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This research investigates the potential of bioactive compounds derived from cyanobacteria as inhibitors of alphaamylase and beta-glucosidase enzymes, which are involved in starch digestion and glucose release. The study reveals strong molecular interactions between these compounds and the enzyme active sites through docking analysis. Notably, compounds such as Abietic, Anilide, Nostocarboline, Noscomin, Tanikolide, Tubercidin, Cryptophycin, and Cyanobacteria exhibit the lowest binding energies when interacting with alpha-amylase. Among them, Noscomin demonstrates the lowest docking score and binding energy against alpha-amylase, outperforming the reference compound metformin. Similarly, these compounds also display low binding energies when interacting with beta-glucosidase. The bioactive compounds from cyanobacteria show significant potential as inhibitors of alpha-amylase and beta-glucosidase, suggesting their efficacy in managing diabetes by slowing down starch digestion and controlling glucose release. Their superior binding affinities and lower binding energies, particularly Noscomin, indicate their potential in regulating blood sugar levels by interacting effectively with these enzymes. Thus, these compounds hold promise as valuable leads for developing alpha-amylase and beta-glucosidase inhibitors, contributing to the management of diabetes. Further research is required to understand the underlying mechanisms of action and assess the bioavailability, toxicity, and pharmacological potential of these cyanobacterial compounds. This investigation provides valuable insights into the potential of cyanobacterial bioactive compounds as effective candidates for the development of novel therapeutics targeting alphaamylase and beta-glucosidase enzymes in diabetes management. [ABSTRACT FROM AUTHOR]

The current in-vivo study was premeditated to uncover the protective role of ezetimibe (EZ) against advanced glycation endproducts (AGEs)-related pathologies in experimental diabetes. Our results showed that EZ markedly improved the altered biochemical markers of diabetes mellitus (DM) (FBG, HbA1c, insulin, microalbumin, and creatinine) and cardiovascular disease (in-vivo lipid/lipoprotein level and hepatic HMG-CoA reductase activity) along with diminished plasma carboxymethyl-lysine (CML) and renal fluorescent AGEs level. Gene expression study revealed that EZ significantly down-regulated the renal AGEs-receptor (RAGE), nuclear factor-κB (NFκB-2), transforming growth factor-β (TGF-β1), and matrix metalloproteinase-2 (MMP-2) mRNA expression, however, the neuropilin-1 (NRP-1) mRNA expression was up-regulated. In addition, EZ also maintained the redox status via decreasing the lipid peroxidation and protein-bound carbonyl content (CC) and increasing the activity of high-density lipoprotein (HDL)-associated-paraoxonase-1 (PON-1) and renal antioxidant enzymes as well as also protected renal histopathological features. We conclude that EZ exhibits antidiabetic and reno-protective properties in diabetic rats. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MG) is a precursor for advanced glycation end-products (AGEs), which have a significant role in diabetes. The present study is designed to probe the immunological response of native and glycated low-density lipoprotein (LDL) in experimental animals. The second part of this study is to probe glycoxidative lesion detection in low-density lipoproteins (LDL) in diabetes subjects with varying disease duration. The neo-epitopes attributed to glycation-induced glycoxidative lesion of LDL in DM patients' plasma were, analyzed by binding of native and MG-modified LDL immunized animal sera antibodies using an immunochemical assay. The plasma purified human LDL glycation with MG, which instigated modification in LDL. Further, the NewZealand-White rabbits were infused with unmodified natural LDL (N-LDL) and MG-glycatedLDL to probe its immunogenicity. The glycoxidative lesion detection in LDL of DM with disease duration (D.D.) of 5–15 years and D.D. > 15 years was found to be significantly higher as compared to normal healthy subjects (NHS) LDL. The findings support the notion that prolonged duration of diabetes can cause structural alteration in LDL protein molecules, rendering them highly immunogenic in nature. The presence of LDL lesions specific to MG-associated glycoxidation would further help in assessing the progression of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Hyperglycemia is a poorly controlled diabetic condition, affects about 70% of people all round the world. In the year 2015, about 41.5 crore people were diabetic and is expected to reach around 64.3 crore by the year 2040. Cardiovascular diseases (CVDs) are considered as one of the major risk factors that cause more than half of the death of diabetic patients and promote related comorbidities. Atherosclerosis and amyloidosis are the prime factors linked with CVDs. Apolipoprotein A-I (ApoA-I) of HDL has protective action against CVDs, participates in reverse cholesterol transport mechanism and lipid metabolism, but gets easily glycated under prolonged hyperglycemic aura, i.e. glycation. ApoA-I has a potent role in maintenance of glucose level, providing a compelling link between diabetes and CVDs. Increased protein glycation in people with diabetes promotes atherosclerosis, which might play possible role in promotion of protein aggregation by altering the protein structure and its conformation. Here, we intend to investigate the mechanistic behavior of ApoA-I under the menace of glycation and its impact on ApoA-I structure and function that possibly link with aggregation or amyloidosis. [ABSTRACT FROM AUTHOR]

