (HFD) and streptozotocin (STZ). The glucose metabolism indicators and behavioral performance were detected. The mRNA expression of IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds and protein expression of APP, p-Tau, p-IRS1, p-AKT, p-ERK, and TREM1/2 were measured. The fluorescence intensities of MAP-2, NeuN, APP, p-Tau, GFAP, and IBA-1 were observed. The results showed that combination of HFD and STZ/I.P. could induce glucose metabolic turmoil and Alzheimer's disease (AD)-like neuropsychiatric dysfunction in mice, as indicated by the increased concentrations of fasting blood glucose and impaired learning and memory ability. Moreover, the model mice presented increased levels of APP, p-Tau, p-IRS1, TREM2, IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds; decreased levels of p-AKT, p-ERK, and TREM1; and neuron damage and the hyperactivation of astrocytes and microglia in the hippocampus as compared with control mice. Only male mice were used in this study. Although AD and type 2 diabetes mellitus (T2DM) are distinct pathologies, our results suggested that combination of HFD and STZ/I.P., a widely used T2DM modeling method, could successfully induce AD-like behavioral impairments and neuropathological injuries in mice; the mechanism might be involved with neuroinflammation and its associated dysfunction of IRS1/AKT/ERK signaling pathway. Our findings further support the potential overlap between T2DM and AD pathophysiology, providing insight into the mechanisms underlying the comorbidity of these diseases.

Chronic kidney disease-mineral and bone metabolism disorder (CKD-MBD) is a common chronic kidney disease (CKD)-associated complication that increases the risk of metabolic bone diseases, fractures, osteoblastic trans-differentiation of vascular smooth muscle cells, and cardiovascular events. SD rats were randomised into five groups with six rats per group: sham, CKD, CKD + advanced glycosylation end products (AGEs), CKD + Quercetin, and CKD + AGEs + Quercetin. The protective effects of AGEs and quercetin on SD rats were assessed by renal function, renal pathology, bone metabolism, osteoblastic trans-differentiation of vascular smooth muscle cells, and the receptor for AGE (RAGE) expression. Compared with the control group, rats in the CKD and CKD + AGEs groups had significantly lower body weight, higher serum AGEs levels, impaired renal function, increased levels of oxidative stress in the kidney and bone marrow tissues, lower femoral bone mineral density (BMD), callus mineralised volume fraction (mineralised bone volume/total volume), abnormal serum bone metabolism levels, and increased renal tissue, bone tissue, and abdominal aorta RAGE expression levels, and the RAGE downstream NF-κB signalling pathway was upregulated. Quercetin significantly improved renal dysfunction, attenuated serum AGE levels, reduced oxidative stress levels in the kidney and bone marrow tissues, and downregulated RAGE expression in the kidney, bone, and abdominal aorta and the RAGE downstream NF-κB signalling pathway in rats with CKD. AGEs are involved in the pathogenesis of CKD-MBD by promoting osteoblastic trans-differentiation of vascular smooth muscle cells and abnormal bone metabolism. Quercetin plays a role in the prevention and treatment of CKD-MBD by reducing the production of AGEs.

Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM).

T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings.

SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues.

These findings highlight SITG's neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations.

While there is ample evidence indicating an increased occurrence of general neurological conditions among individuals with diabetes, there has been limited exploration into the cause-and-effect connection between type 2 diabetes (T2D) and specific neurological disorders, including conditions like carpal tunnel syndrome and Bell's palsy. We used Mendelian randomization (MR) approach to investigate the causal effects of T2D on 67 neurological diseases. We primarily utilized the inverse-variance weighted method for the analysis, and also employed the weighted median and MR-Egger methods in our study. To detect and correct potential outliers, MR-PRESSO analysis was used. Heterogeneity was assessed using Cochrane Q-values. The MR analyses found a possible relationship between T2D and a risk increase of 8 diseases at suggestive level of evidence (P < .05). Notably, among the positive findings that met the false discovery rate threshold, nerve, nerve root, and plexus disorders (odds ratio [OR] = 1.11; 95% confidence interval [CI] = 1.08-1.15); neurological diseases (OR = 1.05; 95% CI = 1.03-1.07) and carpal tunnel syndrome (OR = 1.10; 95% CI = 1.05-1.16) were identified. Our findings affirm a cause-and-effect association between T2D and certain neurological disorders.

Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model.

Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages. Diabetes-related systemic profile and histopathological hallmarks were evaluated using biochemical assays, microscopic imaging, immunoblot, and real-time PCR analyses, supported by cinnamaldehyde-albumin interaction assessed using STD-NMR and in silico site-directed interactions in the presence of glucose.

Cinnamaldehyde-treatment significantly reversed DN hallmarks, fasting blood glucose (FBG), serum insulin, glycated hemoglobin (HbA1c), urinary microalbumin, and creatinine contrasted to non-treated DN rats and aminoguanidine, a positive reference advanced glycation end products (AGEs) inhibitor. The pathological depositions of AGEs, receptor for advanced glycation end products (RAGE), and carboxymethyl lysine (CML), and transcriptional levels of AGE-RAGE targeted immunomodulatory factors (IL1β, TNF-α, NF-κB, TGF-β) were significantly improved in cinnamaldehyde treated rats as compared to aminoguanidine. Cinnamaldehyde post-treatment improved pancreatic pathology and systemic glycemic index (0.539 ± 0.01 vs. 0.040 ± 0.001, P < 0.001) in DN rats. Subsequently, in silico profiling of cinnamaldehyde defined the competitive binding inhibition with glucose in AGE and RAGE receptors that was further confirmed by in vitro STD-NMR analysis.

These findings suggest potential role of cinnamaldehyde in reversing STZ-induced diabetic nephropathic impairments; therefore, appears promising candidate for further pharmacological explorations towards diabetes-associated complications.

With the increasing global prevalence of type 2 diabetes (T2D) and obesity, there is a pressing need for novel therapeutic interventions. Lavandula stoechas, a medicinal plant traditionally used for various ailments, holds promise as a potential agent for T2D management, particularly in Morocco, where it is commonly used to treat diabetes. This study aims to evaluate the pharmacological potential of L. stoechas aqueous extract (AqLs) by assessing its lipase inhibition antioxidant and anti-inflammatory activities, identifying phenolic compounds, and examining its efficacy in reducing diabetic complications.

The pharmacological potential of L. stoechas aqueous extract was investigated using in vitro assays. The inhibitory effect on pancreatic lipase, antioxidant power (FRAP), and anti-inflammatory activity (albumin denaturation method) was assessed. High-performance liquid chromatography (HPLC) analysis identified phenolic compounds. Additionally, albumin glycation was evaluated by estimating fructosamine, carbonyl groups, and amyloid β-structures to assess efficacy in mitigating diabetic complications.

The extract demonstrated concentration-dependent inhibition of pancreatic lipase (IC50 = 0.132 ± 0.006 mg/mL), potent antioxidant activity (IC50 = 604.99 ± 1.01 μg/mL), and dose-dependent anti-inflammatory effects (IC50 = 207.01 ± 34.94 mg/mL). HPLC analysis revealed phenolic compounds: naringin (38.28%), syringic acid (25.72%), and cinnamic acid (15.88%) were the most abundant, with 4-hydroxybenzoic acid, hydrated catechin, and catechin ranging from 9.60% to 5.24%, and p-coumaric acid (1.73%). Furthermore, the extract inhibited albumin glycation and fructosamine production, suggesting efficacy in mitigating diabetic complications.

These findings highlight the multifaceted pharmacological potential of L. stoechas aqueous extract in T2D management, suggesting that this plant can be highly beneficial for diabetic individuals.

Epidemiological evidence suggests an association between dioxin and dioxin-like compound (DLC) exposure and human liver disease. The prototypical DLC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to induce the progression of reversible hepatic steatosis to steatohepatitis with periportal fibrosis and biliary hyperplasia in mice. Although the effects of TCDD toxicity are mediated by aryl hydrocarbon receptor (AHR) activation, the underlying mechanisms of TCDD-induced hepatotoxicity are unresolved. In the present study, male C57BL/6NCrl mice were gavaged every 4 days for 28 days with 0.03 - 30 μg/kg TCDD and evaluated for liver histopathology and gene expression as well as complementary 1-dimensional proton magnetic resonance (1D- 1H NMR) urinary metabolic profiling. Urinary trimethylamine (TMA), trimethylamine N-oxide (TMAO), and 1-methylnicotinamide (1MN) levels were altered by TCDD at doses ≤ 3 μg/kg; other urinary metabolites, like glycolate, urocanate, and 3-hydroxyisovalerate, were only altered at doses that induced moderate to severe steatohepatitis. Bulk liver RNA-seq data suggested altered urinary metabolites correlated with hepatic differential gene expression corresponding to specific metabolic pathways. In addition to evaluating whether altered urinary metabolites were liver-dependent, published single-nuclear RNA-seq (snRNA-seq), AHR ChIP-seq, and AHR knockout gene expression datasets provide further support for hepatic cell-type and AHR-regulated dependency, respectively. Overall, TCDD-induced liver effects were preceded by and occurred with changes in urinary metabolite levels due to AHR-mediated changes in hepatic gene expression.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)-receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. SIGNIFICANCE STATEMENT: BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2β and TGF-β/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.

