Search

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. [ABSTRACT FROM AUTHOR]

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. Significance statement: Provide a low cost green synthesis method for the synthesis of biologically active titanium dioxide (TiO2) nanoparticles.Provide the structural characterization of green synthesized TiO2 nanoparticles (TNP).An insight to identify the TNP as significant glycation inhibitor.Study suggest antiglycation potential detection of plant based TNP as possible therapeutic invention for hyperglycemia assisted diabetes and associated diseases. [ABSTRACT FROM AUTHOR]

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 β‐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. Highlights: Metformin is the first drug which interacts with dicarbonyl compounds and blocks the formation of AGEs.Metformin is bioconjugated with glycation‐derived synthesized gold nanoparticles (GNPs) of significant size.MTF‐GNPs were able to inhibit AGEs development by reducing hyperchromicity, early glycation products (EGEPs), carbonyl (CC), and Hydxoxymethylfurfural (HMF) content etc.MTF‐GNPs possess a considerable anti‐glycation property and may be developed as an outstanding anti‐AGEs treatment drug. Significance The key concluding of the current research demonstrates that the efficacy of the metformin (MTF) is enhanced by bioconjugating it with gold nanoparticles (MTF‐GNPs). Our findings also depict that MTF‐GNPs have higher antiglycation activity (utilized at lower doses) in contrast to the pure metformin antiglycation drug (utilized at higher doses, responsible for causing side‐effects in an individual). Therefore, MTF‐GNPs can be utilized as a promising anti‐AGE therapeutic drug (possessing high effectiveness and lower side effects) and, perhaps, diabetic problems in the future. [ABSTRACT FROM AUTHOR]

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. Significance statement: 1.D‐ribose‐induced glycation leads to structural perturbations in immunoglobulin G (IgG), the formation of IgG‐advanced glycation end products, and the generation of oxidative stress. 2.UV‐visible spectroscopy revealed the hyperchromicity of glycated IgG increases with the increase in the concentration of D‐ribose and time interval. 3.The early glycation products that is, Amadori products or ketoamines formed during D‐ribose mediated glycation of IgG were assessed by nitroblue tetrazolium assay and found to be increased initially in the first 5 days. 4.Hydroxymethylfurfural, carbonyl content, thiobarbituric acid reactive substances, and fluorescence intensity were found to be increased in glycated IgG as compared to the native analog. 5.Free lysine and arginine were found to be decreased in glycated IgG in comparison to the native conformer of the protein. [ABSTRACT FROM AUTHOR]

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. Significance statement: KIFC1 can bind with two antiparallel microtubules (MTs) at opposite ends via end‐binding protein family member 1 (EB1) and evolutionary conserved SxIP motif. The positive‐end association is needed to identify and catch kinetochore MTs, consequently permitting their carriage to the spindle pole and managing bipolar divisions. Inhibition of KIFC1 via small molecules can facilitate the onset of apoptosis. In the purview of this rationale, the study identified a small molecule named Mcule‐4895338547 that showed a significant binding propensity, indicating stability and consequent effectiveness in inhibiting KIFC1 α4/α6 cleft. Moreover, physicochemical properties, lipophilicity, solubility, pharmacokinetics, drug‐likeness, and medicinal chemistry attributes of Mcule‐4895338547 were found to be better than AZ82. Thus, it could be promising for kinesin‐mediated drug discovery and development. [ABSTRACT FROM AUTHOR]

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. Significance statement: Collagen type II suspension was used to make a rheumatoid arthritis model of rat.Hesperidin treatment was effective against bone loss.Hesperidin effectively reduced the concentrations of advanced glycation end products like Nε‐(carboxymethyl)lysine and pentosidine.Treatment with hesperidin resulted in the alleviation of rheumatoid arthritis disease through free radical scavenging and antiglycation activities.Hesperidin may be useful to alleviate the severity of rheumatoid arthritis disease. [ABSTRACT FROM AUTHOR]

