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Diabetic vascular complication including diabetic retinopathy is a major morbidity in Saudia Arabia. The polyol pathway aka aldose reductase (AR) pathway has gained significant association with diabetic retinopathy with regard to chronically enhanced glucose metabolism. Considerable research has been put forth to develop more effective therapeutic strategies to overcome the overwhelming challenges of vascular complications associated with diabetes. In this regard, constituents of Cichorium intybus can offer strong AR inhibitory potential because of their strong antidiabetic properties. Therefore, aim of this study was to investigate the AR inhibitory as well as antiglycation potential of C. intybus extract/compounds. The preliminary in vitro results showed that methanolic extract of C. intybus could significantly inhibit AR enzyme and advanced glycation end product formation. Eventually, based on previous studies and reviews, we selected one hundred fifteen C. intybus root constituents and screened them through Lipinski's rule of five and ADMET analysis. Later, after molecular docking analysis of eight compounds, five best were selected for molecular dynamics simulation to deduce their binding affinity with the AR enzyme. Finally, three out of five compounds were further tested in vitro for their AR inhibitory potential and antiglycation properties. Enzyme assay and kinetic studies showed that all the three tested compounds were having potent AR inhibitory properties, although to a lesser extent than ellagic acid and tolrestat. Similarly, kaempferol showed strong antiglycation property equivalent to ellagic acid, but greater than aminoguanidine. Intriguingly, significant reduction in sorbitol accumulation in RBCs by the tested compounds substantiated strong AR inhibition by these compounds. Moreover, decrease in sorbitol accumulation under high glucose environment also signifies the potential application of these compounds in diabetic retinopathy and other vascular complications. Thus, in sum, the in silico and in vitro studies combinedly showed that C. intybus root is a treasure for therapeutic compounds and can be explored further for drug development against diabetic retinopathy.
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Improvements in the homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-ß) significantly reduce the risk of disabling diabetic pathies. Nanoparticle (AuNP-AgNP)-metformin are concentration dependent cross-interacting drugs as they may have a synergistic as well as antagonistic effect(s) on HOMA indicators when administered concurrently. We have employed a blend of machine learning: Artificial Neural Network (ANN), and evolutionary optimization: multiobjective Genetic Algorithms (GA) to discover the optimum regime of the nanoparticle-metformin combination. We demonstrated how to successfully employ a tested and validated ANN to classify the exposed drug regimen into categories of interest based on gradient information. This study also prescribed standard categories of interest for the exposure of multiple diabetic drug regimen. The application of categorization greatly reduces the time and effort involved in reaching the optimum combination of multiple drug regimen based on the category of interest. Exposure of optimum AuNP, AgNP and Metformin to Diabetic rats significantly improved HOMA ß functionality (â¼63 %), Insulin resistance (HOMA IR) of Diabetic animals was also reduced significantly (â¼54 %). The methods explained in the study are versatile and are not limited to only diabetic drugs.
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Diabetes Mellitus Experimental , Hipoglucemiantes , Resistencia a la Insulina , Metformina , Redes Neurales de la Computación , Animales , Metformina/uso terapéutico , Metformina/farmacología , Ratas , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Inteligencia Artificial , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacosRESUMEN
Objective: Recent years have seen a rise in the usage of dental implants to restore lost teeth. The stability of a dental implant is the main factor in determining its success. Implant stability is influenced by various factors. Several approaches have been employed clinically to evaluate stability at different time intervals. One non-invasive way to assess implant stability is by resonance frequency analysis. Utilizing the resonance frequency analysis method, this study seeks to understand how implant length and diameter affect primary and secondary stability. Methods: The current prospective study was conducted in the Prosthodontics Department of Institute of Dentistry, CMH Lahore Medical College. The duration of the study was six months. A total of 90 implants of sizes 4.5 x 8.5 mm and 4 x 10mm were placed. Resonance frequency measurements were recorded using Osstell™ AB device for primary stability at implant insertion and at 12 weeks for secondary stability. All the measurements were carried out by only one of the researchers to minimize inter-observer bias. Results: The average primary stability was 70.33±6.60, and the average secondary stability was 71.43±5.44. The data was stratified for age, gender, and implant site, and the mean primary and secondary stability of both sizes didn't show any statistically significant differences. Conclusion: Without forfeiting implant stability, both implant sizes (4 x 10mm and 4.5 x 8.5mm) can be used interchangeably, depending on available space and anatomical constraints.