Endometriosis is a prevalent gynecological condition, affecting around 10% of reproductive-age women. Inflammatory processes associated with endometriosis may contribute to endothelial dysfunction. Increased skin accumulation of advanced glycation end-products (AGEs), reflecting arterial stiffness, potentially links endometriosis with elevated risk of cardiovascular events. We hypothesized that patients with endometriosis have impaired endothelial function as well as increased arterial stiffness and AGE skin accumulation, compared to healthy controls. We compared endothelial function, arterial stiffness, and levels of AGEs in patients suffering from endometriosis and in healthy controls. The study included 45 women aged 20 to 40: 21 patients with endometriosis and 24 healthy controls, matched in terms of age, BMI, and blood pressure values. Endo-PAT 2000 device was used for non-invasive assessment of (i) endothelial function, expressed as Reactive Hyperemia Index (RHI), and (ii) arterial stiffness, expressed as Augmentation Index (AI) and Augmentation Index at 75 heart beats/min (AI@75). Endothelial dysfunction was defined as an RHI value ≤ 1.67. AGE Reader device was used for non-invasive evaluation of skin AGE level accumulation. Patients with endometriosis had lower mean RHI values (1.69 ± 0.54 vs. 2.02 ± 0.48, p = 0.037) and a higher prevalence of endothelial dysfunction, (52.4% vs. 20.8%, p = 0.027) compared to healthy controls. Skin AGE level was higher in patients with endometriosis, compared to controls (2.00 ± 0.57 vs. 1.70 ± 0.24, p = 0.013). There were no significant differences in AI and AI@75 between the two groups. Patients with endometriosis have impaired endothelial function and higher AGE skin accumulation, which are well-established preclinical manifestations of increased cardiovascular risk. There is a great need for comprehensive cardiovascular risk assessments in women with endometriosis to prevent the development of potential atherosclerotic-based complications.

In chronic hyperglycemia, the advanced glycation end product (AGE) interacts with its receptor (RAGE) and contributes to impaired wound healing by inducing oxidative stress, generating dysfunctional macrophages, and prolonging the inflammatory response. Additionally, uncontrolled levels of proteases, including metallomatrix protease-9 (MMP-9), in the diabetic wound bed degrade the extracellular matrix (ECM) and biological cues that augment healing. A multifunctional antimicrobial hydrogel (Immuno-gel) containing RAGE and MMP-9 inhibitors can regulate the wound microenvironment and promote scar-free healing.

Immuno-gel was characterized and the wound healing efficacy was determined in vitro cell culture and in vivo diabetic Wistar rat wound model using ELISA, Western blot, and Immunofluorescence staining. The Immuno-gel exhibited a highly porous morphology with excellent in vitro cytocompatibility. AGE-stimulated macrophages treated with the Immuno-gel released higher levels of pro-healing cytokines in vitro. In the hydrogel-wound interface of diabetic Wistar rats, Immuno-gel treatment significantly reduced MMP-9 and NF-κB expression and enhanced pro-healing (M2) macrophage population and pro-healing cytokines.

Altogether, this study suggests that Immuno-gel simultaneously attenuates macrophage dysfunction through the inhibition of AGE/RAGE signaling and reduces MMP-9 overexpression, both of which favor scar-free healing. The combinatorial treatment with RAGE and MMP-9 inhibitors via Immuno-gel simultaneously modulates the diabetic wound microenvironment, making it a promising novel treatment to accelerate diabetic wound healing.

Prolonged catabolic states in type 2 diabetes (T2D), exacerbated by excess substrate flux and hyperglycemia, can challenge metabolic flexibility and antioxidative capacity. We investigated cellular responses to glucose load after prolonged fasting in T2D.