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

Advanced glycation end products (AGEs) are a cohort of heterogeneous compounds that are formed after the nonenzymatic glycation of proteins, lipids and nucleic acids. Accumulation of AGEs in the body is implicated in various pathophysiological conditions like diabetes, cardiovascular diseases and atherosclerosis. Numerous studies have reported the connecting link between AGEs and the various complications associated with diseases. Hence, detection and measurement of AGEs becomes centrally important to understand and manage the menace created by AGEs inside the body. In recent years, an increasing number of immunotechniques as well as bioanalytical techniques have been developed to efficiently measure the levels of AGEs, but most of them are still far away from being clinically consistent, as relative disparity and ambiguity masks their standardization. This article is designed to critically review the recent advances and the emerging techniques for detection of AGEs. It is an attempt to summarize the major techniques that exist currently for the detection of AGEs both qualitatively and quantitatively. This review primarily focuses on the detection and quantification of AGEs which are formed in vivo. Immunochemical approach though costly but most effective and accurate method to measure the level of AGEs. Literature review suggests that detection of autoantibody targeting AGEs is a promising way that can be utilized for detection of AGEs. Future research efforts should be dedicated to develop this method in order to push forward the clinical applications of detection of AGEs. [ABSTRACT FROM AUTHOR]

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

There are accumulating evidences suggesting that interaction between advanced glycation end products (AGEs) and their receptors (RAGEs) induces oxidative stress and subsequently encourages inflammatory reactions, thereby resulting in progressive alteration in renal architecture and function. Interventions that reduce the tissue burden of AGEs have yielded significant positive results in inhibiting the progression of diabetic complications such as diabetic nephropathy. Lycopene, a carotenoid, plays an important role in protection against oxidative stress and hence might prove an efficient antiglycating agent. Current study investigates the effect of lycopene in downregulating the menace caused by ribose-induced glycation both in vitro and in vivo. We observed that treatment with lycopene decelerated the ribose induced AGE formation in HK-2 cells and in rat kidneys thereby downregulating the expression RAGE. HK-2 cells with decreased levels of RAGE showed a decline in nuclear factor κB (NFκB) and matrix metalloproteinase 2 (MMP 2) expressions. Administration of ribose not only induced hyperglycemia in Wistar rats but also developed diabetic nephropathy (DN). However, lycopene was found effective in relieving the biochemical symptoms of DN. Thus lycopene provides protection against development of diabetic nephropathy and ameliorates renal function by halting AGE-RAGE axis. © 2015 BioFactors, 41(5):372-381, 2015. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products comprise a complex and heterogeneous group of compounds that have been implicated in diabetes-related complications. The importance of the Maillard reaction is depicted by the formation of reactive intermediate products known as α-oxoaldehydes, such as 3-deoxyglucosone (3-DG). This product has been found to be involved in accelerated vascular damage in diabetes. In the present study, calf thymus histone H2A was reacted with 3-DG, and the generation of advanced glycation end products was investigated by determining the degree of side chain modifications (lysine and arginine residues), Amadori products, carbonyl content, Nε-carboxymethyl lysine, and pentosidine using various physicochemical techniques. Moreover, fluorescence, absorbance as well as structural characteristics of glycated-H2A were comprehensively investigated. Overall, this study demonstrates structural perturbation, formation of different intermediates, and AGEs that are believed to hamper the normal functioning of H2A histone, compromising the integrity of chromatin structures and function in secondary complications of diabetes. © 2014 IUBMB Life, 66(10):686-693, 2014 [ABSTRACT FROM AUTHOR]

The present study is initially intended to evaluate antioxidant and [beta]-hydroxy-[beta]-methylglutaryl-CoA reductase (HMGR) inhibitory property of Ficus virens Ait., first by in vitro analyses followed by a corroboratory molecular informatics study. Our results show that of all the sequentially extracted fraction of F. virens bark and leaves extract, F. virens bark methanol extract exhibits strong radical scavenging, antioxidant and oxidative DNA damage protective activity, which is well correlated with its total phenolic content. In addition, F. virens bark methanol extract, which is non-cytotoxic, significantly and non-covalently inhibit the HMGR activity (IC50 = 3.45 ± 0.45 ug/ml) in comparison with other extracts. The mechanistic aspect of this inhibition activity is authenticated by molecular docking study of bioactive compounds as revealed from gas chromatography-mass spectrometry data, with HMGR. The analysis for the first time indicates that quinic acid ([Delta]G: -8.11 kcal/mol) and paravastatin ([Delta]G: -8.22 kcal/mol) exhibit almost same binding energy, while other compounds also showed good binding energy, suggesting that quinic acid alone or in combination with other major bioactive compound is probably responsible for HMGR inhibitory property of the extract and plausibly can be used in in vivo system for the management, prevention, and alleviation of hypercholesterolemia as well as hypercholesterolemia-induced oxidative stress. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study is initially intended to evaluate antioxidant and β-hydroxy-β-methylglutaryl-CoA reductase (HMGR) inhibitory property of Ficus virens Ait., first by in vitro analyses followed by a corroboratory molecular informatics study. Our results show that of all the sequentially extracted fraction of F. virens bark and leaves extract, F. virens bark methanol extract exhibits strong radical scavenging, antioxidant and oxidative DNA damage protective activity, which is well correlated with its total phenolic content. In addition, F. virens bark methanol extract, which is non-cytotoxic, significantly and non-covalently inhibit the HMGR activity (IC50 = 3.45 ± 0.45 μg/ml) in comparison with other extracts. The mechanistic aspect of this inhibition activity is authenticated by molecular docking study of bioactive compounds as revealed from gas chromatography-mass spectrometry data, with HMGR. The analysis for the first time indicates that quinic acid (ΔG: -8.11 kcal/mol) and paravastatin (ΔG: -8.22 kcal/mol) exhibit almost same binding energy, while other compounds also showed good binding energy, suggesting that quinic acid alone or in combination with other major bioactive compound is probably responsible for HMGR inhibitory property of the extract and plausibly can be used in in vivo system for the management, prevention, and alleviation of hypercholesterolemia as well as hypercholesterolemia-induced oxidative stress. [ABSTRACT FROM AUTHOR]

