Linking elevated HbA1c with atherogenic lipid profile among high risk cardiovascular patients at Qassim, Saudi Arabia.

The relationship between glycated hemoglobin (HbA1c) and an atherogenic lipid profile which is associated with a higher risk of cardiovascular disease is of interest. A retrospective cross-sectional study was conducted on 83 participants aged between 14 and 77 years. Their venous blood was drawn to determine the HbA1c and fasting lipid profile including total cholesterol triglycerides and high-density lipoprotein cholesterol (HDL-C) low-density lipoprotein cholesterol (LDL-C) non-HDL cholesterol and the LDL/HDL ratio were also calculated. The correlations between HbA1c levels and these lipid profile parameters were analyzed. The study showed a significant correlation between HbA1c and LDL-C non-HDL-C and the LDL/HDL ratio. Although there was no significant difference in total cholesterol levels among all groups the levels of total cholesterol and HbA1c were positively correlated. HDL-C exhibited direct correlations with HbA1c there was no correlation between HbA1c and clinical characteristics except for age. Data shows that HbA1c can be used as a predictor of dyslipidemia in diabetic patients there is a significant correlation between HbA1c and an atherogenic lipid profile which highlights the importance of glycemic control in reducing the risk of cardiovascular disease.

Vitamin D supplementation modulates glycated hemoglobin (HBA1c) in diabetes mellitus.

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.

Generation of autoantibodies against glycated fibrinogen: Role in diabetic nephropathy and retinopathy.

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.

Identification of Glycoxidative Lesion in Isolated Low-Density Lipoproteins from Diabetes Mellitus Subjects.

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.

Identifying potential inhibitors of C-X-C motif chemokine ligand10 against vitiligo: structure-based virtual screening, molecular dynamics simulation, and principal component analysis.

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW ≤ 500 Da), hydrogen bond donor (HBD ≤ 5), hydrogen bond acceptor (HBA ≤ 10), and lipophilicity (logP ≤ 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer's Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry's pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein.Communicated by Ramaswamy H. Sarma.

CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway.The present study identifies the small molecule as a potential inhibitor of CXCL10 using SBVS, MD simulation, and PCA.Ten ligand hits have been identified as having better binding propensity than the known inhibitor Baicalein.MCULE2726078782-0-2 may be suggested as a therapeutic agent to inhibit CXCL10 because it has all the druggable properties necessary to specify an oral drug molecule.

Cytoplasmic amino acid profiles of clinical and ATCC 29213 strains of Staphylococcus aureus harvested at different growth phases.

Staphylococcus aureus strains are a great contributor to both hospital acquired infections as well as community acquired infections. The objective of the present investigation was to compare potential differences in cytoplasmic amino acid levels between clinical and ATCC 29213 strains of S. aureus. The two strains were grown under ideal conditions to mid-exponential and stationary growth phases, after which they were harvested to analyze their amino acid profiles. Initially, the amino acid patterns of both strains were compared at the mid-exponential phase when grown in controlled conditions. At the mid-exponential phase, both strains shared common features in cytoplasmic amino acid levels, with glutamic acid, aspartic acid, proline, and alanine identified as key amino acids. However, the concentration profiles of seven amino acids exhibited major variances between the strains, even though the total cytoplasmic levels of amino acids did not alter significantly. At the stationary phase, the magnitudes of the amino acids abundant in the mid-exponential phase were altered. Aspartic acid became the most abundant amino acid in both strains accounting for 44% and 59% of the total amino acids in the clinical and ATCC 29213 strains, respectively. Lysine was the second most abundant amino acid in both strains, accounting for 16% of the total cytoplasmic amino acids, followed by glutamic acid, the concentration of which was significantly higher in the clinical strain than in the ATCC 29213 strain. Interestingly, histidine was clearly present in the clinical strain but was virtually lacking in the ATCC 29213 strain. This study reveals the dynamic diversity of amino acid levels among strains, which is an essential step toward illustrating the variability in S. aureus cytoplasmic amino acid profiles and could be significant in explaining variances among strains of S. aureus.