Glucose-tolerant individuals (CON, n = 10) and individuals with T2D with (T2D+, n = 10) and without (T2D-, n = 10) diabetes complications underwent oral glucose tolerance test before and after a 5-day fasting-mimicking diet. Peripheral blood mononuclear cell (PBMC) resistance to ex vivo dicarbonyl methylglyoxal (MG) exposure after glucose load was assessed. Markers of dicarbonyl detoxification, oxidative stress, and mitochondrial biogenesis were analyzed by quantitative PCR, with mitochondrial complex protein expression assessed by Western blotting.

T2D+ exhibited decreased PBMC resistance against MG, while T2D- resistance remained unchanged, and CON improved postglucose load and fasting (-19.0% vs. -1.7% vs. 12.6%; all P = 0.017). T2D+ showed increased expression in dicarbonyl detoxification (mRNA glyoxalase-1, all P = 0.039), oxidative stress (mRNA glutathione-disulfide-reductase, all P = 0.006), and mitochondrial complex V protein (all P = 0.004) compared with T2D- and CON postglucose load and fasting. Citrate synthase activity remained unchanged, indicating no change in mitochondrial number. Mitochondrial biogenesis increased in T2D- compared with CON postglucose load and fasting (mRNA HspA9, P = 0.032). T2D-, compared with CON, exhibited increased oxidative stress postfasting, but not postglucose load, with increased mRNA expression in antioxidant defenses (mRNA forkhead box O4, P = 0.036, and glutathione-peroxidase-2, P = 0.034), and compared with T2D+ (glutathione-peroxidase-2, P = 0.04).

These findings suggest increased susceptibility to glucose-induced oxidative stress in individuals with diabetes complications after prolonged fasting and might help in diet interventions for diabetes management.

Chronic kidney disease (CKD) is a chronic and progressive systemic condition that characterizes irreversible alterations in the kidneys' function and structure over an extended period, spanning months to years. CKD is the one of the major causes of mortality worldwide. However, very limited treatment options are available in the market for management of the CKD. Diabetes and hypertension are the key risk factors for the progression of CKD. It is majorly characterised by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Plants are considered safe and effective in treating various chronic conditions. A diverse group of phytoconstituents, including polyphenols, flavonoids, alkaloids, tannins, saponins, and terpenes, have found significant benefits in managing chronic ailments. Terpenes constitute a diverse group of plant compounds with various therapeutic benefits. Evidence-based pharmacological studies underscore the crucial role played by terpenes in preventing and managing CKD. These substances demonstrate the capacity to hinder detrimental pathways, such as oxidative stress, inflammation and fibrosis, thereby demonstrating benefit in renal dysfunction. This review offers a comprehensive overview of the roles and positive attributes of commonly occurring terpenes in managing the causes and risk factors of CKD and the associated conditions.

Significance: Aging is a complex process associated with an increased risk of many diseases, including thrombosis. This review summarizes age-related prothrombotic mechanisms in clinical settings of thromboembolism, focusing on the role of fibrin structure and function modified by oxidative stress. Recent Advances: Aging affects blood coagulation and fibrinolysis via multiple mechanisms, including enhanced oxidative stress, with an imbalance in the oxidant/antioxidant mechanisms, leading to loss of function and accumulation of oxidized proteins, including fibrinogen. Age-related prothrombotic alterations are multifactorial involving enhanced platelet activation, endothelial dysfunction, and changes in coagulation factors and inhibitors. Formation of more compact fibrin clot networks displaying impaired susceptibility to fibrinolysis represents a novel mechanism, which might contribute to atherothrombosis and venous thrombosis. Alterations to fibrin clot structure/function are at least in part modulated by post-translational modifications of fibrinogen and other proteins involved in thrombus formation, with a major impact of carbonylation. Fibrin clot properties are also involved in the efficacy and safety of therapy with oral anticoagulants, statins, and/or aspirin. Critical Issues: Since a prothrombotic state is observed in very elderly individuals free of diseases associated with thromboembolism, the actual role of activated blood coagulation in health remains elusive. It is unclear to what extent oxidative modifications of coagulation and fibrinolytic proteins, in particular fibrinogen, contribute to a prothrombotic state in healthy aging. Future Directions: Ongoing studies will show whether novel therapies that may alter oxidative stress and fibrin characteristics are beneficial to prevent atherosclerosis and thromboembolic events associated with aging.

