RESUMEN
This computational study investigates 21 bioactive compounds from the Asteraceae family as potential inhibitors targeting the Spike protein (S protein) of SARS-CoV-2. Employing in silico methods and simulations, particularly CDOCKER and MM-GBSA, the study identifies two standout compounds, pterodontic acid and cichoric acid, demonstrating robust binding affinities (-46.1973 and -39.4265 kcal/mol) against the S protein. Comparative analysis with Favipiravir underscores their potential as promising inhibitors. Remarkably, these bioactives exhibit favorable ADMET properties, suggesting safety and efficacy. Molecular dynamics simulations validate their stability and interactions, signifying their potential as effective SARS-CoV-2 inhibitors.
Asunto(s)
Asteraceae , Simulación de Dinámica Molecular , SARS-CoV-2 , Antivirales/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Nanotechnology is considered a successful approach for cancer diagnosis and treatment. Preferentially, cancer cell recognition and drug targeting via nano-delivery system include the penetration of anticancer agents into the cell membrane to damage the cancer cell by protein modification, DNA oxidation, or mitochondrial dysfunction. The past research on nano-delivery systems and their target has proven the beneficial achievement in a malignant tumor. Modern perceptions using inventive nanomaterials for cancer management have been offered by a multifunctional platform based on various nano-carriers with the probability of imaging and cancer therapy simultaneously. Emerging nano-delivery systems in cancer therapy still lack knowledge of the biological functions behind the interaction between nanoparticles and cancer cells. Since the potential of engineered nanoparticles addresses the various challenges, limiting the success of cancer therapy subsequently, it is a must to review the molecular targeting of a nano-delivery system to enhance the therapeutic efficacy of cancer. This review focuses on using a nano-delivery system, an imaging system, and encapsulated nanoparticles for cancer therapy.
Asunto(s)
Antineoplásicos , Nanomedicina , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Nanomedicina/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Nanopartículas/química , Sistemas de Liberación de Medicamentos , Animales , Portadores de Fármacos/químicaRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2 , Deficiencia de Vitamina D , Humanos , Hemoglobina Glucada , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/epidemiología , Estudios Transversales , Vitamina D/uso terapéutico , Vitaminas , Suplementos Dietéticos , Estudios Observacionales como AsuntoRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Enfermedades de la Retina , Humanos , Nefropatías Diabéticas/complicaciones , Autoanticuerpos , Ribosa , Productos Finales de Glicación Avanzada/metabolismo , Fibrinógeno , Enfermedades de la Retina/complicacionesRESUMEN
BACKGROUND: Proprotein convertase subtilisin/kexin type-9 (PCSK-9) is a serine protease with profound effects on plasma LDL-C, the major risk factor for cardiovascular diseases (CVDs). However, plasma PCSK-9 level and its association with the biomarkers of CVDs, diabetes, and associated complications have not yet been reported in the northeastern population of India. METHODS: Of the total cohort (n = 233), we analyzed healthy controls (HC; n = 50), freshly diagnosed type-2-diabetes mellitus (T2DM-FD; n = 46), T2DM treated (T2DM-T; n = 49), diabetic nephropathy (T2DM-N; n = 43), and diabetic dyslipidemia (T2DM-DL; n = 45) subjects. Plasma PCSK-9 and other biological determinants associated with T2DM, CVD, and nephrotic dysfunction were assessed. RESULTS: The level of plasma PCSK-9 in HC, T2DM-FD, T2DM-T, T2DM-N, and T2DM-DL groups was found to be 184.1 ± 13.83, 183.1 ± 24.4.3, 241.8 ± 75.42, 403.7 ± 85.94, and 641.3 ± 135.5 ng/mL, respectively, indicating its role in the severity of the here-mentioned complications. Moreover, plasma PCSK-9 levels further showed a significant correlation with the biomarkers of hyperglycemia, particularly HbA1c, as well as LDL-C in T2DM-FD, T2DM-N, and T2DM-DL subjects of the Indian population, while moderate association in T2DM-T subjects. CONCLUSIONS: Our first-of-its-kind clinical study aiming to quantify the circulatory PCSK-9 level in the Indian population concluded that elevated PCSK-9 was significantly associated with the severity of diabetes and associated complications. Moreover, such elevation in PCSK-9 might be attributed to the lipid- and glucoselowering medication-induced SREBP-2-dependent mechanisms. Since our conclusion is based on a pilot study, further cohort studies in larger populations of India are required to get a generalization regarding the role of PCSK-9 in DM and associated complications.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Proyectos Piloto , LDL-Colesterol , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Factores de Riesgo , Biomarcadores , Enfermedades Cardiovasculares/diagnósticoRESUMEN