This study aims to describe the therapeutic potential of C. nocturnum leaf extracts against diabetes and neurological disorders via the targeting of α-amylase and acetylcholinesterase (AChE) activities, followed by computational molecular docking studies to establish a strong rationale behind the α-amylase and AChE inhibitory potential of C. nocturnum leaves-derived secondary metabolites. In our study, the antioxidant activity of the sequentially extracted C. nocturnum leaves extract was also investigated, in which the methanolic fraction exhibited the strongest antioxidant potential against DPPH (IC50 39.12 ± 0.53 µg/mL) and ABTS (IC50 20.94 ± 0.82 µg/mL) radicals. This extract strongly inhibited the α-amylase (IC50188.77 ± 1.67 µg/mL) and AChE (IC50 239.44 ± 0.93 µg/mL) in a non-competitive and competitive manner, respectively. Furthermore, in silico analysis of compounds identified in the methanolic extract of the leaves of C. nocturnum using GC-MS revealed high-affinity binding of these compounds with the catalytic sites of α-amylase and AChE, with binding energy ranging from −3.10 to −6.23 kcal/mol and from −3.32 to −8.76 kcal/mol, respectively. Conclusively, the antioxidant, antidiabetic, and anti-Alzheimer activity of this extract might be driven by the synergistic effect of these bioactive phytoconstituents. [ABSTRACT FROM AUTHOR]

Cytokines are proteins that play a critical role in immune cells' development, maturation, and functional activities. For the first time, we have investigated the potential role of Terminalia arjuna as IL-4 and IL-13 modulators for preventing T1DM, i.e., autoimmune diabetes. It has been well documented that the stimulation of IL-4 and IL-13 can regulate the level of type 2 cytokines which can be maintained with the level of type 1 cytokines. The present study investigated gallic acid, arjunolic acid, luteolin, ellagic acid, and arjunone for their potential modulating activity of IL-4 and IL-13. The active amino acid residues identified for IL-4 are VAL51, HIS58, ASP87, THR30, GLN54, THR63, ARG64, LYS84, and GLU60. The active amino acid residues identified for IL-13 are H: GLU46, H: TRP47, H: GLN61, L: PHE98, L: VAL97, L: GLU162, L: THR163, H: ARG105, L: GLN38, L: ASP85, H: GLY42, L: GLY41, H: PRO41, H: TRP47, and L: PHE98. The phytoconstituents demonstrated better modulating activity towards IL-13 than IL-4. Luteolin displayed better potential for both IL-4 and IL-13, and therefore we concluded that it could be used to modulate the activity of IL-4 and IL-13 for the prevention of autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Glycation refers to carbonyl group condensation of the reducing sugar with the free amino group of protein, which forms Amadori products and advanced glycation end products (AGEs). These AGEs alter protein structure and function by configuring a negative charge on the positively charged arginine and lysine residues. Glycation plays a vital role in the pathogenesis of metabolic diseases, brain disorders, aging, and gut microbiome dysregulation with the aid of 3 mechanisms: (i) formation of highly reactive metabolic pathway-derived intermediates, which directly affect protein function in cells, (ii) the interaction of AGEs with its associated receptors to create oxidative stress causing the activation of transcription factor NF-κB, and (iii) production of extracellular AGEs hinders interactions between cellular and matrix molecules affecting vascular and neural genesis. Therapeutic strategies are thus required to inhibit glycation at different steps, such as blocking amino and carbonyl groups, Amadori products, AGEs-RAGE interactions, chelating transition metals, scavenging free radicals, and breaking crosslinks formed by AGEs. The present review focused on explicitly elaborating the impact of glycation-influenced molecular mechanisms in developing and treating noncommunicable diseases. [ABSTRACT FROM AUTHOR]