Opuntia ficus-indica (L.) Mill is frequently observed in the Moroccan traditional medicinal system, where these approaches are employed to mitigate the onset of diabetes and the subsequent complications it may entail.

The aim of this research was to examine the effectiveness of Opuntia ficus-indica seed oil in preventing diabetic complications. Specifically, the study assessed its ability to counteract glycation at various stages, protected red blood cells from the harmful effects of glycated albumin, and inhibited pancreatic lipase digestive enzymes to understand its potential antihyperglycemic properties. Additionally, the study aimed to identify the chemical components responsible for these effects, evaluate antioxidant and anti-inflammatory properties, and conduct computational investigations such as molecular docking.

The assessement of Opuntia ficus-indica seed oil antiglycation properties involved co-incubating the extract oil with a bovine serum albumin-glucose glycation model. The study investigated various stages of glycation, incorporating fructosamine (inceptive stage), protein carbonyls (intermediate stage), and AGEs (late stage). Additionally, measurement of β-amyloid aggregation of albumin was performed using Congo red, which is specific to amyloid structures. Additionally, the evaluation of oil's safeguarding effect on erythrocytes against toxicity induced by glycated albumin included the measurement of erythrocyte hemolysis, lipid peroxidation, reduced glutathione. The fatty acid of Opuntia ficus-indica seed oil were analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). The in vitro evaluation of antihyperglycemic activity involved the use of pancreatic lipase enzyme, while the assessement of antioxidant capability was carried out through the utilization of the ABTS and FRAP methods. The in vitro assessement of the denaturation of albumin activity was also conducted. In conjunction with the experimental outcomes, computational investigations were undertaken, specifically employing ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. Furthermore, molecular docking was utilized to predict antioxidant and antiglycation mechanisms based on protein targets.

In vitro glycation assays, Opuntia ficus-indica seed oil displayed targeted inhibitory effects at multiple distinct stages. Within erythrocytes, in addition to mitigating hemolysis and lipid peroxidation induced by glycated albumin. GC-MS investigation revealed a richness of fatty acids and the most abundant compounds are Linoleic acid (36.59%), Palmitic acid (20.84%) and Oleic acid (19.33%) respectively. The findings of antioxidant ability showed a remarkable activity on FRAP and ABTS radicals. This oil showed a pronounced inhibitory impact (p < 0.001) on pancreatic lipase enzyme. It also exerted a notibale inhibition of albumin denaturation, in vitro.

The identified results were supported by the abundant compounds of fatty acids unveiled through GC-MS analysis, along with the computational investigation and molecular docking.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia, leading to various vascular complications. Accumulating evidence indicates that endothelial colony-forming cells (ECFCs) have attractive prospects for repairing and restoring blood vessels. Thus, ECFCs may be a novel therapeutic option for diabetic patients with vascular complications who require revascularization therapy. However, it has been reported that the function of ECFCs is impaired in DM, which poses challenges for the autologous transplantation of ECFCs. In this review, we summarize the molecular mechanisms that may be responsible for ECFC dysfunction and discuss potential strategies for improving the therapeutic efficacy of ECFCs derived from patients with DM. Finally, we discuss barriers to the use of ECFCs in human studies in light of the fact that there are no published reports using these cells in humans.

Meteorin-like (Metrnl), a secreted myokine, is a newly discovered neurotrophic factor. The aim of this study was to determine if there is a correlation between the Metrnl level and diabetic peripheral neuropathy (DPN).

The investigation was conducted on a sample of 80 patients with type 2 diabetes mellitus (T2DM) and 60 healthy controls. The T2DM patients were categorized into two subgroups based on skin biopsy: the DPN subgroup (n = 20) and the diabetes without neuropathy subgroup (n = 60).

The T2DM groups had higher serum Metrnl concentrations compared with the controls. The serum Metrnl concentration was significantly lower in the DPN group than in T2DM patients without neuropathy. Logistic regression analysis demonstrated a notable correlation between serum Metrnl and DPN (OR: 0.997, 95% CI: 0.995-1.000, P < 0.05). Serum Metrnl level was negatively correlated with age and SBP after a simple logistic regression analysis.

Serum Metrnl concentration is independently correlated with DPN.