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BACKGROUND: Cytokines, including interleukin-12 (IL-12), are proteins that regulate cell survival, proliferation, differentiation, and function. IL-12 is a heterodimeric proinflammatory cytokine. It possesses tumoricidal properties and promotes M1 macrophage polarization and IFN-γ production by T helper (Th1) cells, which in turn stimulates the antitumor cytotoxic cluster of eight positive (CD8+) and natural killer cells, therefore activating an effector immune response against tumor cells. MATERIALS AND METHODS: Herein, the IL-2 levels of 60 patients with generalized chronic periodontitis (GCP) were assessed. Plaque index, gingival index, pocket probing depth, bleeding on probing percentage (BOP %), and clinical attachment loss were the clinical indicators reported. RESULTS: Patients with GCP in the pretreatment group had substantially lower mean IL-12 levels than those in the post-treatment group. Short-term, nonsurgical treatment (NST) considerably improved periodontal indices and increased IL-12 levels, thereby reducing oral cancer risk. CONCLUSION: NST is a cost-effective and accessible cancer prevention procedure for general dentists.
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Periodontitis Crónica , Interleucina-12 , Neoplasias de la Boca , Humanos , Interleucina-12/sangre , Masculino , Persona de Mediana Edad , Femenino , Neoplasias de la Boca/terapia , Adulto , Periodontitis Crónica/terapia , Periodontitis Crónica/inmunología , Índice PeriodontalRESUMEN
A major obstacle in the treatment of tuberculosis (TB) is to combat the emerging resistant strains of its causing agent i.e. Mycobacterium tuberculosis (MTb). The emergence of multidrug-resistant and extensively drug-resistant -TB strains raise a requirement of new potential anti-tubercular compounds. In this direction, different plant parts of Morus alba were tested against MTb and found to be active with a minimum inhibitory concentration ranging between 125 µg/ml to 31.5 µg/ml. Further to identify the phytochompounds having anti-mycobacterium activity, phytocompounds of the plant were docked against the five MTb proteins (PDB ID: 3HEM, 4OTK, 2QO0, 2AQ1 and 6MNA). Among twenty-two tested phytocompounds, four phytocompounds with effective binding energy (kcal/mol): Petunidin-3-rutinoside (3HEM: -8.2, 4OTK: -6.9, 2QO0: -9.0, 2AQ1: -8.3 and 6MNA:-7.8), Quercetin-3'-glucoside (3HEM:-6.7, 4OTK:-7.6, 2QO0:-7.6, 2AQ1:7.6 and 6MNA:-6.4), Rutin (3HEM:-7.8, 4OTK:-7.5, 2QO0:-9.1, 2AQ1:9.3 and 6MNA:-6.9) and Isoquercitrin (3HEM:-7.3, 4OTK:-6.6, 2QO0:-7.7, 2AQ1:8.3 and 6MNA:-6.6) shows promising activity against all the five target proteins. Further molecular dynamics studies of Petunidin-3-rutinoside with three target proteins 3HEM, 2AQ1 and 2QO0 resulted with low values of average RMSD (3.723 Å, 3.261 Å, and 2.497 Å, respectively) show that the complexes have better conformational stability. The wet lab validation of the current study will pave the new dimensions for the cure of TB patients.Communicated by Ramaswamy H. Sarma.
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Morus , Mycobacterium tuberculosis , Ácidos Naftalenoacéticos , Tuberculosis , Humanos , Simulación de Dinámica Molecular , Antituberculosos/química , Tuberculosis/microbiología , Simulación del Acoplamiento MolecularRESUMEN
Leprosy is a chronic infectious disease caused by a bacillus, Mycobacterium leprae. According to official data from 139 countries in the 6 WHO Regions, there were 127558 new leprosy cases worldwide in 2020. Leprosy mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract, and the eyes. If this disease is left untreated, can harm the skin, nerves, limbs, eyes, and skin permanently. The disease is curable with multidrug therapy. Over a period of time Mycobacterium leprae has become resistant to these drugs. Therefore, new therapeutic molecules are warranted. This study was aimed to carry out the in-silico analysis to determine the inhibitory effect of natural compounds on Dihydropteroate synthase (DHPS) of Mycobacterium leprae. The DHPS is a key enzyme in the folate biosynthesis pathway in M. leprae and acts as a competitive inhibitor of PABA. The 3D structure of DHPS protein was modeled using homology modeling and was validated. Molecular docking and simulation along with other in-silico methods were employed to determine the inhibitory effect of ligand molecules towards DHPS target protein. Results revealed ZINC03830554 molecule as a potential inhibitor of DHPS. Binding experiments and bioassays utilizing this strong inhibitor molecule against purified DHPS protein are necessary to validate these early findings.Communicated by Ramaswamy H. Sarma.