Cell cycle, growth, survival and metabolism are tightly regulated together and failure in cellular regulation leads to carcinogenesis. Several signaling pathways like the PI3K, WNT, MAPK and NFKb pathway exhibit aberrations in cancer and help achieve hallmark capabilities. Clinical research and in vitro studies have highlighted the role of epigenetic alterations in cancer onset and development. Altered gene expression patterns enabled by changes in DNA methylation, histone modifications and RNA processing have proven roles in cancer hallmark acquisition. The reversible nature of epigenetic processes offers robust therapeutic targets. Dietary bioactive compounds offer a vast compendium of effective therapeutic moieties. Isothiocyanates (ITCs) sourced from cruciferous vegetables demonstrate anti-proliferative, pro-apoptotic, anti-inflammatory, anti-migratory and anti-angiogenic effect against several cancers. ITCs also modulate the redox environment, modulate signaling pathways including PI3K, MAPK, WNT, and NFkB. They also modulate the epigenetic machinery by regulating the expression and activity of DNA methyltransferases, histone modifiers and miRNA. This further enhances their transcriptional modulation of key cellular regulators. In this review, we comprehensively assess the impact of ITCs such as sulforaphane, phenethyl isothiocyanate, benzyl isothiocyanate and allyl isothiocyanate on cancer and document their effect on various molecular targets. Overall, this will facilitate consolidation of the current understanding of the anti-cancer and epigenetic modulatory potential of these compounds and recognize the gaps in literature. Further, we discuss avenues of future research to develop these compounds as potential therapeutic entities.
Asunto(s)
Epigenoma , Neoplasias , Epigénesis Genética , Humanos , Isotiocianatos/farmacología , Isotiocianatos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosfatidilinositol 3-QuinasasRESUMEN
The non-enzymatic glycosylation or non-enzymatic covalent modifications (NECMs) or glycation of cellular proteins result in the generation and accumulation of advanced glycation end products (AGEs) that are associated with the epigenetics of cancer. Epigenetic modifications are inheritable changes without alterations in the sequences of DNA. Glycation-mediated epigenetic mechanisms change the accessibility of transcriptional factors to DNA via rearrangement or modification in the chromatin structure and collaborate with gene regulation in the pathogenesis of cancer. Epigenetic mechanisms play a critical role in sustaining the tissue-specific gene expression. Distraction from normal epigenetic mechanism results in alteration of gene function, initiation and progression of cancer, and cellular malignant transformation. Epigenetic modifications on DNA and histones control enzymatic expressions of corresponding metabolic pathways, which in turn influence epigenetic regulation. Glycation of histones due to persistent hyperglycemia results in histone-histone and histone-DNA cross-linking in chromatin by compromising the electrostatic interactions, that affect the dynamic architecture of chromatin. Histone proteins are highly prone to glycation due to their basic nature and long half-lives, but the exact role of histone glycation in the epigenetics of cancer is still in the veil. However, recent studies have suggested the role of histone glycation mediated epigenetic modifications that affect cellular functioning by altering the gene expressions of related metabolic pathways. Moreover, dicarbonyls-induced NECMs of histones perturb the architecture of chromatin and transcription of genes via multiple mechanisms. Contrary to the genetic causes of cancer, a possible reversal of glycation-mediated epigenetic modifications might open a new realm for therapeutic interventions. In this review, we have portrayed a mechanistic link between histone glycation and cancer epigenetics.
