Advanced Glycation End-products Inhibitors Research Articles

Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy.

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.

Soluble receptors for advanced glycation endproducts are predictors of insulin sensitivity and affected by weight loss

BackgroundMice experiments have underscored the efficacy of pharmacological inhibition of advanced glycation endproducts (AGEs) through the use of soluble receptors for advanced glycation endproducts (sRAGE) in mitigating obesity-linked metabolic disruptions and insulin resistance. However, human studies have presented conflicting findings regarding the correlation between circulating sRAGE levels and insulin resistance, as well as glucose tolerance. Here, we aimed to delve deeper into the relationship between sRAGE levels and systemic insulin sensitivity.MethodsPlasma sRAGE levels, hyperinsulinemic-euglycemic clamp, and continuous glucose monitoring were measured in two independent cross-sectional case-control studies [cohort 1 (n = 180) and cohort 2 (n = 124)]. In addition, a subgroup of 42 participants with obesity were followed for 12 months. In 14 of these participants, weight loss was achieved through bariatric surgery intervention.ResultsOur results revealed a significant association between plasma sRAGE levels and both insulin sensitivity and glycemic control parameters, even after adjustments for age, sex, and BMI. Furthermore, longitudinal analysis demonstrated that interventions aimed at weight loss led to reductions in fasting glucose and HbA1c levels, concurrently with increases in sRAGE levels.ConclusionsThese findings underscore that sRAGE levels were strongly associated with insulin sensitivity and glycemic control, suggesting a possible role of sRAGE in preserving insulin sensitivity and maintaining glycemic control, which should be confirmed in further studies.

Mango peel extracts and mangiferin chromatographic Fourier-transform infrared correlation with antioxidant, antidiabetic, and advanced glycation end product inhibitory potentials using in silico modeling and in vitro assays.

Mangifera indica peels are a rich source of diverse flavonoids and xanthonoids; however, generally these are discarded. Computational studies revealed that mangiferin significantly interacts with amino acid residues of transcriptional regulators 1IK3, 3TOP, and 4f5S. The methanolic extract of Langra variety of mangoes contained the least phenol concentrations (22.6 ± 0.32 mg/gGAE [gallic acid equivalent]) compared to the chloroform (214.8 ± 0.12 mg/gGAE) and ethyl acetate fractions (195.6 ± 0.14 mg/gGAE). Similarly, the methanolic extract of Sindhri variety contained lower phenol concentrations (42.3 ± 0.13 mg/gRUE [relative utilization efficiency]) compared with the chloroform (85.6 ± 0.15 mg/gGAE) and ethyl acetate (76.1 ± 0.32 mg/gGAE) fractions. Langra extract exhibited significant α-glucosidase inhibition (IC50 0.06 mg/mL), whereas the ethyl acetate fraction was highly active (IC50 0.12 mg/mL) in Sindhri variety. Mangiferin exhibited significant inhibition (IC50 0.026 mg/mL). A moderate inhibition of 15-LOX was observed in all samples, whereas mangiferin was least active. In advanced glycation end product inhibition assay, the chloroform fraction of Langra variety exhibited significant inhibition in nonoxidative (IC50 64.4μg/mL) and oxidative modes (IC50 54.7μg/mL). It was concluded that both Langra and Sindhri peel extracts and fractions possess significant antidiabetic activities. The results suggest the potential use of peel waste in the management and complications of diabetes.

Advanced Glycation End Products-Induced Alzheimer's Disease and Its Novel Therapeutic Approaches: A Comprehensive Review.

Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.

Mechanisms of inhibition of advanced glycation end-products (AGEs) and α-glucosidase by Heliotropium bacciferum: Spectroscopic and molecular docking analysis