Frailty is a multifaceted geriatric syndrome characterized by an increased vulnerability to stressful events. metabolomics studies are valuable tool for better understanding the underlying mechanisms of pathologic conditions. This review aimed to elucidate the metabolomics profile of frailty.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 statement. A comprehensive search was conducted across multiple databases. Initially, 5027 results were retrieved, and after removing duplicates, 1838 unique studies were subjected to screening. Subsequently, 248 studies underwent full-text screening, with 21 studies ultimately included in the analysis. Data extraction was performed meticulously by two authors, and the quality of the selected studies was assessed using the Critical Appraisal Skills Program (CASP) checklist.

The findings revealed that certain Branched-chain amino acids (BCAAs) levels were lower in frail subjects compared to robust subjects, while levels of glutamate and glutamine were higher in frail individuals. Moreover, sphingomyelins and phosphatidylcholines (PC) displayed a decreasing trend as frailty advanced. Additionally, other metabolic derivatives, such as carnitine, exhibited significant associations with frailty. These metabolites were primarily interconnected through biochemical pathways related to the tricarboxylic acid and urea cycles. Notably, frailty was associated with a decrease in metabolic derivatives, including carnitine.

This study underscores the intricate relationship between essential metabolites, including amino acids and lipids, and their varying levels in frail individuals compared to their robust counterparts. It provides a comprehensive panel of metabolites, shedding light on their potential associations with frailty and expanding our understanding of this complex syndrome.

Advanced glycation end products (AGEs), derived from the non-enzymatic glycation reaction, are defined as glycotoxins in various diseases including aging, diabetes and kidney injury. Exploring AGEs as potential biomarkers for these diseases holds paramount significance. Nevertheless, the high chemical structural similarity and great heterogeneity among AGEs present a formidable challenge when it comes to the comprehensive, simultaneous, and accurate detection of multiple AGEs in biological samples. In this study, an UPLC/MS/MS method for simultaneous quantification of 20 free AGEs in human serum was firstly established and applied to quantification of clinical samples from individuals with kidney injury. Simple sample preparation method through protein precipitation without derivatization was used. Method performances including imprecision, accuracy, sensitivity, linearity, and carryover were systematically validated. Intra- and inter- imprecision of 20 free AGEs were 1.93-5.94 % and 2.30-8.55 %, respectively. The method accuracy was confirmed with good recoveries ranging from 96.40 % to 103.25 %. The LOD and LOQ were 0.1-3.13 ng/mL and 0.5-6.25 ng/mL, respectively. Additionally, the 20 free AGEs displayed excellent linearity (R2 >0.9974) across a wide linear range (1.56-400 ng/mL). Finally, through simultaneous quantitation of 20 Free AGEs in 100 participants including kidney injury patient and healthy controls, we identified six free AGEs, including N6-carboxyethyl-L-arginine (CEA), N6-carboxymethyl-L-lysine (CML), methylglyoxal-derived hydroimidazolones (MG-H), N6-formyl-lysine, N6-carboxymethyl-L-arginine (CMA), and glyoxal-derived hydroimidazolone (G-H), could well distinguish kidney injury patients and healthy individuals. Among them, the levels of four free AGEs including CML, CEA, MG-H, and G-H strongly correlate with traditionally clinical markers of kidney disease. The high area under the curve (AUC) values (AUC=0.965) in receiver operating characteristic (ROC) curve indicated that these four free AGEs can be served as combined diagnostic biomarkers for the diagnosis of kidney disease.

In this study, we report a small molecule optical marker BI-CyG derived from the structural engineering of a cyanine scaffold. The developed probe offers suitable advantages over existing cyanine-based albumin specific probes in terms of its excitation and emission wavelengths, which are 760 and 830-832 nm, respectively. Structural tuning of the cyanine architecture leading to extended π-conjugation and resulting in a suitable bathochromic shift in the emission wavelength of the probe is represented in this study. The probe besides emitting in the NIR region, also possesses the desirable characteristics of being a potential target selective optical marker, as established from various biophysical studies. Molecular modelling and simulation studies provided critical insights into the binding of the probe in the protein microenvironment, which was further supported by experimental studies. The probe displayed intracellular albumin selectivity and was utilized for demonstrating alteration in albumin levels in pathological states such as hyperglycemia in hepatic cells. The present study also sheds some light on using BI-CyG as an imaging probe and on the role of metformin as a suitable drug for balancing hyperglycemia-induced reduced intra-hepatic albumin levels. The study, thus, attempts to highlight the structural derivatization of cyanine to afford a potential probe for serum albumin and its deployment to image altering albumin levels in an induced pathological condition, hyperglycemia.