Asunto(s)
Epigénesis Genética , Neoplasias , Transformación Celular Neoplásica/genética , Cromatina/genética , Metilación de ADN , Glicosilación , Histonas/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
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.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Hiperglucemia , Humanos , Lipoproteínas HDL/metabolismo , Apolipoproteína A-I/química , Apolipoproteína A-I/metabolismo , Reacción de Maillard , Aterosclerosis/metabolismoRESUMEN
Nanotechnology is reshaping health care strategies and is expected to exert a tremendous impact in the coming years offering better healthcare facilities. It has led to not only therapeutic drug delivery feasibility but also to diagnostics. Materials in the size of nano range (1-100 nm) used in the design, fabrication, regulation, and application of therapeutic drugs or devices are classified as medical nanotechnology and nanopharmacology. Delivery of more complex molecules to the specific site of action as well as gene therapy has pushed forward the nanoparticle-based drug delivery to its maximum. Areas that benefit from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic-related ailments. Moreover, development of nanotherapeutics with multi-functionalities has a considerable potential to fill the gaps that exist in the present therapeutic domain. In cancer treatment, nanomedicines have superiority over current therapeutic practices as they can effectively deliver the drug to the affected tissues, thus reducing drug toxicities. Along this line, polymeric conjugates of asparaginase and polymeric micelles of paclitaxel have recently been recommended for the treatment of various types of cancers. Nanotechnology-based therapeutics and diagnostics provide greater effectiveness with less or no toxicity concerns. Similarly, diagnostic imaging holds promising future applications with newer nano-level imaging elements. Advancements in nanotechnology have emerged to a newer direction which use nanorobotics for various applications in healthcare. Accordingly, this review comprehensively highlights the potentialities of various nanocarriers and nanomedicines for multifaceted applications in diagnostics and drug delivery, especially the potentialities of polymeric nanoparticle, nanoemulsion, solid-lipid nanoparticle, nanostructured lipid carrier, self-micellizing anticancer lipids, dendrimer, nanocapsule and nanosponge-based therapeutic approaches in the field of cancer. Furthermore, this article summarizes the most recent literature pertaining to the use of nano-technology in the field of medicine, particularly in treating cancer patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanomedicina , Nanopartículas/administración & dosificación , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Animales , Humanos , Nanopartículas/químicaRESUMEN
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.
Asunto(s)
Productos Finales de Glicación Avanzada , Enfermedades no Transmisibles , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , Lisina/química , Arginina/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
C-phycocyanin (C-PC), the integral blue-green algae (BGA) constituent has been substantially delineated for its biological attributes. Numerous reports have illustrated differential extraction and purification techniques for C-PC, however, there exists paucity in a broadly accepted process of its isolation. In the present study, we reported a highly selective C-PC purification and characterization method from nontoxic, filamentous and non-heterocystous cyanobacterium Plectonema sp. C-PC was extracted by freeze-thawing, desalted and purified using ion-exchange chromatography. The purity of C-PC along with its concentration was found to be 4.12 and 245 µg/ml respectively. Comparative characterization of standard and purified C-PC was performed using diverse spectroscopic techniques namely Ultra Violet-visible, fluorescence spectroscopy and Fourier transform infrared (FT-IR). Sharp peaks at 620 nm and 350 nm with UV-visible and FT-IR spectroscopy respectively, confirmed amide I bands at around 1638 cm-1 (C=O stretching) whereas circular dichroism (CD) spectra exhibited α-helix content of secondary structure of standard 80.59% and 84.59% of column purified C-PC. SDS-PAGE exhibited two bands of α and ß subunits 17 and 19 kDa respectively. HPLC evaluation of purified C-PC also indicated a close resemblance of retention peak time (1.465 min, 1.234 min, 1.097 min and 0.905 min) with standard C-PC having retention peak timing of 1.448 min, 1.233 min and 0.925 min. As a cautious approach, the purified C-PC was further lyophilized to extend its shelf life as compared to its liquid isoform. To evaluate the bioactive potential of the purified C-PC in silico approach was attempted. The molecular docking technique was carried out of C-PC as a ligand-protein with free radicals and α-amylase, α-glucosidase, glycogen synthase kinase-3 and glycogen phosphorylase enzymes as receptors to predict the free radical scavenging (antioxidant) and to target antidiabetic property of C-PC. In both receptors free radicals and enzymes, ligand C-PC plays an important role in establishing interactions within the cavity of active sites. These results established the antioxidant potential of C-PC and also give a clue towards its antidiabetic potential warranting further research.
