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The widespread use of oxidative hair colouring cosmetics threatens public health. Phenylenediamine derivatives serve as the main pigment in permanent hair colours. They interact with biological macromolecules, altering their functional and structural physiology. The study aimed to investigate the effect of a typical synthetic hair dye pigment, 4-Chloro-orthophenylenediamine (4-Cl-OPD), under a nitrating environment of DEANO on the calf thymus DNA molecule. The results showed single-stranded regions, base/sugar-phosphate backbone alterations, molecular changes, and nitro-oxidative lesions. These modifications are referred to as neo-epitopes on the DNA molecule. IgGs from cancer patients with a history of permanent hair dye use were screened for the recognition of neo-epitopes on DNA molecules. Hepatocellular carcinoma IgG showed the highest binding with 56% inhibition in the competition ELISA. The immune complex formation was observed through electrophoretic mobility shift assay. In conclusion, synthetic hair dye users are likely to present with heightened immunological triggers under elevated nitric oxide levels. The study reports chronic hair dye exposure as one of the factors responsible for altering the intricacies of the DNA's microarchitectural structure and inducing neo-epitopes on the molecule. The physiological status of NO may define the susceptibility towards 4-Cl-OPD and humoral response in hair dye users. Persistent nitro-oxidative stress due to 4-Cl-OPD and NO may induce a heightened immune response against neoepitopes in the nitro-oxidatively modified DNA. Therefore, chronic hair dye exposure may be identified as a risk to human health. These findings may contribute to a better understanding and reinforcement of hair dye as one of the modifiable risk factors responsible for the pro-inflammatory carcinogenic environment., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression by binding to the 3' untranslated regions (UTR) of target genes. Aberrant expression of miRNAs can lead to disease, including cancer. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Among several factors, differential expression of miRNA can have serious consequences on disease progression. This study was designed to computationally identify and experimentally verify strong miRNA candidates that could influence CRC progression. In silico analysis of publicly available gene expression microarray datasets revealed significant upregulation of miR-1183 in CRC. Comparison of mRNA microarray expression data with predicted miR-1183 targets led to the identification of cell cycle progression gene 1 (CCPG1) as strong, negatively correlated miR-1183 target. Expression analysis by means of quantitative PCR validated the inverse correlation between miR-1183 and CCPG1 in colorectal cancer tissues. CCPG1 indirectly modulates the cell cycle by interacting with the PH/DH domain of Dbs (Rho-specific guanine nucleotide exchange factor). Interestingly, the computational analysis also showed that miR-1183 is upregulated in liver and gastric cancer. This finding is notable as the liver and stomach are the primary metastatic sites for colorectal cancer and hepatocellular carcinoma respectively. This novel finding highlights the broader implications of miR-1183 dysregulation beyond primary CRC, potentially serving as a valuable prognostic marker and a therapeutic target for both primary and metastatic CRC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Fatima et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To investigate willingness to vaccination, conspiracy mentality, and belief in vaccine conspiracies among undergraduate students as well as the level of adherence to non-pharmaceutical interventions during the coronavirus disease-2019 pandemic., Methods: The cross-sectional study was conducted from January to June, 2021, and comprised undergraduate students from Islamabad and Rawalpindi, Pakistan. Data was gathered using the General Conspiracy Mentality Scale and the Belief in Vaccine Conspiracies Scale. Willingness for vaccination and degree of adherence to non-pharmaceutical interventions was measured on a 5-point rating scale. Data was analysed using SPSS 26., Results: Of the 300 subjects, 154 were males and 146 were females. The overall mean age of the sample was (23.47 ±2.17). A sample of 121(40.33%) respondents believed in vaccine conspiracies, while only 83(27.66%) showed disagreement. High scores on conspiracy mentality (p<0.020) and belief in vaccine conspiracies (p<0.006) were associated with little adherence to behavioural recommendations for coronavirus disease-2019. High scorers on conspiracy mentality (p<0.006) and belief in vaccine conspiracies (p<0.004) had less willingness for vaccination. There was no significant difference in the conspiracy mentality and belief in vaccine conspiracies with reference to gender (p>0.05)., Conclusions: Medical practitioners and healthcare organisations need to understand the connection between belief in vaccine conspiracies and related vaccine resistance and noncompliance with behavioural recommendations in the face of a pandemic.