Diabetes mellitus is characterized by hyperglycemia that makes insulin more prone to glycation and form advanced glycation end products (AGEs). Here, we report the effect of glyoxal (GO) on the formation of AGEs using human insulin as model protein and their structural modifications. The present investigation also reports the anti-AGE potential of Heliotropium bacciferum (Leaf) extracts. The phytochemical analysis of H. bacciferum revealed that free phenolic extract contains higher amount of total phenolic (3901.58 ± 17.06 mg GAE/100 g) and total flavonoid content (30.41 ± 0.32 mg QE/100 g) when compared to bound phenolic extract. Naringin and caffeic acid were identified as the major phenolic ingredients by UPLC-PAD method. Furthermore, bound phenolics extract showed significantly higher DPPH and superoxide radicals scavenging activity (IC50 17.53 ± 0.36 μg/mL and 0.306 ± 0.038 mg/ mL, respectively) (p ≤ 0.05). Besides, the bound phenolics extract also showed significant (p ≤ 0.05) chelating power (IC50 0.063) compared to free phenolic extract. In addition, bound phenolic extract could efficiently trap GO under physiological conditions. Spectroscopic investigation of GO-modified insulin illustrated changes in the tertiary structure of insulin and formation of AGEs. On the other hand, no significant alteration in secondary structure was observed by far UV-CD measurement. Furthermore, H. bacciferum extract inhibited α-glucosidase activity and AGEs formation implicated in diabetes. Molecular docking analysis depicted that GO bind with human insulin in both chains and forms a stable complex with TYR A: 14, LEU A:13, ASN B:3, SER A:12 amino acid residues with binding energy of – 2.53 kcal/mol. However, caffeic acid binds to ASN A:18 and GLU A:17 residues of insulin with lower binding energy of −4.67 kcal/mol, suggesting its higher affinity towards human insulin compared to GO. Our finding showed promising activity of H. bacciferum against AGEs and its complications. The major phenolics like caffeic acid, naringin and their derivatives could be exploited for the drug development for management of AGEs in diabetes.

Mirror, mirror on the wall, which phytochemicals in Clinacanthus nutans inhibits advanced glycation end products of them all?

In our quest to discover advanced glycation end products (AGEs) inhibitors from Clinacanthus nutans (Burm.f.) Lindau leaves, we conducted a bioactivity-based molecular networking. This approach integrates LC-MS2 profiling and in vitro antiglycation data to predict bioactive compounds. We began by screening three extracts: 100% ethanol, 70% ethanol and 100% water alongside the in vitro antioxidant activity, total phenolics content (TPC) and schaftoside content. Among these extracts, 100% ethanol extract exhibited the highest total AGEs inhibition effects (IC50 = 80.18 ± 11.6 μg/mL), DPPH scavenging activity (IC50 = 747.40 ± 10.30 μg/mL) and TPC (26.54 ± 2.09 μg GAE /mg extract). Intriguingly, 100% ethanol extract contained the lowest amount of schaftoside, suggesting the involvement of other phytochemicals in the antiglycation effects. The molecular networking and in silico structural annotations of 401 LC-MS features detected in the fractions from 100% ethanol extract predicted 21 bioactive compounds (p < 0.05, r > 0.90), including several C40 carotenoids, alkaloids containing tetrapyrrole structures and fatty acids. On the contrary, all phenolics showed weak correlations with antiglycation effects. These predictions were further validated in vitro, where carotenoid lutein showed half maximal inhibitory concentration, IC50 = 96 ± 8 μM and selected flavonoid-C-glycosides exhibited weaker inhibitions (IC50 between 568 and 1922 μM). Notably, lutein content was higher in freeze-dried leaves (12.42 ± 0.82 mg/100 g) than oven-dried, although the former was associated with elevated mercury levels. In summary, C. nutans exhibited potential antiglycation and antioxidant activity, and lutein was identified as the main bioactive principle.

Effect of Thermal Treatment of Ribes magellanicum on the Extraction of Polyphenols, Advanced Glycation End Products Inhibition, Gastrointestinal Digestion and Cytoprotection of AGS Cells

Effect of Thermal Treatment of Ribes magellanicum on the Extraction of Polyphenols, Advanced Glycation End Products Inhibition, Gastrointestinal Digestion and Cytoprotection of AGS Cells

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.

&lt;i&gt;Alpinia zerumbet&lt;/i&gt;: A Review of the Chemistry, Quantity, and Pharmacological Properties of Selected Kavalactones