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Lepra , Mycobacterium leprae , Humanos , Leprostáticos/farmacología , Dapsona/farmacología , Dihidropteroato Sintasa/química , Dihidropteroato Sintasa/metabolismo , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Quimioterapia Combinada , Lepra/tratamiento farmacológicoRESUMEN
BACKGROUND: Gene regulation of IL-6 is characterized by the presence of inflammatory cytokines, bacterial products, viral infection, and activation of the diacylglycerol-, cyclic AMP-, or Ca + + -activated signal transduction pathways. AIM: Scaling and root planning (SRP), a non-surgical periodontal therapy, was studied in connection to several clinical parameters for its effect on salivary IL-6 levels in patients with generalized chronic periodontitis. METHODS: For this study, a total of 60 GCP patients were included. Plaque index (PI), gingival index (GI), pocket probing depth (PPD), bleeding on probing percentage (BOP%), and clinical attachment loss were among the clinical indicators covered (CAL). RESULTS: Following SRP, mean IL-6 levels in patients with GCP were significantly higher in the pre-treatment group (2.93 5.17 pg/ml; p 0.05) than in the posttreatment group (5.78 8.26 pg/ml; baseline). Pre- and post-treatment IL-6 levels for PI (pre), BOP percent (pre/post), GI (post), and PPD were found to be positively correlated (post). In patients with GCP, the study showed a statistically significant correlation between periodontal metrics and salivary IL-6. CONCLUSIONS: Changes in periodontal indices and IL-6 levels that are statistically significant over time indicate that non-surgical treatment is effective, and IL-6 can be regarded as a potent disease activity marker.
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Periodontitis Crónica , Humanos , Periodontitis Crónica/tratamiento farmacológico , Interleucina-6 , Aplanamiento de la RaízRESUMEN
Melanoma is an extremely dangerous disease. The diagnosis and treatment of it may be difficult because of its diversity and complexity. More than 90% of the marine biomass (microflora and microalgae) constitutes the natural biodiversity reserves. TLR-related research developments indicate possible cancer therapeutic possibilities. In addition to its significant function in innate immunity, TLR activation is connected to the start of pyroptosis, apoptosis, or autophagy in malignance cells. For these reasons, TLR agonists are appealing candidates for the production of cancer medications. From the web databases, the ternary structures of the receptors (TLR3 and TLR4) and ligands are extracted. Sixty-nine compounds were subjected to a drug likeness filter, but only twenty-two were screened further for evaluating ADMET criteria, in which only seven compounds satisfied the pharmacological properties. These compounds are further analyzed for docking parameters against TLRs (TLR3 and TLR4) and molecular simulation investigation of the best cluster to evaluate the complex stability. Molecular docking methodology discovered that Scytonmein has a significant binding potential energy of -5.21 and -7.92 kcal/mol against TLR3 and TLR4, respectively, in comparison to the redock co-crystal structure (-3.98 and -4.30 kcal/mol, respectively). The simulation analysis demonstrates the significant stability of the Scytonemin and TLR4 complexes in terms of average RMSD and RMSF compared to the redock complex, while criteria like solvent-accessible surface area (SASA), gyration (Rg) and hydrogen bonding have further supported the significant interaction and stability of the conformations.Communicated by Ramaswamy H. Sarma.
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Neoplasias Cutáneas , Receptor Toll-Like 3 , Humanos , Simulación del Acoplamiento Molecular , Receptor Toll-Like 4 , Bacterias , Simulación por Computador , Receptores Toll-Like , Simulación de Dinámica MolecularRESUMEN
The objective of this study is to discover any possible association of gender or practitioner classification with orthodontic knowledge and attitudes towards orthodontic treatment. Descriptive cross-sectional research was conducted on two groups of dentists in the Ha'il region of Saudi Arabia. Group I included general practitioners, while Group II had non-orthodontic specialists. The findings suggest a statistically significant (p < 0.05) difference between the knowledge and attitudes of general practitioners and non-orthodontic specialists. Independent two tailed t-scores for difference in Knowledge (t-score = 3.19919, p = 0.003) and Attitude (t-score = 2.16314, p = 0.048319), highlight significant disparities in the knowledge and attitudes of general practitioners and non-orthodontic specialists. However, no statistically significant difference was observed in terms of knowledge and attitudes based on gender differences. This study captures and highlights subtle information that is very significant in dealing with critically important orthodontics issues. The study suggests that it is possible that a non-orthodontic specialist may suggest an altogether different line of treatment with different consequences when compared to a general practitioner and vice versa. This may result in unwanted, permanent orthodontic effects, highlighting the significance of the early stage of orthodontic treatment awareness. This research reveals disparities between the perceptions of general practitioners and non-orthodontic specialists about the stage and relevance of orthodontic treatment. It is strongly advised to see an orthodontic expert rather than a general practitioner or non-orthodontic specialist for orthodontic issues.