Hundreds of millions of people around the globe are afflicted by diabetes mellitus. The alteration in glucose fixation process might result into hyperglycaemia and could affect the circulating plasma proteins to undergo nonenzymatic glycation reaction. If it is unchecked, it may lead to diabetes with increase in advanced glycation end products (AGEs). Therefore, the present study was designed to inhibit the diabetes and glycation by using natural antioxidant "ellagic acid" (EA). In this study, we explored the antidiabetes and antiglycation potential of EA in both in vitro (EA at micromolar concentration) and in vivo systems. The EA concentrations of 10 and 20 mg kg-1B.W./day were administered orally for 25 days to alloxan-induced diabetic rats, a week after confirmation of stable diabetes in animals. Intriguingly, EA supplementation in diabetic rats reversed the increase in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) level. EA also showed an inhibitory role against glycation intermediates including dicarbonyls, as well as AGEs, investigated in a glycation mixture with in vitro and in vivo animal plasma samples. Additionally, EA treatment resulted in inhibition of lipid peroxidation-mediated malondialdehyde (MDA) and conjugated dienes (CD). Furthermore, EA exhibited an antioxidant property, increased the level of plasma glutathione (GSH), and also helped to decrease histological changes evaluated by histoimmunostaining of animal kidney tissues. The results from our investigation clearly indicates the antiglycative property of EA, suggesting EA as an adequate inhibitor of glycation and diabetes, which can be investigated further in preclinical settings for the treatment and management of diabetes-associated complications. [ABSTRACT FROM AUTHOR]

Proteins undergo glycation resulting in the generation of advanced glycation end products (AGEs) that play a central role in the onset and advancement of diabetes-associated secondary complications. Aminoguanidine (AG) acts as an antiglycating agent by inhibiting AGE generation by blocking reactive carbonyl species (RCS) like, methylglyoxal (MGO). Previous studies on antiglycating behavior of AG gave promising results in the treatment of diabetes-associated microvascular complications, but it was discontinued as it was found to be toxic at high concentrations (>10 mmol/L). The current article aims at glycation inhibition by conjugating gold nanoparticles (Gnp) with less concentration of AG (0.5-1.0 mmol/L). The HPLC results showed that AG-Gnp fairly hampers the formation of glycation adducts. Moreover, the in vivo studies revealed AG-Gnp mediated inhibition in the production of total-AGEs and - N ε -(carboxymethyl)lysine (CML) in the diabetic rat model. This inhibition was found to be directly correlated with the antioxidant parameters, blood glucose, insulin, and glycosylated hemoglobin levels. Furthermore, the histopathology of AG-Gnp-treated rats showed good recovery in the damaged pancreatic tissue as compared to diabetic rats. We propose that this approach might increase the efficacy of AG at relatively low concentrations to avoid toxicity and might facilitate to overcome the hazardous actions of antiglycating drugs. [ABSTRACT FROM AUTHOR]