Alpinia zerumbet or shell ginger is a ginger plant with diverse chemical constituents and medicinal and non-medicinal uses. Dihydro-5,6-dehydrokawain (DDK) and Dehydrokawain (DK) are two kavalactones (also known as kava pyrones or styrylpyrones) from A. zerumbet. Both DDK and DK have a carbonyl group at C2, a methoxy group at C4, and a double bond at C5 and C6. DK has a double bond at C7 and C8 that is absent in DDK. Quantity of DDK in A. zerumbet can be ranked as rhizome &gt; leaf &gt; flower &gt; stem &gt; seed. The pericarp and seed placenta of the fruit has higher quantity of DDK than the leaf. In most plant parts, the contents of DDK are higher than those of DK. Hispidin (HP) is synthesized from DK by hydrolysis. These three kavalactones from A. zerumbet have the most promising pharmacological properties that include insecticidal, fungicidal, antioxidant, inhibition of enzymes, inhibition of Advanced Glycation End-products (AGEs), inhibition of p21-activated kinase 1 (PAK1), inhibition of LIM domain kinase 1 (LIMK1), promotion of hair growth, anti-cancer, inhibition of melanogenesis, anti-inflammatory, anti-obesity, HIV-1 integrase inhibition, neuraminidase inhibition, osteogenic, anti-platelet aggregation, cytoprotective, anti-ulcerative, and singlet oxygen quenching activities. Some fields for further research are suggested. Sources of information in this review were from Google, Google Scholar, Science Direct, PubMed, J-Stage, China National Knowledge Infrastructure (CNKI), and PubChem.

HMGB 1 acetylation mediates trichloroethylene-induced immune kidney injury by facilitating endothelial cell-podocyte communication

More and more clinical evidence shows that occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) patients often present immune kidney damage. However, the exact mechanisms of cell-to-cell transmission in TCE-induced immune kidney damage remain poorly understood. The present study aimed to explore the role of high mobility group box-1 (HMGB 1) in glomerular endothelial cell-podocyte transmission. 17 OMDT patients and 34 controls were enrolled in this study. We observed that OMDT patients had renal function injury, endothelial cell activation and podocyte injury, and these indicators were associated with serum HMGB 1. To gain mechanistic insight, a TCE-sensitized BALB/c mouse model was established under the interventions of sirtuin 1 (SIRT 1) activator SRT 1720 (0.1 ml, 5 mg/kg) and receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM 1 (0.1 ml, 1.5 mg/kg). We identified HMGB 1 acetylation and its endothelial cytoplasmic translocation following TCE sensitization, but SRT 1720 abolished the process. RAGE was located on podocytes and co-precipitated with extracellular acetylated HMGB 1, promoting podocyte injury, while SRT 1720 and FPS-ZM 1 both alleviated podocyte injury. The results demonstrate that interventions to upstream and downstream pathways of HMGB 1 may weaken glomerular endothelial cell-podocyte transmission, thereby alleviating TCE-induced immune renal injury.

Deficiency of S100 calcium binding protein A9 attenuates vascular dysfunction in aged mice

BackgroundS100 calcium-binding protein A9 (S100A9) is a danger-associated molecular pattern molecule that mediates the inflammatory response. Inflammation is essential in aging-related cardiovascular diseases. However, less is known regarding the role of S100A9 in vascular aging. MethodsS100A9 null mice were used to investigate the role of S100A9 in aging-related pathologies. Artery rings were used to measure the functional characteristics of vascular with a pressurized myograph. Telomere length, Sirtuin activity, oxidative stress, and endothelial nitric oxide synthetase (eNOS) activity were used to elevate vascular senescence. Intraperitoneal glucose tolerance (IPGTT) and insulin sensitivity test (IST) were employed to investigate the effects of S100A9 on insulin resistance. Inflammation response was reflected by the concentration of inflammatory cytokines. The Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) inhibitors were used to identify the downstream molecular mechanisms of S100A9 in aging-induced senescence in endothelial cells. ResultsS100A9 expression in vascular increased with aging in mice and humans. Deficiency of S100A9 alleviated vascular senescence in aged mice, as evidenced by increased telomere length, Sirtuin activity, and eNOS activity. Meanwhile, S100A9 knockout improved endothelium-dependent vasodilatation and endothelial continuity in aged mice. Moreover, the increased insulin resistance, oxidative stress, and inflammation were mitigated by S100A9 deletion in aged mice. In vitro, S100A9 induced senescence in endothelial cells, and that effect was blunted by TLR4 but not RAGE inhibitors. ConclusionThe present study suggested that S100A9 may contribute to aging-related pathologies and endothelial dysfunction via the TLR4 pathway. Therefore, targeting S100A9/TLR4 signaling pathway may represent a crucial therapeutic strategy to prevent age-related cardiovascular diseases.