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Leprosy is a major health concern and continues to be a source of fear and stigma among people worldwide. Despite remarkable achievements in the treatment, understanding of pathogenesis and transmission, epidemiology of leprosy still remains inadequate. The prolonged incubation period, slow rates of occurrence in those exposed and deceptive clinical presentation pose challenges to develop reliable strategies to stop transmission. Hence, there is a need for improved diagnostics and therapies to prevent mortality caused by leprosy. The objectives of this study are to identify significant genes from protein-protein interactions (PPIs) network of leprosy and to choose the most effective therapeutic targets. Fifty genes related with leprosy were discovered by literature mining. These genes were used to construct a primary network. Leading Eigen Vector method was used to break down the primary network into various sub-networks or communities. It was found that the primary network was divided into many sub-networks at the 6 levels. Seed genes were traced at each level till key regulatory genes were identified. Three seed genes, namely, GNAI3, NOTCH1, and HIF1A, were able to make their way till the final motif stage. These genes along with their interacting partners were considered key regulators of the leprosy network. This study provides leprosy-associated key genes which can lead to improved diagnosis and therapies for leprosy patients.
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Mycobacterium Aspartate beta semialdehyde dehydrogenase (ASADH) was studied using various spectroscopic techniques and size exclusion chromatography to examine the unfolding of free (apo) and NADP/H-bound (holo) forms of ASADH. Non-cooperative guanidinium chloride (GdnHCl)-induced unfolding of the apo ASADH was discovered, and no partially folded intermediate structures were stabilized. On the other hand, it was observed that GdnHCl's unfolding of holoenzyme was a cooperative process without any stable intermediate structure. The native form of holoenzyme is found to be stable against the lower concentration of GdnHCl only (namely up to 1.25 M GdnHCl). The tryptophan environment appears to unfold cooperatively in case of the holoenzyme and is in well coordination with the overall unfolding of the holoenzyme. The presence of NADP/H shows a stabilizing effect on the tryptophan environment as well as on the native NADP/H-bound enzyme. ΔGSolvento values reveal nearly two-fold (â¼1.9) conformationally more stable folded holoenzyme compared to its native apo state. The Cm for the apo and holo forms of ASADH are 1.3 and 1.9 M, respectively. Novel drug leads targeting the NADP/H binding domain of ASADH could offer promising drugs against extremely infective Mycobacterium tuberculosis.Communicated by Ramaswamy H. Sarma.
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Development of low-cost and economic cellulase production is among the key challenges due to its broad industrial applications. One of the main topics of research pertaining to sustainable biomass waste based biorefinaries is the development of economic cellulase production strategies. The main cause of the increase in cellulase production costs is the use of commercial substrates; as a result, the cost of any cellulase-based bioprocess can be decreased by employing a productive, low-cost substrate. The goal of the current study is to develop low-cost cellulase using the carbohydrate-rich, renewable, and widely accessible cyanobacteria algae Oscillatoria obscura as the production substrate. Maximum cellulase was produced utilising the fungus Rhizopus oryzae at substrate concentration of 7.0 g among various tested concentrations of algal biomass. Maximum production rates of 22 IU/gds FP, 105 IU/gds BGL, and 116 IU/gds EG in 72 h were possible under optimal conditions and substrate concentration. Further investigations on the crude enzyme's stability in the presence of iron oxide nanoparticles (IONPs) revealed that it was thermally stable at 60 °C for up to 8 h. Additionally, the crude enzyme demonstrated pH stability by maintaining its complete activity at pH 6.0 for 8 h in the presence of the optimal dose of 15 mg IONPs. The outcomes of this research may be used to investigate the possibility of producing such enzymes in large quantities at low cost for industrial use.