Asunto(s)
Cianobacterias , Plectonema , Antioxidantes/química , Antioxidantes/farmacología , Cianobacterias/química , Radicales Libres , Hipoglucemiantes , Ligandos , Simulación del Acoplamiento Molecular , Ficocianina/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The kinesin family member C1 (KIFC1) is an essential protein that facilitates the bipolar division of neoplastic cells. Inhibiting KIFC1 by small molecules is a lucrative strategy to impede bipolar mitosis leading to the apoptosis of cancerous cells. The research aims to envisage small-molecule inhibitors targeting KIFC1. The Mcule database, a comprehensive online digital platform containing more than five million chemical compounds, was used for structure-based virtual screening (SBVS). Druglikeness filtration sifted 2,293,282 chemical hits that further narrowed down to 49 molecules after toxicity profiling. Finally, 39 compounds that comply with the BOILED-Egg permeation predictive model of the ADME rules were carried forward for multiscoring docking using the AutoDock Vina inbuilt to Mcule drug discovery platform, DockThor and SwissDock tools. The mean of ΔG terms produced by docking tools was computed to find consensus top ligand hits. AZ82 exhibited stronger binding (Consensus ΔG: -7.99 kcal mol-1 ) with KIFC1 among reference inhibitors, for example, CW069 (-7.57 kcal mol-1 ) and SR31527 (-7.01 kcal mol-1 ). Ten ligand hits namely, Mcule-4895338547 (Consensus ΔG: -8.69 kcal mol-1 ), Mcule-7035674888 (-8.42 kcal mol-1 ), Mcule-5531166845 (-8.53 kcal mol-1 ), Mcule-3248415882 (-8.55 kcal mol-1 ), Mcule-291881733 (-8.41 kcal mol-1 ), Mcule-5918624394 (-8.44), Mcule-3470115427 (-8.47), Mcule-3686193135 (-8.18 kcal mol-1 ), Mcule-3955355291 (8.09 kcal mol-1 ) and Mcule-9534899193 (-8.01 kcal mol-1 ) depicted strong binding interactions with KIFC1 in comparison to potential reference inhibitor AZ82. The top four ligands and AZ82 were considered for molecular dynamics simulation of 50 ns duration. Toxicity profiling, physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, SASA, ΔGsolv and Rg analyses forecast the ligand mcule-4895338547 as a promising inhibitor of KIFC1.
Asunto(s)
Cinesinas , Simulación de Dinámica Molecular , Descubrimiento de Drogas , Ligandos , Simulación del Acoplamiento MolecularRESUMEN
Biosynthetic procedure is one of the best alternatives, inexpensive and ecologically sound for the synthesis of titanium dioxide (TiO2 ) nanoparticles using a methanolic extract of medicinal plant. The main prospect of this study was to investigate the antiglycation activity of the TiO2 nanoparticles (TNP) prepared by ethanolic leaf extract of the Coleus scutellarioides. In this study, biosynthesized TNP characterized with UV-Visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscope. These TNP were further investigated with respect to their antiglycation property and it was checked in the mixture of d-ribose glycated bovine serum albumin (BSA) by measuring ketoamine, carbonyl content, Advanced glycation end products (AGEs) and aggregation of protein instigated by glycation process. The inhibitory effect of TNP to restore the structure of BSA in presence of d-ribose were also characterize by biophysical techniques mentioned above. Therefore, the findings of this study suggest repurposing of TNP for its antiglycation property that could be helpful in prevention of glycation instigated AGEs formation and structural loss of proteins.
Asunto(s)
Nanopartículas , Albúmina Sérica Bovina , Productos Finales de Glicación Avanzada/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ribosa/química , Ribosa/metabolismo , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , TitanioRESUMEN
Rheumatoid arthritis (RA), a chronic inflammatory disease, and its exact aetiology is not defined clearly. The free radicals produced in large amount in RA are associated with alteration in molecular structure resulting in glycation of proteins. As a result of glycation, advanced glycation end products (AGEs) produced. In this study, collagen type II suspension was injected into Wistar rats to make RA model of rats. Simultaneously, hesperidin 50 mg kg-1 body weight was orally administrated to the rats for 21 days. X-rays of the rat hind paws were analyzed and found to be significantly effective against bone loss after treatment with hesperindin. Nε -(carboxymethyl)lysine (CML) and pentosidine (PTD) concentrations in collagen-induced RA plasma were determined as 565.29 ± 30.15 and 37.23 ± 1.02 ng ml-1 , respectively, while CML and PTD in IgG were 6.63 ± 0.44 ng mg-1 IgG and 425.33 ± 37.26 ng g-1 IgG, respectively. After treatment with hesperidin, the elevated levels of CML in plasma and in IgG were significantly (p < 0.001) lowered to 450.95 ± 15.05 mg ml-1 and 5.23 ± 0.27 ng mg-1 IgG, respectively. Similarly, concentrations of PTD in plasma and IgG of rats treated with hesperidin were 28.46 ± 1.20 ng ml-1 and 359.35 ± 31.11 ng g-1 IgG, respectively. Thus, after treatment with drug, plasma CML and IgG PTD levels were restored as 93% and 16%, respectively, through free radical scavenging activity of hesperidin resulting in alleviation of RA disease by decreasing the AGEs concentrations. Therefore, use of hesperidin may be useful to alleviate severity of RA disease.