Phytochemical profiling of Symplocos tanakana Nakai and S. sawafutagi Nagam. leaf and identification of their antioxidant and anti-diabetic potential

Symplocos sp. contains various phytochemicals and is used as a folk remedy for treatment of diseases such as enteritis, malaria, and leprosy. In this study, we discovered that 70% ethanol extracts of Symplocos sawafutagi Nagam. and S. tanakana Nakai leaves have antioxidant and anti-diabetic effects. The components in the extracts were profiled using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry; quercetin-3-O-(6′′-O-galloyl)-β-d-galactopyranoside (6) and tellimagrandin II (7) were the main phenolic compounds. They acted as strong antioxidants with excellent radical scavenging activity and as inhibitors of non-enzymatic advanced glycation end-products (AGEs) formation. Mass fragmentation analysis demonstrated that compounds 6 and 7 could form mono- or di-methylglyoxal adducts via reaction with methylglyoxal, which is a reactive carbonyl intermediate and an important precursor of AGEs. In addition, compound 7 effectively inhibited the binding between AGE2 and receptor for AGEs as well as the activity of α-glucosidase. Enzyme kinetic study revealed that compound 7 acts as a competitive inhibitor of α-glucosidase, through interaction with the active site of the enzyme. Therefore, compounds 6 and 7, the major constituents of S. sawafutagi and S. tanakana leaves, are promising for developing drugs for preventing or treating diseases caused by aging and excessive sugar consumption.

Extraction optimization and identification of four advanced glycation-end products inhibitors from lotus leaves and interaction mechanism analysis

Previous research indicated lotus leaves extract could effectively inhibit advanced glycation end-products (AGEs) formation, but the optimal extraction condition, bio-active compounds and interaction mechanism remain unclear. The current study was designed to optimize the extraction parameters of AGEs inhibitors from lotus leaves by bio-activity-guided approach. The bio-active compounds were enriched and identified, the interaction mechanisms of inhibitors with ovalbumin (OVA) were investigated by fluorescence spectroscopy and molecular docking. The optimum extraction parameters were solid–liquid ratio of 1:30, ethanol concentration of 70 %, ultrasonic time of 40 min, temperature of 50 °C, and power of 400 W. Isoquercitrin, hyperoside, astragalin, and trifolin were identified from the 80 % ethanol fraction of lotus leaves (80HY). Hyperoside and isoquercitrin were dominant AGEs inhibitors and accounted for 55.97 % of 80HY. Isoquercitrin, hyperoside, trifolin interacted with OVA via the same mechanism, hyperoside exhibited the strongest affinity, trifolin caused the most conformational changes.

Inhibition of Advanced Glycation End-Products by Tamarindus indica and Mitragyna inermis Extracts and Effects on Human Hepatocyte and Fibroblast Viability

Tamarindus indica and Mitragyna inermis are widely used by herbalists to cure diabetes mellitus. The aim of this study is to investigate the inhibitory potential of aqueous and various organic solvent fractions from both plants and some isolated compounds against advanced glycation end-products (AGEs). For this purpose, an in vitro BSA-fructose glycation model was used to evaluate the inhibition of AGE formation. Furthermore, the effects of the fractions on mouse fibroblast (NIH-3T3) and human hepatocyte (HepG2) survival were evaluated. The leaf, stem, and root fractions of both plants exhibited significant inhibition of AGEs formation. The IC50 values appeared to be less than 250 µg/mL; however, all fractions presented no adverse effects on NIH-3T3 up to 500 µg/mL. Otherwise, our phytochemical investigation afforded the isolation of a secoiridoid from the Mitragyna genus named secoiridoid glucoside sweroside (1), along with three known quinovic acid glycosides: quinovic acid-3β-O-β-d-glucopyranoside (2), quinovic acid-3-O-β-d-6-deoxy-glucopyranoside, 28-O-β-d-glucopyranosyl ester (3), and quinovic acid 3-O-α-l-rhamnopyranosyl-(4→1)-β-d-glucopyranoside (4). In particular, 1-3 are compounds which have not previously been described in Mitragyna inermis roots. However, the isolated compounds did not exhibit AGE inhibitory activity. Further investigation on these potent antiglycation fractions may allow for the isolation of new antidiabetic drug candidates.

A Narrative Review of New Treatment Options for Diabetic Nephropathy.