4-Aminobiphenyl (4-ABP), an aromatic amine is a major environmental carcinogen found mainly in cigarette smoke. It has been vastly implicated in mutagenesis and cancer development. In this study, commercially available human placental DNA was exposed to 4-ABP (1.3 mM) in presence of sodium nitroprusside (SNP; 8 mM) at 37°C for 3 h. The 4-ABP + SNP-mediated structural changes in human DNA were studied by ultraviolet, circular dichroism and fluorescence spectroscopy, thermal melting profile, agarose gel electrophoresis, and nuclease S1 digestibility assay. Spectroscopical analysis and melting temperature studies suggest structural perturbations in the DNA as a result of modification. This might be due to generation of single-stranded regions and destabilization of hydrogen bonds. Modification was also visualized in agarose gel electrophoresis. Furthermore, nuclease S1 digestibility confirmed the generation of single strand breaks. Rabbits challenged with 4-ABP-SNP-modified human DNA-induced high-titer immunogen-specific antibodies, which showed Cross-reaction with modified/unmodified DNA bases and ss-DNA in competitive inhibition assay. The immunogen specificity of induced antibodies against 4-ABP-SNP-modified human DNA was further confirmed in gel retardation assay. It may be concluded that induction of anti-modified DNA antibodies could be due to perturbation in the DNA structure and its subsequent recognition by immunoregulatory cells as a foreign molecule. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 568-576, 2014. [ABSTRACT FROM AUTHOR]

4-Aminobiphenyl, a known carcinogen, has many environmental sources like cigarette smoke, industrial waste, and so forth. It can be metabolized to form a potent mutagen, N-hydroxy- N-acetyl-4-aminobiphenyl ( N-OH-AABP) that undergoes further processing to form electrophilic nitrenium ions which interact with DNA-forming covalent adducts, thereby exerting genotoxic effects. While the mutagenicity of N-OH-AABP has been amply reported, no extensive studies have been performed to assess the immunogenicity of N-OH-AABP-modified DNA. In this study, human placental DNA was modified with N-OH-AABP, and the structural perturbations in the DNA molecule were evaluated by ultraviolet spectroscopy and nuclease S1 digestion. Native and N-OH-AABP-modified DNA were used as antigens for immunizing female rabbits. The modified DNA was found to be highly immunogenic, eliciting high titer immunogen-specific antibodies, while the native form was almost nonimmunogenic. The induced antibodies exhibited wide range of heterogeneity in recognizing various nucleic acid conformers and DNA bases. We also detected deposits of immune complex in glomerular basement membrane in rabbits immunized with N-OH-AABP-DNA. Possible role of N-OH-AABP-DNA in the induction of antibodies in cancer patients and the related consequences have been discussed. © 2012 IUBMB Life, 64(4): 340-345, 2012 [ABSTRACT FROM AUTHOR]

Biosynthetic procedure is one of the best alternatives, inexpensive and ecologically sound for the synthesis of titanium dioxide (TiO 2 ) nanoparticles using a methanolic extract of medicinal plant. The main prospect of this study was to investigate the antiglycation activity of the TiO 2 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., (© 2022 John Wiley & Sons Ltd.)