Plant-derived secondary metabolites possess diverse biological activities that are beneficial to humans. Modern medications used for diabetes and Alzheimer's often cause side effects, prompting reliance on traditional alternatives. Therefore, we aimed to uncover the potential of Mazus pumilus in countering diabetes and Alzheimer's by in-vitro inhibition of α-amylase and AChE. Additionally, antioxidant activity and phytochemical analyses were performed. Mazus pumilus The plant was extracted sequentially using n-hexane, ethyl acetate, dichloromethane, methanol, and water. The methanolic fraction, notably, manifested marked antioxidant efficacy against DPPH and ABTS radicals. Subsequently, this extract evinces noteworthy inhibitory attributes against α-amylase and AChE, respectively, in a competitive manner. Moreover, the bioactive phytoconstituents present in the methanolicextracts were determined through GC–MS analysis, and subsequent computational molecular docking studies revealed that these compounds strongly bound to the active site of both α-amylase and AChE. The calculated least binding energies, for α-amylase and AChE, underscore the viability of the molecular interactions. In conclusion, the antioxidant, antidiabetic, and anti-Alzheimer attributes of Mazus pumilus extract likely emanate from the synergistic interplay of its bioactive phytoconstituents. A comprehensive in-vitro and in-vivo study is essential to fully explore the anti-diabetic and anti-Alzheimer potential of secondary metabolites of Mazus pumilus. [ABSTRACT FROM AUTHOR]

Nymphaea is a genus of aquatic perennial plants having many medicinal properties; one of the species Nymphaea rubra (N. rubra) usually recognized as “Kumuda” and belongs to the family Nymphaeaceae. Here, the anti-inflammatory, hypoglycemic and antibacterial effect of ethyl acetate fraction of Nymphea rubra flowers was investigated. Ethyl acetate fractions of Nymphea rubra flower lowers fasting blood glucose profile and inhibit interleukin-6 (IL-6) and tumour necrosis factor-α (TNFα) secretion in serum of high fat diet low dose STZ induced diabetic model. Antimicrobial activity of different solvent extracts of N. rubra flower were tested against Gram positive and Gram negative bacterial strains by observing the zone of inhibition. The bacteria used in the study were S. aureus (Gram-positive) and E. coli (Gram-negative). Ethyl acetate and aqueous extracts showed the highest activity against the tested bacteria. These results were compared with the zones of inhibition produced by commercially available standard antibiotics. The inhibitory effects of extracts are higher or very close and comparable with the standard antibiotics used. [ABSTRACT FROM AUTHOR]

Glycation of biological macromolecules, due to hyperglycemia, promotes the formation of advanced glycation end products (AGEs). It is accelerated in diabetic patients and is responsible for the pathophysiology and progression of diabetes. Previous reports have shown that amount of AGEs formation and glycation-induced structural damage is higher in hemoglobin (Hb) than other proteins present in blood. In our previous study, we have shown structural changes in Hb by D-ribose which may result into the generation of immunogenic neo-epitopes. Thus, we hypothesized that D-ribose induced structural perturbations in Hb, could result in the formation of neo-epitopes which may provoke an auto-immune response and may also be involved in the immuno-pathogenesis of diabetes type-2 associated complications. Therefore, in the current study, we analyzed the prevalence of autoantibodies in diabetic patient's sera against D-ribose glycated-Hb by direct binding and competitive ELISA. Direct binding ELISA confirmed that autoantibodies in diabetic patients exhibit significantly high binding with D-ribose glycated-Hb as compared to its native form. The antigen binding specificity of these antibodies was also screened by competitive inhibition ELISA. We also used D-glucose glycated-Hb as a positive control to detect the presence of auto-antibodies by direct binding and inhibiton ELISA. We found that D-glucose glycated-Hb binds with T2DM samples but the affinity to binding is lower than D-ribose glycated-Hb. The overall findings of this study suggest the prevalence of circulating autoantibodies against D-ribose glycated-Hb in diabetic patients and thus, the level of these autoantibodies may be used as biomarker for progression of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The glycation reaction is the addition of free carbonyl group of reducing sugar to the free amino groups of proteins, lipoproteins and nucleic acids which results in the formation of an Amadori product which may ultimately lead to the generation of advanced glycation products (AGEs). The impact of AGEs on proteins consequently generates free radicals, “a key player” for the pathogenesis of diabetes mellitus. Gel electrophoresis was carried out to see the visual changes taking place as a result of the glycation reaction. In this study, the anti‐glycation and anti‐diabetic effect of wedelolactone (WED) was seen both in vitro and in vivo. WED reverted various biochemical markers in streptozotocin‐induced diabetic rats along‐with the improvements in the oxidative stress markers. It also decreased the levels of the glycated serum protein and fasting blood glucose. Broadly, WED not only inhibited glycation in vitro but also proved to be an effective in vivo anti‐glycating agent. © 2018 IUBMB Life, 70(6):547–552, 2018 [ABSTRACT FROM AUTHOR]