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Hesperidina , Animales , Antioxidantes/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Colágeno , Productos Finales de Glicación Avanzada/metabolismo , Hesperidina/farmacología , Hesperidina/uso terapéutico , Inmunoglobulina G , Ratas , Ratas WistarRESUMEN
The generation of advanced glycation end products (AGEs) through nonenzymatic protein glycation contributes to the pathogenesis of long-lived diabetic problems. Metformin (MTF) is the very first drug having antihyperglycemic effects on type II diabetes mellitus which also possess interaction with dicarbonyl compounds and blocks the formation of AGEs. In the current study, MTF is bioconjugated with glycation-derived synthesized gold nanoparticles (GNPs) of significant size. Additionally, using various biophysical and biochemical approaches, we investigated the antiglycating capacity MTF-GNPs in contrast to MTF against d-ribose-derived glycation of bovine serum albumin. Our key findings via utilizing various assays demonstrated that MTF-GNPs were able to inhibit AGEs development by reducing hyperchromicity, early glycation products, carbonyl content, hydxoxymethylfurfural content, production of fluorescent AGEs, normalizing the loss of secondary structure (i.e., α-helix and ß-sheets) of proteins, elevating the levels of free lysine and free arginine more efficiently compared to pure MTF. Based on these results, we concluded that MTF-GNPs possess a considerable antiglycation property and may be developed as an outstanding anti-AGEs treatment drug. Further in vivo and clinical research are necessary to determine the therapeutic effects of MTF-GNPs against AGE-related and metabolic disorders.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nanopartículas del Metal , Metformina , Arginina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Productos Finales de Glicación Avanzada/metabolismo , Oro , Humanos , Hipoglucemiantes/farmacología , Lisina/química , Metformina/farmacología , Ribosa/química , Ribosa/metabolismo , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismoRESUMEN
Glycation is vital in terms of its damaging effect on macromolecules resulting in the formation of end products, which are highly reactive and cross-linked irreversible structures, known as advanced glycation end products (AGEs). The continuous accumulation of AGEs is associated with severe diabetes and its associated ailments. Saccharides with their reducing ends can glycate amino acid side chains of proteins, among them glucose is well-known for its potent glycating capability. However, other reducing sugars can be more reactive glycating agents than glucose. The D-ribose is a pentose sugar-containing an active aldehyde group in its open form and is responsible for affecting the biological processes of the cellular system. D-ribose, a key component of many biological molecules, is more reactive than most reducing sugars. Protein glycation by reducing monosaccharides such as D-ribose promotes the accelerated formation of AGEs that could lead to cellular impairments and dysfunctions. Also, under a physiological cellular state, the bioavailability rate of D-ribose is much higher than that of glucose in diabetes, which makes this species much more active in protein glycation as compared with D-glucose. Due to the abnormal level of D-ribose in the biological system, the glycation of proteins with D-ribose needs to be analyzed and addressed carefully. In the present study, human immunoglobulin G (IgG) was isolated and purified via affinity column chromatography. D-ribose at 10 and 100 mM concentrations was used as glycating agent, for 1-12 days of incubation at 37°C. The postglycation changes in IgG molecule were characterized by UV-visible and fluorescence spectroscopy, nitroblue tetrazolium assay, and various other physicochemical analyses for the confirmation of D-ribose mediated IgG glycation.
Asunto(s)
Productos Finales de Glicación Avanzada , Ribosa , Glucosa/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , Humanos , Inmunoglobulina G/metabolismo , Ribosa/química , Ribosa/metabolismoRESUMEN
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.