Directional preference for glioblastoma cancer cell membrane encapsulated nanoparticle population: A probabilistic approach for cancer therapeutics.

Background: Selective cancer cell recognition is the most challenging objective in the targeted delivery of anti-cancer agents. Extruded specific cancer cell membrane coated nanoparticles, exploiting the potential of homotypic binding along with certain protein-receptor interactions, have recently proven to be the method of choice for targeted delivery of anti-cancer drugs. Prediction of the selective targeting efficiency of the cancer cell membrane encapsulated nanoparticles (CCMEN) is the most critical aspect in selecting this strategy as a method of delivery. Materials and methods: A probabilistic model based on binding scores and differential expression levels of Glioblastoma cancer cells (GCC) membrane proteins (factors and receptors) was implemented on python 3.9.1. Conditional binding efficiency (CBE) was derived for each combination of protein involved in the interactions. Selective propensities and Odds ratios in favour of cancer cells interactions were determined for all the possible combination of surface proteins for 'k' degree of interaction. The model was experimentally validated by two types of Test cultures. Results: Several Glioblastoma cell surface antigens were identified from literature and databases. Those were screened based on the relevance, availability of expression levels and crystal structure in public databases. High priority eleven surface antigens were selected for probabilistic modelling. A new term, Break-even point (BEP) was defined as a characteristic of the typical cancer cell membrane encapsulated delivery agents. The model predictions lie within ±7% of the experimentally observed values for both experimental test culture types. Conclusion: The implemented probabilistic model efficiently predicted the directional preference of the exposed nanoparticle coated with cancer cell membrane (in this case GCC membrane). This model, however, is developed and validated for glioblastoma, can be easily tailored for any type of cancer involving CCMEN as delivery agents for potential cancer immunotherapy. This probabilistic model would help in the development of future cancer immunotherapeutic with greater specificity.

Antiglycation and chemopreventive effects of leaf extracts of Ficus palmata Forssk. found in the Hail region of Saudi Arabia.

The antioxidant and antiglycation activities of the Ficus leaf extracts were evaluated using in vitro assays. The antioxidant activity was determined using the α, α-diphenyl-ß-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assays. In vitro ferric reducing activity was evaluated using the ferric reducing antioxidant power assay. The antiglycation potential of the extract was evaluated using dinitrophenylhydrazine, thiobarbituric acid and protein thiol assays. The inhibition of the formation of advanced glycation end products (AGEs) was detected using AGE-specific fluorescence with a fluorescence spectrophotometer. This study was aimed at investigating the potential of Ficus palmata Forssk. leaf extracts, which have abundant bioactive constituents, including polyphenols and flavonoids, in inhibiting glycation and cancer. The results show that the aqueous and methanolic Ficus leaf extracts are rich in phenolic and flavonoid compounds. Both extracts showed potent antioxidant activities. Furthermore, the methanolic extract showed antiglycation activities, as assessed using an in vitro model of bovine serum albumin glycation with D-ribose. The polyphenol- and flavonoid-rich Ficus leaf extracts exhibit antiglycation, chemopreventive and antioxidant activities and have potential for use in the treatment of diseases, such as cancer, which involve oxidative and glycative impairment of cellular proteins.

Differential impact of glycation on apolipoprotein A-I of high-density lipoprotein: a review.

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.

Therapeutic Efficacy of Natural Product 'C-Phycocyanin' in Alleviating Streptozotocin-Induced Diabetes via the Inhibition of Glycation Reaction in Rats.