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Celulasa , Oscillatoria , Biomasa , Celulasa/metabolismo , Estabilidad de Enzimas , Fermentación , Nanopartículas Magnéticas de Óxido de Hierro , Oscillatoria/metabolismo , Plantas/metabolismoRESUMEN
Coronavirus 2019 (COVID-19) disease management is highly dependent on the immune status of the infected individual. An increase in the incidence of depression has been observed during the ongoing COVID-19 pandemic. Autoantibodies against in vitro reactive oxygen species (ROS) modified BSA and Lys as well as antibodies against receptor binding domain subunit S1 (S1-RBD) (S1-RBD-Abs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were estimated using direct binding and competition ELISA. Serum samples were also tested for fasting blood glucose (FBG), malondialdehyde (MDA), carbonyl content (CC), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Significant structural changes were observed in ROS modified BSA and Lys. Female depressed subjects who were also smokers (F-D-S) showed the highest levels of oxidative stress (MDA and CC levels). Similarly, increased levels of autoantibodies against ROS modified proteins were detected in F-D-S subjects, in males who were depressed and in smokers (M-D-S) compared to the other subjects from the rest of the groups. However, contrary to this observation, levels of S1-RBD-Abs were found to be lowest in the F-D-S and M-D-S groups. During the pandemic, large numbers of individuals have experienced depression, which may induce excessive oxidative stress, causing modifications in circulatory proteins. Thus, the formation of neo-antigens is induced, which lead to the generation of autoantibodies. The concomitant effect of increased autoantibodies with elevated levels of IFN-γ and TNF-α possibly tilt the immune balance toward autoantibody generation rather than the formation of S1-RBD-Abs. Thus, it is important to identify individuals who are at risk of depression to determine immune status and facilitate the better management of COVID-19.
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The question of the origin of coronavirus spread like wildfire ever since it wreaked havoc among humankind, and ever since the scientific community has worked tirelessly to trace the history of the virus. In this review, we have tried to compile relevant literature pertaining to the different theories of origin of SARS-CoV-2, hopefully without any bias, and we strongly support the zoonotic origin of the infamous SARS-CoV-2 in bats and its transfer to human beings through the most probable evolutionary hosts, pangolins and minks. We also support the contemporary 'Circulation Model' that simply mirrors the concept of evolution to explain the origin of the virus which, the authors believe, is the most rational school of thought. The most recent variant of SARS-CoV-2, Omicron, has been taken as an example to clarify the concept. We recommend the community to refer to this model for further understanding and delving deep into this mystery of the origin of SARS-CoV-2.
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The robust use of osmolytes (i.e., polyols and sugars) in the key therapeutic regimens/formulations has questioned their impact beyond the stability of therapeutic proteins as these osmolytes trigger structural alterations into proteins including misfolding and subsequent aggregation into amyloid fibrils. Therefore, the current study is the first to delineate the inhibitory effect of carvacrol (CRV) on the carbonyl osmolyte-induced aggregation as well as structural alterations to the bovine serum albumin (BSA) via a set of physicochemical as well as artificial intelligence (AI)-based molecular docking studies. Our initial findings from physicochemical investigations revealed that CRV exhibits substantial protection to BSA under carbonyl osmolyte stress as evident by the compromised hyperchromicity, Schiff's bases, carbonyl and hydroxymethyl furfural content, reduced fluorescent signals, low Rayleigh scattering and prevention of covalent modifications at Lys and Arg residues. The protection against aggregate formation by CRV was further confirmed through the reduced amyloid-specific congo red absorbance as well as fluorescent signals recorded after adding the fibril-specific extrinsic fluorophore probes (i.e., ThT and ANS). The AI-based molecular docking analysis further revealed that CRV (ΔG: -4.96 kcal/mol) competes with d-fructose (ΔG: -4.40 kcal/mol) to mask the Lys and Arg residues to restrict the osmolyte-mediated protein modifications. In conclusion, CRV exhibits substantial protective impact against carbonyl osmolyte-induced structural alterations and protein misfolding and aggregation.