Diabetic nephropathy (DN) is a type of nephropathy that is caused by a diabetic condition. Diabetic nephropathyis seen in type 1 and type2 diabetes. End-stage renal disorders are brought on by DN. Diabetic nephropathy is thought to be linked to metabolic changes in the body. Proteinuria and glomerular filtration rate are the two most crucial diagnostic and prognosis measures for diabetic kidney disease (DKD), yet both have significant disadvantages. Novel biomarkers are thus increasingly required to improve risk factors and detect disease at an early stage. Controlling blood glucose and vital sign like body temperature and blood pressure, reducing cholesterol levels, and blocking the renin-angiotensin system are the standard treatments for diabetic patients. On the other hand, if used too late within the course of the disease, these therapeutic techniques can only provide partial relief from nephropathy. The complicated pathophysiology of the diabetic kidney, which experiences a variety of severe structural, metabolic, and functional alterations, represents one of the most important obstacles to the event of effective therapeutics for DN. Despite these issues, new diabetes models have identified promising treatment targets by identifying the mechanisms that control important functions of podocytes and glomerular endothelial cells. It has been shown in the vast majority of trials that renin-angiotensin system inhibitors combined with integrative therapies work well for DN. Combining sodium-glucose cotransporter-2 inhibitors and renin-angiotensin-aldosterone system blockers is a novel way to slow down the course of DKD by lowering inflammatory and fibrotic indicators brought on by hyperglycemia, which is more effective than using either medicine alone. Aldosterone receptor inhibitors and advanced glycation end-product inhibitors are two recently produced medications that may be used successfully to treat DN.

Chronic E-Cigarette Use Impairs Endothelial Function on the Physiological and Cellular Levels.

The harmful vascular effects of smoking are well established, but the effects of chronic use of electronic cigarettes (e-cigarettes) on endothelial function are less understood. We hypothesized that e-cigarette use causes changes in blood milieu that impair endothelial function. Endothelial function was measured in chronic e-cigarette users, chronic cigarette smokers, and nonusers. We measured effects of participants' sera, or e-cigarette aerosol condensate, on NO and H2O2 release and cell permeability in cultured endothelial cells (ECs). E-cigarette users and smokers had lower flow-mediated dilation (FMD) than nonusers. Sera from e-cigarette users and smokers reduced VEGF (vascular endothelial growth factor)-induced NO secretion by ECs relative to nonuser sera, without significant reduction in endothelial NO synthase mRNA or protein levels. E-cigarette user sera caused increased endothelial release of H2O2, and more permeability than nonuser sera. E-cigarette users and smokers exhibited changes in circulating biomarkers of inflammation, thrombosis, and cell adhesion relative to nonusers, but with distinct profiles. E-cigarette user sera had higher concentrations of the receptor for advanced glycation end products (RAGE) ligands S100A8 and HMGB1 (high mobility group box 1) than smoker and nonuser sera, and receptor for advanced glycation end product inhibition reduced permeability induced by e-cigarette user sera but did not affect NO production. Chronic vaping and smoking both impair FMD and cause changes in the blood that inhibit endothelial NO release. Vaping, but not smoking, causes changes in the blood that increase microvascular endothelial permeability and may have a vaping-specific effect on intracellular oxidative state. Our results suggest a role for RAGE in e-cigarette-induced changes in endothelial function.

Volatile composition, antidiabetic, and anti-obesity potential of Brassica incana leaf and flowering top extracts

Context Brassica incana Ten. (Brassicaceae) is an edible plant with very limited available information. Previous studies have demonstrated the polyphenolic profile and the antioxidant and cytotoxic properties of the leaf and flowering top hydroalcoholic extracts. Objective The volatile composition and the antidiabetic and anti-obesity potential of B. incana leaf and flowering top extracts have been investigated. Material and methods The volatile characterization of the extracts was attained by HS-SPME-GC/MS analysis. The antidiabetic and anti-obesity potential was investigated spectrophotometrically in vitro by the ability to modulate pancreatic lipase and α-glucosidase at different concentrations using orlistat and acarbose as reference drugs. The inhibition of advanced glycation end-products (AGEs) was measured with aminoguanidine as reference and the antioxidant activity with the xanthine/xanthine oxidase system and Trolox for comparative purposes. Results Several volatiles belonging to different chemical classes were identified, being sulphur compounds the most abundant in both leaf and flowering top extracts (56.33% and 64.40% of all volatiles). Although the leaf extract showed lower IC50 values in most of the assays (0.968 and 1.921 mg/mL for α-glucosidase; 0.192 and 0.262 mg/mL for AGEs; 0.022 and 0.038 mg/mL for superoxide scavenging), there were no statistically significant differences between both samples. These extracts showed a similar behaviour to Trolox in the xanthine oxidase assay (IC50 values of 0.022 mg/mL for leaf extract; 0.038 mg/mL for flowering top and 0.028 for Trolox). Conclusions Leaves and flowering tops from B. incana can be used as sources of functional compounds that could act as antidiabetic and anti-obesogenic agents.