Diabetes is a long-term metabolic disorder characterized by persistently elevated blood sugar levels. Chronic hyperglycemia enhances glucose-protein interactions, leading to the formation of advanced glycation end products (AGEs), which form irreversible cross-links with a wide variety of macromolecules, and accumulate rapidly in the body tissues. Thus, the objective of this study was to assess the therapeutic properties of C-phycocyanin (C-PC) obtained from Plectonema species against oxidative stress, glycation, and type 2 diabetes mellitus (T2DM) in a streptozotocin (STZ)-induced diabetic Wistar rat. Forty-five days of C-PC administration decreased levels of triglycerides (TGs), blood glucose, glycosylated hemoglobin, (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), liver and kidney function indices, and raised body weight in diabetic rats. C-PC suppressed biochemical glycation markers, as well as serum carboxymethyllysine (CML) and fluorescent AGEs. Additionally, C-PC maintained the redox state by lowering lipid peroxidation and protein-bound carbonyl content (CC), enhancing the activity of high-density lipoprotein cholesterol (HDL-C) and renal antioxidant enzymes, and preserving retinal and renal histopathological characteristics. Thus, we infer that C-PC possesses antidiabetic and antiglycation effects in diabetic rats. C-PC may also act as an antidiabetic and antiglycation agent in vivo that may reduce the risk of secondary diabetic complications.

d-ribose-mediated glycation of fibrinogen: Role in the induction of adaptive immune response.

A nonenzymatic reaction between reducing sugars and amino groups of proteins results in the formation of advanced glycation end products, which are linked to a number of chronic progressive diseases with macro- and microvascular complications. In this research, we sought to ascertain the immunological response to d-ibose-glycated fibrinogen. New Zealand White female rabbits were immunized with native and d-ribose-glycated (Rb-gly-Fb) fibrinogen and used for studying the immunological response. Serum from these rabbits analyzed using direct binding and competitive inhibition ELISA was found to contain a high titer of antibodies against Rb-gly-Fb; Rb-gly-Fb was much more immunogenic than its native form. The IgG against Rb-gly-Fb (Rb-gly-Fb-IgG) was highly specific against the immunogenic protein. Moreover, histopathology and immunofluorescence studies revealed the deposition of the Rb-gly-Fb-IgG immune complex in the glomerular basement membrane of the kidneys of immunized rabbits. Furthermore, immunization with Rb-gly-Fb increased the expression of genes encoding proinflammatory cytokines, tumour necrosis factor α, interleukin-6, interleukin-1ß, and interferon-gamma, which is indicative of increased inflammation and the antigenic role of Rb-gly-Fb in provoking an immune response.

Glyoxal induced glycative insult suffered by immunoglobulin G and fibrinogen proteins: A comparative physicochemical characterization to reveal structural perturbations.

Glycation of proteins results in structural alteration, functional deprivation, and generation of advanced glycation end products (AGEs). Reactive oxygen species (ROS) that are generated during in vivo autoxidation of glucose induces glycoxidation of intermediate glycation-adducts, which in turn give rise to aldehyde and/or ketone groups containing dicarbonyls or reactive carbonyl species (RCS). RCS further reacts non-enzymatically and starts the glycation-oxidation vicious cycle, thus exacerbating oxidative, carbonyl, and glycative stress in the physiological system. Glyoxal (GO), a reactive dicarbonyl that generates during glycoxidation and lipid peroxidation, contributes to glycation. This in vitro physicochemical characterization study focuses on GO-induced glycoxidative damage suffered by immunoglobulin G (IgG) and fibrinogen proteins. The structural alterations were analyzed by UV-vis, fluorescence, circular dichroism, and Fourier transform infrared (FT-IR) spectroscopy. Ketoamines, protein carbonyls, hydroxymethylfurfural (HMF), free lysine, free arginine, carboxymethyllysine (CML), and protein aggregation were also quantified. Structural perturbations, increased concentration of ketoamines, protein carbonyls, HMF, and malondialdehyde (MDA) were reported in glycated proteins. The experiment results also validate increased oxidative stress and AGEs formation i.e. IgG-AGEs and Fib-AGEs. Thus, we can conclude that AGEs formation during GO-mediated glycation of IgG and fibrinogen could hamper normal physiology and might play a significant role in the pathogenesis of diabetes-associated secondary complications.

Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals.

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.

Optimization of methods for peripheral blood mononuclear cells isolation and expansion of human gamma delta T cells.