The repertoire of known auto-antigens is limited to a very small proportion of all human proteins, and the reason why only some proteins become auto-antigens is unclear. The 65 kDa isoform of the enzyme glutamic acid decarboxylase (GAD-65) is a major auto-antigen in type I diabetes, and in various neurological diseases. Most patients with type I diabetes (70-80%) have auto-antibodies against GAD-65, which often appear years before clinical onset of the autoimmune diabetes. Thus, the aim of the study is to focus on the immunogenicity of GAD65 and its reactive oxygen species (ROS) conformer in STZ-induced diabetic rats and on human diabetic patients. In the present study, GAD-65 was modified by hydroxyl radical following Fenton's reaction. The modifications in the structure of the GAD-65 are supported by UV-vis and fluorescence spectral studies. Immunogenicity of both native and hydroxyl radical modified GAD-65 (ROS-GAD-65) was studied in experimental rabbits and was confirmed by inducing type I diabetes in experimental male albino rats using streptozotocin (45 mg/kg). We found that ROS-GAD-65 was a better immunogen as compared to the native GAD-65. A considerable high binding to ROS-GAD-65 was observed as compared to native GAD-65 in both the serum antibodies from diabetes animal models and as well as in the serum samples of type I diabetes. Hydrogen peroxide under the exposure of UV light produces hydroxyl radical (·OH) which is most potent oxidant, and could cause protein damage (GAD-65) to the extent of generating neo-epitopes on the molecule, thus making it immunogenic. © 2015 IUBMB Life, 67(10):746-756, 2015 [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) are known to be mutagenic, diabetogenic and vascular disease risk factors. Methylglyoxal (MG) is a dicarbonyl species that reacts with biological macromolecule (proteins, DNA and lipids) to give AGEs. Nonenzymatic glycation of MG with lysine (Lys) in the presence of copper (Cu2+) is reported to generate reactive oxygen species (ROS) capable of causing DNA damage. We show that DNA modification in MG–Lys–Cu2+ system results in the generation of strand breaks, base modification, hyperchromicity and increased fluorescence intensity. Superoxide generation in the MG–Lys system was found to be significantly higher when compared with that in the MG and Lys alone. Moreover, d-penicillamine and pyridoxal phosphate significantly inhibited the formation of glycation products. The presence of a major DNA glycation adduct, N2-carboxyethyl-2′-deoxyguanosine (CEdG), was detected by high performance liquid chromatography (HPLC) and confirmed by nuclear magnetic resonance (NMR). As reported earlier, modified DNA (MG–Lys-Cu2+-DNA) was highly immunogenic in experimental animals. Furthermore, induced anti-MG–Lys–Cu2+–DNA antibodies were effective probe for detecting glycoxidative lesions in human genomic DNA of type I diabetes patients. Our results clearly imply that interaction of MG–Lys and Cu2+ leads to the formation of AGEs and also the production of potent ROS, capable of causing DNA damage, thereby playing an important role in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Glycation of proteins and DNA, results in the generation of free radicals causing structural modification of biomacromolecule. This leads to the generation of neo-antigenic epitopes having implication in diabetes mellitus. In this study, human placental DNA was glycated with fructose and its binding was probed with the serum antibodies from type 1 and 2 diabetes patients. Methods: Glycation was carried out by incubating DNA (10μg/ml) with fructose (25mM) for 5 days at 37°C. The induced structural changes in DNA were studied by spectroscopic techniques, thermal denaturation studies and agarose gel electrophoresis. Furthermore, binding characteristics of autoantibodies in diabetes (type 1 and 2) patients were assessed by direct binding and competitive ELISA. Results: DNA glycation with fructose resulted in single strand breaks, hyperchromicity in UV spectrum and increased fluorescence intensity. Thermal denaturation studies demonstrated the unstacking of bases and early onset of duplex unwinding. Type 1 diabetes patients exhibited enhanced binding with glycated DNA as compared to native form, while for type 2 diabetes only those with secondary complications (Nephropathy) showed higher binding. Conclusions: Glycation of DNA has resulted in structural perturbation causing generation of neo-antigenic epitopes that are better antigens for antibodies in diabetes patients. [Copyright &y& Elsevier]