Optimization of Phlorizin Extraction from Annurca Apple Tree Leaves Using Response Surface Methodology.

Phlorizin is a plant-derived molecule with relevant anti-diabetic activity, making this compound a potential functional component in nutraceutical formulations for the management of glycemia. It is noteworthy that promising sources for the extraction of phlorizin include apple tree leaves, a by-product of apple fruit production. The main aim of this study was to optimize the extraction process of phlorizin from Annurca apple tree leaves (AALs) using response surface methodology (RSM), and to determine the potential nutraceutical application of the obtained extract. The results of the RSM analysis indicate a maximum phlorizin yield of 126.89 ± 7.579 (mg/g DW) obtained under the following optimized conditions: MeOH/H2O, 80:20 + 1% HCOOH as the extraction solvent; 37.7 °C as the extraction temperature; and 170 min as the time of extraction. The HPLC-DAD-HESI-MS/MS analysis performed on the extract obtained under such conditions, named optimized Annurca apple leaves extract (OAALE), led to the identification of twenty-three phenolic molecules, with fifteen of them quantified. To explore the nutraceutical potential of OAALE, the in vitro antioxidant activity was evaluated by DPPH, ABTS, and FRAP assays, resulting in 21.17 ± 2.30, 38.85 ± 0.69, and 34.14 ± 3.8 μmol Trolox equivalent/g of extract, respectively. Moreover, the IC50 of 0.330 mg/mL obtained from the advanced glycation end-product inhibition assay, further supported the antidiabetic potential of OAALE.

Bioactive phlorotannin as autophagy modulator in cervical cancer cells and advanced glycation end products inhibitor in glucotoxic C. elegans

Brown algae produce varieties of potent metabolites in order to adapt to extreme environment. Among these metabolites, polyphenols comprised of phlorotannins serve as powerful multifaceted bioactive with vast pharmacological potentials against non-communicable diseases like cancer and diabetes. In this study, a new phlorotannin was extracted from Padina tetrastromatica and characterized by Fourier Transform-Infrared, Nuclear Magnetic Resonance & Electronspray Ionization-Mass Spectroscopy. The phlorotannin exhibited potent DPPH and nitric oxide radical-scavenging activity in in-vitro, which were better than the standard antioxidants and other phlorotannins, previously reported. Further, the novel phlorotannin explicitly inhibited advanced glycation end-products formation in both in-vitro and in-vivo studies using hyperglycaemic C. elegans as an animal model and confirmed by live-cell fluorescence imaging. In addition, a significant modulation in expression of stress-responsive genes daf-2 and daf-16 were observed in phlorotannin treated hyperglycemic C. elegans. Moreover, the cytotoxic potential of phlorotannin (2,4,6-trioxa-1,3,5(1,3) tribenzenacyclohexaphane-15,35,55-triol) was explored for the first time in human cervical cancer cells (HeLa) and interesting observation was made that the cancer cell death was induced by activation of autophagy and pro-apoptotic protein markers i.e., LC3I/II, p21 and p53 that were confirmed by western-blot technique. Therefore, phlorotannin can be postulated as a potential bioactive for oxidative stress-mediated diseases, including diabetes and cancer.

Chemical constituents of Antidesma bunius aerial parts and the anti-AGEs activity of selected compounds

Thirty-three natural products were isolated from the aerial parts of Antidesma bunius, Euphorbiaceae, a plant used in Vietnamese traditional medicine against rheumatoid arthritis. All compounds were reported the first time for this species, and nine constituents resembled undescribed natural products, noticeably three coumarinolignans with 2,2-dimethyl-1,3-dioxolane moiety, two cyclopeptides, and two furofuran-type lignans connected with a phenylpropanoid moiety. The individual structures were elucidated by combining NMR and MS data, and their configuration was established by NOESY and ECD experiments and NMR calculations. Compounds with sufficient amount were analyzed for their inhibition of advanced glycation endproducts (AGEs) formation, metabolites involved in many diseases like Alzheimer, joint diseases or diabetes. With IC50 values below 0.2 mM rutin and p-hydroxyphenethyl trans-ferulate showed to be moderately active, both still being 10-times more active than the positive control aminoguanidine.