Human Vg9/Vδ2 T cells (γδ T cells) are immune surveillance cells both in innate and adaptive immunity and are a possible target for anticancer therapies, which can induce immune responses in a variety of cancers. Small non-peptide antigens such as zoledronate can do activation and expansion of T cells in vitro. It is evident that for adoptive cancer therapies, large numbers of functional cells are needed into cancer patients. Hence, optimization of methods needs to be carried out for the efficient expansion of these T cells. Standardization of peripheral blood mononuclear cells (PBMCs) isolation was devised. Cytokines (interleukin 2 (IL-2) and interleukin 15 (IL-15)) and zoledronate were also standardized for different concentrations. It was found that an increased number of PBMCs were recovered when washing was done at 1100 revolution per minute (rpm). Significantly high expansion fold was (2524 ± 787 expansion fold) achieved when stimulation of PBMCs was done with 1 µM of zoledronate and both cytokines IL-2 and IL-15 supported the expansion and survival of cells at the concentrations of 100 IU/ml and 10 ng/ml respectively. 14-day cultures showed highly pure (91.6 ± 5.1%) and live (96.5 ± 2.5%) expanded γδ T cells. This study aimed to standardize an easy to manipulate technique for the expansion of γδ T cells, giving a higher yield.

Gold Nanoparticle-Bioconjugated Aminoguanidine Inhibits Glycation Reaction: An In Vivo Study in a Diabetic Animal Model.

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.

Insights into Multifunctional Nanoparticle-Based Drug Delivery Systems for Glioblastoma Treatment.

Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood-brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.

Methylglyoxal mediated glycation leads to neo-epitopes generation in fibrinogen: Role in the induction of adaptive immune response.

In diabetes mellitus, hyperglycemia mediated non-enzymatic glycosylation of proteins results in the pathogenesis of diabetes-associated secondary complications via the generation of advanced glycation end products (AGEs). The focus of this study is to reveal the immunological aspects of methylglyoxal (MG) mediated glycation of fibrinogen protein. The induced immunogenicity of modified fibrinogen is analyzed by direct binding and inhibition ELISA. Direct binding ELISA confirmed that MG glycated fibrinogen (MG-Fib) is highly immunogenic and induces a high titer of antibodies in comparison to its native analog. Cross-reactivity and antigen-binding specificity of induced antibodies were confirmed by inhibition ELISA. The enhanced affinity of immunoglobulin G (IgG) from immunized rabbits' sera and MG glycated fibrinogen is probably the aftermath of neo-epitopes generation in the native structure of protein upon modification. Thus, we deduce that under the glycative stress, MG-mediated structural alterations in fibrinogen could induce the generation of antibodies which might serve as a potential biomarker in diabetes mellitus and its associated secondary disorders.

New Framework for the Discovery of PRC2 Inhibitors: Epigenetic Drugs.

Over the past several years, remarkable progress towards the recognition of new therapeutic targets in tumor cells has led to the discovery and development of newer scaffolds of anti-tumor drugs. The exploration and exploitation of epigenetic regulation in tumor cells are of immense importance to both the pharmaceutical and academic biomedical literatures. Epigenetic mechanisms are indispensable for the normal development and maintenance of tissue-specific gene expression. Disruption of epigenetic processes to eradicate tumor cells is among the most promising intervention for cancer control. Polycomb repressive complex 2 (PRC2), a complex that methylates lysine 27 of histone H3 to promote transcriptional silencing, is involved in orchestrating significant pathways in a cell. Overexpression of PRC2 has been found in a number of cancerous malignancies, making it a major target for anti-cancer therapy. Despite its well-understood molecular mechanism, hyperactivation and drug resistance mutations in its subunits have become a matter of discussion. This review outlines the current understanding of the components of PRC2 in active complex formation and assesses their potential as a promising therapeutic target for cancer therapy. We also review the effects of mutations in the PRC2 components, in the purview of human cancers. Finally, we discuss some of the current challenges for therapeutic drug designs targeting the PRC2 complex.

An in vitro approach to unveil the structural alterations in d-ribose induced glycated fibrinogen.