Asunto(s)
Productos Biológicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglucemia , Ratas , Animales , Diabetes Mellitus Experimental/metabolismo , Estreptozocina , Ficocianina/farmacología , Ficocianina/uso terapéutico , Productos Biológicos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratas Wistar , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hiperglucemia/tratamiento farmacológico , HDL-ColesterolRESUMEN
The influence of advanced glycation end products (AGEs) in the biological processes contribute to the life-changing complications such as progression of cancer, diabetes and other chronic disorders. The receptor of AGEs while interacting with its ligands causes a never-ending irregularity in the cell-signaling communication. Hence, AGEs are considered as an important link between progression and contribution to cancer. This study focuses on the presence and/or absence of oxidative and glycative stress in the serum samples of various cancer patients. During analysis of the early and intermediate glycation product in cancer patient's sera, our result indicates an increasing trend of both the adducts as compared to normal healthy subjects. Similarly, one of the AGEs i.e., carboxymethyllysine was found to be enhanced in cancer sera as compared to NHS. The binding characteristics of circulating auto-antibodies in cancer patient's sera against human serum albumin (HSA)-AGEs were assessed through ELISA and furthermore, the maximum percent inhibition against HSA-AGEs was observed as 57-63%, 46-62% and 42-64% in prostate cancer, lung cancer and head and neck cancer. Hence, our result successfully assisted the presence of AGEs in all the cancer patient's sera though it is not clear which specific cancer is more potent to AGEs.
Asunto(s)
Productos Finales de Glicación Avanzada/metabolismo , Neoplasias/metabolismo , Albúmina Sérica Humana/metabolismo , Adolescente , Adulto , Anciano , Femenino , Productos Finales de Glicación Avanzada/sangre , Glicosilación , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Oxidación-Reducción , Adulto JovenRESUMEN
AIMS: Non-enzymatic reaction of biomolecules leads to the formation of advanced glycation end products (AGEs). AGEs plays significant role in the pathophysiology of type 2 diabetes mellitus. Methylglyoxal (MG) is a highly reactive carbonyl compound which causes formation of early (ketoamines), intermediate (dicarbonyls) and advanced glycation end products (AGEs). Glycation also results in the generation of free radicals causing structural perturbations which leads to the generation of neoantigenic epitopes on LDL molecules. The aim of the present study was to investigate whether the modification of LDL results in auto-antibodies generation in type 2 diabetes patients'. METHODS: The binding affinity of circulating autoantibodies in patients against native and MG modified LDL were assessed as compared with healthy and age-matched controls (n = 50) and T2DM patients with disease duration (DD) 5-15 yrs (n = 80) and DD > 15 yrs (n = 50) were examined by direct binding ELISA. KEYFINDINGS: The high affinity binding were observed in 50% of T2DM with DD 5-15 and 62% of T2DM with DD > 15 of patient's sera antibodies to MG-LDL antigen, in comparison to its native analog (P < 0.05). NHS sera showed negligible binding with both native and glycated LDL. Competitive inhibition ELISA results exhibit greater affinity sera IgG than the direct binding ELISA results. The increase in glycation intermediate and ends product were also observed in T2DM patient's sera and NHS sera. SIGNIFICANCE: There might be the generation of neoantigenic epitopes on LDL macromoleucle which results in generation of antibodies in T2DM. The prevalence of antibodies was dependent on disease duration.
Asunto(s)
Autoinmunidad/inmunología , Diabetes Mellitus Tipo 2/inmunología , Lipoproteínas LDL/inmunología , Piruvaldehído/inmunología , Adulto , Anciano , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Epítopos de Linfocito B/inmunología , Femenino , Productos Finales de Glicación Avanzada/inmunología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Non-enzymatic protein glycation results in the formation of advanced glycation end products (AGEs) leads to the pathogenesis of long-term diabetic complications. Iridin (ID), an antioxidant, plays an important role in protecting against oxidative stress and could therefore be an efficacious anti-glycating regimen. Herein, we assessed the anti-glycating potential of ID against d-ribose induced glycation of bovine serum albumin (BSA) by various biophysical and biochemical techniques. Our results from several physicochemical assays advocated that ID was able to evidently prevent the AGEs generation via reducing hyperchromicity, early glycation products (EGPs), carbonyl content (CC), hydroxymethyl furfural (HMF) content, production of fluorescent AGEs, protection against loss of secondary structure (i.e. α-helix and ß-sheets) of proteins, increasing the free lysine and free arginine content, reduced binding of congo red (CR), and reduced thioflavin T (ThT) and 8-aninilo-1-napthalene sulphonate (ANS)-specific fuorescence in glycated-BSA (Gly-BSA). On the basis of these findings, we concluded that ID possesses the significant anti-glycation potential and may be established as a remarkable anti-AGEs therapeutic agent. Further in-vivo and clinical studies are still warranted to uncover the therapeutic effects of ID against age-related as well as metabolic diseases.