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Inteligencia Artificial , Albúmina Sérica , Amiloide/química , Cimenos , Simulación del Acoplamiento Molecular , Albúmina Sérica Bovina/químicaRESUMEN
Background: Two years into the pandemic, yet the threat of new SARS-CoV-2 variants continues to loom large. Sustained efforts are required to fully understand the infection in asymptomatic individuals and those with complications. Identification, containment, care, and preventative strategies rely on understanding the varied humoral immune responses. Methods: An in-house ELISA was developed and standardized to screen for serum IgG antibodies against the SARS-CoV-2 S1-RBD protein as an antigen. This study aims to investigate the seroprevalence of serum antibodies against S1-RBD antigen in pre-pandemic (n = 120) and during the early pandemic period (n = 120) in subjects from the Hail region, KSA and to correlate it with clinical and demographic factors. Results: Samples collected from both male (n = 60) and female (n = 60) subjects during the pandemic in the age groups of 20-40 (0.31 ± 0.029 and 0.29 ± 0.024, respectively) and 41-60 years (0.35 ± 0.026 and 0.30 ± 0.025, respectively) showed significantly higher levels of serum antibodies against S-RBD antigen than the age-matched pre-pandemic samples [male (n = 60) and female (n = 60)]. Pandemic subjects exhibited significantly (p < 0.01) higher inhibition (80-88%) than age-matched pre-pandemic subjects (32-39%). Antibodies against S1-RBD antigen were detected in approximately 10% of the total pre-pandemic population (males and females). However, subjects > 60 years did not show antibodies. Conclusion: Antibody levels increased in samples collected during the pandemic, even though these subjects were not clinically COVID-19 positive. A small number of pre-pandemic subjects showed serum antibodies, suggesting prior exposure to other coronaviruses in the region. With dwindling neutralizing antibody levels and reduced vaccine efficacy against newer variants, it remains crucial to develop better assays for surveillance, management, and future research.
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COVID-19 , Pandemias , Anticuerpos Antivirales , COVID-19/epidemiología , Femenino , Humanos , Masculino , SARS-CoV-2 , Estudios Seroepidemiológicos , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: Papacarie pre-treatment of dentin surface has been reported to exhibit good bond strength values between dentin and composites. Its desirable properties like high pH, sites specify and anti-inflammatory response makes it a future material in place acid etching pre-treatment. Acid etching may cause sensitivity and collapse of dentinal matrix. METHODS: This in-vitro study involved, 60 caries free extracted premolars, randomly divided into three groups. Control Group (Group A) No pre-treatment of dentin prior adhesive application. Experimental Group B acid etchant was applied before adhesive application. Experimental Group C Papacarie was used as a pre-treatment agent. All these specimens were tested for shear bond strength with the help of Universal Testing Machine. All the collected data was entered in SPSS version 20.0. ANOVA was used to determine the mean SBS (Shear Bond strength) values of control and experimental groups. RESULTS: The mean shear bond strength of material was 7.74±0.47 in group A, 17.80±1.43 in group B and 15.11±0.70 in group C. Group B showing better strength than other two groups. CONCLUSIONS: The study provides information about longevity of composite restorations and may help in extending the clinical usage of papacarie to avoid harmful effects of acid etching on dentin and pulpal tissue.
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Adhesivos , Recubrimientos Dentinarios , Grabado Ácido Dental , Resinas Compuestas/química , Dentina , Recubrimientos Dentinarios/química , Humanos , Ensayo de Materiales , Papaína , Cementos de ResinaRESUMEN
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.
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Productos Finales de Glicación Avanzada , Glioxal , Fibrinógeno/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Inmunoglobulina G/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
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.
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Complicaciones de la Diabetes , Diabetes Mellitus Experimental , Animales , Antioxidantes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Ácido Elágico/farmacología , Glutatión/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación , RatasRESUMEN
Dysregulated immune response significantly affects hepatocellular carcinoma's (HCC) prognosis. Human Leukocyte Antigens are key in devising immune responses against HCC. Here, we investigated how HLAs modulate HCC development at the transcriptomic level. RNA-seq data of 576 patients from two independent cohorts was retrieved. The clinicopathological relevance of all HLA genes was investigated using Fisher-Exact, correlation, and Kaplan-Meier and cox regression survival tests. Clustering of ~800 immune-related genes against HLAs was completed using a ward-agglomerative method. Networks were generated using 40 HLA associated unique genes and hub genes were investigated. HLAs including HLA-DMA, HLA-DMB, HLA-DOA and HLA-DRB6 were associated with delayed recurrence in both discovery (204 HCC cases) and validation (372 HCC cases) cohorts. Clustering analyses revealed 40 genes associated with these four HLAs in both cohorts. A set of seven genes (NCF4, TYROBP, LCP2, ZAP70, PTPRC, FYN and WAS) was found co-expressed at gene-gene interaction level in both cohorts. Furthermore, survival analysis revealed seven HLA-linked genes as predictors of delayed recurrence. Multivariate analysis also predicted that mean expression of 7-gene is an independent predictor of delayed recurrence in both cohorts. We conclude that the expression of 7-gene signature may lead to improved patient prognosis. Further studies are required for consideration in clinical practice.