This article examines the importance of advanced glycation endproducts (AGEs) and summarizes the structure of AGEs, pathological changes associated with AGEs, the contribution of AGEs to metabolic memory, and the value of AGEs as a predictor of diabetic complications and cardiovascular disease in people with and without diabetes. As a practical focus, skin autofluorescence (SAF) is examined as an attractive approach for estimating AGE burden. The measurement of AGEs may be of significant value to specific individuals and groups, including Black and Hispanic/Latino Americans, as they appear to have higher concentrations of hemoglobin A1c (HbA1c) than would be predicted by other metrics of mean glycemia. We hypothesize that if the amount of glycation of HbA1c is greater than expected from measured glucose levels, and if AGEs are accumulating, then this accumulation of AGEs might account for the increased rate of complications of diabetes in populations with high rates of vascular disease and other complications. Thus, identifying and modifying the burden of AGEs based on measurement of AGEs by SAF may turn out to be a worthwhile metric to determine individuals who are at high risk for the complications of diabetes as well as others without diabetes at risk of vascular disease. We conclude that available evidence supports SAF as both a clinical measurement and as a means of evaluating interventions aimed at reducing the risks of vascular disease and diabetic complications.

Glycation is a physiological process that determines the aging of the organism, while in states of metabolic disorders it is significantly intensified. High concentrations of compounds such as reducing sugars or reactive aldehydes derived from lipid oxidation, occurring for example in diabetes, atherosclerosis, dyslipidemia, obesity or metabolic syndrome, lead to increased glycation of proteins, lipids and nucleic acids. The level of advanced glycation end-products (AGEs) in the body depends on rapidity of their production and the rate of their removal by the urinary system. AGEs, accumulated in the extracellular matrix of the blood vessels and other organs, cause irreversible changes in the biochemical and biomechanical properties of tissues. As a consequence, micro- and macroangiopathies appear in the system, and may contribute to the organ failure, like kidneys and heart. Elevated levels of AGEs also increase the risk of Alzheimer's disease and various cancers. In this paper, we propose a new classification due to modified amino acid residues: arginyl-AGEs, monolysyl-AGEs and lysyl-arginyl-AGEs and dilysyl-AGEs. Furthermore, we describe in detail the effect of AGEs on the pathogenesis of metabolic and old age diseases, such as diabetic complications, atherosclerosis and neurodegenerative diseases. We summarize the currently available data on the diagnostic value of AGEs and present the AGEs as a therapeutic goal in a wide range of medical problems, including SARS-CoV-2 infection and so-called long COVID.

It is unclear if AGEs are involved in the bone fragility of type 1 diabetes (T1D). We evaluated whether skin AGEs by skin autofluorescence and serum AGEs (pentosidine, carboxymethyl-lysine [CML]) are independently associated with BMD by DXA (lumbar spine, hip, distal radius), trabecular bone score (TBS), serum bone turnover markers (BTMs: CTX; P1NP; osteocalcin), and sclerostin in participants with and without T1D. Linear regression models were used, with interaction terms to test effect modification by T1D status. In participants with T1D, correlations between skin and serum AGEs as well as between AGEs and 3-year HbA1C were evaluated using Spearman's correlations. Data are mean ± SD or median (interquartile range). We included individuals who participated in a cross-sectional study and had BMD and TBS assessment (106 T1D/65 controls, 53.2% women, age 43 ± 15 yr, BMI 26.6 ± 5.5 kg/m2). Participants with T1D had diabetes for 27.6 ± 12.3 yr, a mean 3-yr HbA1C of 7.5 ± 0.9% and skin AGEs of 2.15 ± 0.54 arbitrary units. A subgroup of 65 T1D/57 controls had BTMs and sclerostin measurements, and those with T1D also had serum pentosidine (16.8[8.2-32.0] ng/mL) and CML [48.0 ± 16.8] ng/mL) measured. Femoral neck BMD, TBS, and BTMs were lower, while sclerostin levels were similar in participants with T1D vs controls. T1D status did not modify the associations between AGEs and bone outcomes. Skin AGEs were significantly associated with total hip and femoral neck BMD, TBS, BTMs, and sclerostin before, but not after, adjustment for confounders. Serum AGEs were not associated with any bone outcome. There were no significant correlations between skin and serum AGEs or between AGEs and 3-yr HbA1C. In conclusion, skin and serum AGEs are not independently associated with BMD, TBS, BTMs, and sclerostin in participants with relatively well-controlled T1D and participants without diabetes.