Plasma proteins persistently bear non-enzymatic post-translational modifications (NEPTM) that proceeds with nucleophilic addition between free amino groups of proteins, and carbonyl group of reducing sugars. Glycation, a prevalent NEPTM rush by the high availability of reducing sugars results in the generation of advanced glycation end products (AGEs). Plasma proteins are more vulnerable to glycation because of the presence of multiple glycation sites and are widely studied. However, fibrinogen glycation is less studied. Therefore, it was designed as an in vitro study to elucidate d-ribose mediated glycative damage suffered by fibrinogen protein at secondary and tertiary structure level. The glycation induced structural alterations were analyzed by UV-vis, fluorescence, circular dichroism, scanning electron microcopy and Fourier transform infrared spectroscopy. Glycation induced protein aggregation and fibrils formation was confirmed by thioflavin T and congo red assay. Moreover, molecular docking study was performed to further validate physicochemical characterization. Structural alterations, increased ketoamines, protein carbonyls and HMF contents were reported in d-ribose glycated fibrinogen against their native analogues. The results validate structural perturbations, increased glycoxidative stress and AGEs formation, which might influence normal function of fibrinogen especially blood coagulation cascade. Thus, we can conclude that under diabetes induced hyperglycemic state in physiological systems, d-ribose induced fibrinogen glycation might play a crucial role in the onset of micro- and macro-vascular complications, thereby worsen the diabetes associated secondary disorders. Moreover, this in vitro study might pave a path to choose fibrinogen as a future biomarker for the early detection of diabetes mediated vascular complications.Communicated by Ramaswamy H. Sarma.

Can Fasting Blood Sugar be Used as an Indicator of Long-Term Diabetic Control Instead of Estimated Average Glucose?

BACKGROUND: Diabetes mellitus is a chronic illness that is a worldwide issue. HbA1c has been used to monitor glycemic control in patients with diabetes for many years. Although HbA1c measurement is needed for calculating estimated average blood glucose (eAG), it is now recommended that eAG is used instead of HbA1c for expression of blood glucose control and communication with patients and health care providers. This study, investigated fasting blood glucose (FBS) as an indicator of overall chronic blood sugar control by assessing the correlation between FBS with eAG derived from HbA1c. METHODS: The blood samples for HbA1c assay were collected in EDTA tubes and were analyzed by an HPLC analyzer (G8 Tosoh, Japan). Blood samples for FBS were collected in serum separator tubes, transported, and centrifuged for 15 minutes at 3,000 g. FBS levels were determined in serum samples with the enzymatic hexokinase method by a clinical chemistry analyzer (Architect 8000, Abbott, USA). RESULTS: Statistical analysis was performed on 1,740 patients with type 2 diabetes mellitus with HbA1c levels above 6.5 mmol/L. The difference between FBS (9.3 ± 3.7 mmol/L) and eAG (11.14 ± 2.7 mmol/L) was statistically signif-icant (p < 0.0001). The correlation coefficient between FBS and eAG was r = 0.65 (95% CI; 0.62 - 0.69), with a p-value < 0.0001. While the correlation coefficient between FBS and eAG at HbA1c < 6.5% was r = 0.251 (95% CI, 0.16 - 0.34), with a significant p-value of < 0.00001. The combined data, standard deviation (SD), median, and interquartile range of eAG and FBS for all of the diabetic groups (n = 2,315), were 10.1 ± 3.00 mmol/L, 9.5 mmol/L, and 7.75 - 12.03 mmol/L for eAG, respectively. Similarly, these values were 8.5 ± 3.6 mmol/L, 7.5 mmol/L, and 6.0 - 10.00 mmol/L for FBS, respectively. CONCLUSIONS: We concluded that there is a moderate and significant positive correlation between fasting blood sugar and the estimated average blood glucose derived from HbA1c. Although FBS might be helpful for daily monitoring of diabetes. Further studies must be conducted to provide solid results to support that FBS and its derived variable eAG can replace HbA1c as an indicator of long-term overall control of T2DM patients.