Nymphaea rubra (N. rubra) flowers are prevalent in subtropical regions for both dietary and traditional medicinal purposes, attributing to their beneficial properties in supporting overall health. This study first time provides descriptions of the antidiabetic and dyslipidemic properties employing STZ induced high fat diet fed diabetic rats and inhibition of α-amylase enzyme activity first by in vitro analyses, followed by a confirmatory in silico study to create a stronger biochemical rationale. Furthermore, in 3 T3-L1 cells, this extract promoted the suppression of adipogenesis. GC–MS investigation of the ethyl acetate fraction of ethanolic extract of N. rubra flowers revealed the presence of marker compounds of N. rubra , Nuciferine, and Apomorphine, which were the focus of molecular docking studies. The acquired concentrations of Nuciferine (22.39%) and 10, 11-dimethoxy-Apomorphine (1.47%) were detected. Together with other alkaloids identified by GC–MS analysis from this extract, mechanistically suggested that it might be caused by the synergistic impact of these bioactive chemicals. Molecular docking has been done to check the binding affinities of various isolated phytochemicals with HPAA, the dose-response effect of 100 mg/kg and 250 mg/kg of flower extract after 30 days showed a significant effect on body weight, food, water intake, serum insulin, FBG, OGTT, lipid profile, glycated haemoglobin, liver and kidney function test. Kidney histopathology results show a significant effect. These findings offer a strong foundation for the potential application of the ethyl acetate fraction of ethanolic extract from Nymphaea rubra flowers and its bioactive constituent in an in vivo system for the treatment and control of diabetes and its associated condition dyslipidemia. [Display omitted] [ABSTRACT FROM AUTHOR]

Diabetes is a metabolic illness that increases protein glycosylation in hyperglycemic conditions, which can have an impact on almost every organ system in the body. The role of vitamin D in the etiology of diabetes under RAGE (receptor for advanced glycation end products) stress has recently received some attention on a global scale. Vitamin D's other skeletal benefits have generated a great deal of research. Vitamin D's function in the development of type 1 and type 2 diabetes is supported by the discovery of 1,25 (OH)2D3 and 1-Alpha-Hydroylase expression in immune cells, pancreatic beta cells, and several other organs besides the bone system. A lower HBA1c level, metabolic syndrome, and diabetes mellitus all seems to be associated with vitamin D insufficiency. Most of the cross-sectional and prospective observational studies that were used to gather human evidence revealed an inverse relationship between vitamin D level and the prevalence or incidence of elevated HBA1c in type 2 diabetes. Several trials have reported on the impact of vitamin D supplementation for glycemia or incidence of type 2 diabetes, with varying degrees of success. The current paper examines the available data for a relationship between vitamin D supplementation and HBA1c level in diabetes and discusses the biological plausibility of such a relationship. [Display omitted] • Diabetes is a metabolic disorder that affects vital organ in the body and causes an increase in protein glycosylation. • Vitamin D deficiency appears to be linked to diabetes mellitus, metabolic syndrome, and a decreased HBA1c level. • The significance of vitamin D in the genesis of diabetes under RAGE stress is of paramount importance. • Vitamin D's function in the shielding of diabetes is supported by the discovery of 1,25(OH)2D3 in pancreatic beta cells. • Vitamin D supplementation may lower the HBA1c level, insulin resistance, or incidence of type 2 diabetes. [ABSTRACT FROM AUTHOR]