The process of glycation, characterized by the non-enzymatic reaction between sugars and free amino groups on biomolecules, is a key contributor to the development and progression of both microvascular and macrovascular complications associated with diabetes, particularly due to persistent hyperglycemia. This glycation process gives rise to advanced glycation end products (AGEs), which play a central role in the pathophysiology of diabetes complications, including nephropathy. The d-ribose-mediated glycation of fibrinogen plays a central role in the pathogenesis of diabetes nephropathy (DN) and retinopathy (DR) by the generation and accumulation of advanced glycation end products (AGEs). Glycated fibrinogen with d-ribose (Rb-gly-Fb) induces structural changes that trigger an autoimmune response by generating and exposing neoepitopes on fibrinogen molecules. The present research is designed to investigate the prevalence of autoantibodies against Rb-gly-Fb in individuals with type 2 diabetes mellitus (T2DM), DN & DR. Direct binding ELISA was used to test the binding affinity of autoantibodies from patients' sera against Rb-gly-Fb and competitive ELISA was used to confirm the direct binding findings by checking the bindings of isolated IgG against Rb-gly-Fb and its native conformer. In comparison to healthy subjects, 32% of T2DM, 67% of DN and 57.85% of DR patients' samples demonstrated a strong binding affinity towards Rb-gly-Fb. Both native and Rb-gly-Fb binding by healthy subjects (HS) sera were non-significant (p > 0.05). Furthermore, the early, intermediate, and end products of glycation have been assessed through biochemical and physicochemical analysis. The biochemical markers in the patient groups were also significant (p < 0.05) in comparison to the HS group. This study not only establishes the prevalence of autoantibodies against d-ribose glycated fibrinogen in DN but also highlights the potential of glycated fibrinogen as a biomarker for the detection of DN and/or DR. These insights may open new avenues for research into novel therapeutic strategies and the prevention of diabetes-related nephropathy and retinopathy.

Type 2 Diabetes Mellitus (T2DM) has become a major health concern with an increasing prevalence and is now one of the leading attributable causes of death globally. T2DM and cardiovascular disease are strongly associated and T2DM is an important independent risk factor for ischemic heart disease. T-wave abnormalities (TWA) on electrocardiogram (ECG) can indicate several pathologies including ischemia. In this study, we aimed to investigate the association between T2DM and T-wave changes using the Minnesota coding system.

A cross-sectional study was conducted on the MASHAD cohort study population. All participants of the cohort population were enrolled in the study. 12-lead ECG and Minnesota coding system (codes 5-1 to 5-4) were utilized for T-wave observation and interpretation. Regression models were used for the final evaluation with a level of significance being considered at p < 0.05.

A total of 9035 participants aged 35-65 years old were included in the study, of whom 1273 were diabetic. The prevalence of code 5-2, 5-3, major and minor TWA were significantly higher in diabetics (p < 0.05). However, following adjustment for age, gender, and hypertension, the presence of TWAs was not significantly associated with T2DM (p > 0.05). Hypertension, age, and body mass index were significantly associated with T2DM (p < 0.05).

Although some T-wave abnormalities were more frequent in diabetics, they were not statistically associated with the presence of T2DM in our study.

Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to treat various disorders. It is a multi-target drug with multiple mechanisms. Studies have shown that it has antioxidant and anti-inflammatory properties and can also adjust intestinal microbial flora. This review focused on the promising antidiabetic effects of BBR in several cellular, animal, and clinical studies. Based on previous research, BBR significantly reduced levels of fasting blood glucose, hemoglobin A1C, inflammatory cytokines, and oxidative stress markers. Furthermore, BBR stimulated insulin secretion and improved insulin resistance through different pathways, including up-regulation of protein expression of proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT) 4, PI3K/AKT, and AMP-activated protein kinase (AMPK) activation. Interestingly, it was demonstrated that BBR has protective effects against diabetes complications, such as diabetic-induced hepatic damage, cardiovascular disorders, nephropathy, and neuropathy. Furthermore, multiple clinical trial studies have emphasized the ameliorative effects of BBR in type 2 diabetic patients.