Microbial pathogens and bulk amounts of industrial toxic wastes in water are an alarming situation to humans and a continuous threat to aquatic life. In this study, multifunctional silver and graphene nanocomposites (Ag) 1-x (GNPs) x [25% (x = 0.25), 50% (x = 0.50) and 75% (x = 0.75) of GNPs] were synthesized via ex situ approach. Further, the synthesized nanocomposites were explored for their physicochemical characteristics, such as vibrational modes (Raman spectroscopic analysis), optical properties (UV visible spectroscopic analysis), antibacterial and photocatalytic applications. We investigated the antimicrobial activity of silver and graphene nanocomposites (Ag-GNPs), and the results showed that Ag-GNPs nanocomposites exhibit remarkably improved antimicrobial activity (28.78% ( E. coli ), 31.34% ( S. aureus ) and 30.31% ( P. aeruginosa ) growth inhibition, which might be due to increase in surface area of silver nanoparticles (AgNPs)). Furthermore, we investigated the photocatalytic activity of silver (AgNPs) and graphene (GNPs) nanocomposites in varying ratios. Interestingly, the Ag-GNPs nanocomposites show improved photocatalytic activity (78.55% degradation) as compared to AgNPs (54.35%), which can be an effective candidate for removing the toxicity of dyes. Hence, it is emphatically concluded that Ag-GNPs hold very active behavior towards the decolorization of dyes and could be a potential candidate for the treatment of wastewater and possible pathogenic control over microbes. In the future, we also recommend different other in vitro biological and environmental applications of silver and graphene nanocomposites.

Glioblastoma (GBM) is a malignant and aggressive brain tumor with a median survival of ∼15 months. Resistance to treatment arises from the extensive cellular and molecular heterogeneity in the three major components: glioma tumor cells, glioma stem cells, and tumor-associated microglia and macrophages. Within this triad, there is a complex network of intrinsic and secreted factors that promote classic hallmarks of cancer, including angiogenesis, resistance to cell death, proliferation, and immune evasion. A regulatory node connecting these diverse pathways is at the posttranscriptional level as mRNAs encoding many of the key drivers contain adenine- and uridine rich elements (ARE) in the 3' untranslated region. Human antigen R (HuR) binds to ARE-bearing mRNAs and is a major positive regulator at this level. This review focuses on basic concepts of ARE-mediated RNA regulation and how targeting HuR with small molecule inhibitors represents a plausible strategy for a multi-pronged therapeutic attack on GBM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Previous studies have shown patient education material (PEM) in ophthalmology has been written at levels exceeding appropriate reading levels. However, information for readability in the field of oculoplastics remains limited. The aim of this study was to evaluate the readability of patient educational brochures from the American Society of Ophthalmic Plastic & Reconstructive Surgery (ASOPRS)., Methods: Patient educational brochures from ASOPRS were analyzed for readability. The body of text from all 18 ASOPRS patient brochures was analyzed by ten validated tests for English readability assessment: Flesch Reading Ease Test (FRE), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), Coleman-Liau Index (CLI), Gunning Fog Index (GFI), New Dale-Chall Readability (NDC), FORCAST, Fry Graph Readability (FG), Raygor Readability Estimate (RRE), and New Fog Count (NFC)., Results: The mean (± SD) readability scores from the 18 ASOPRS patient brochures were 48 (4.3), 11.0 (0.8), 13.0 (0.7), 11.7 (0.8), 13.6 (0.9), 11.3 (0.8), 11.1 (0.5), 12.1 (1.5), 12.2 (1.0), and 10.6 (1.3) for FRE, FKGL, SMOG, CLI, GFI, NDC, FORCAST, FG, RRE, and NFC, respectively. All ten of the mean readability scores were above the recommended reading levels., Conclusions: These findings show that the average patient may have difficulty understanding educational information provided by ASOPRS patient brochures, thereby hindering their ability to make informed decisions on their healthcare. Revision with readability as a primary goal, with input from patients and caregivers, may be necessary to improve health literacy among patients who seek oculoplastic care.

Background: Granuloma annulare has been linked to diabetes, dyslipidemia, thyroid disease, collagen vascular disease, malignancies, infectious hepatitis, and systemic infections. However, these associations have not been systematically investigated when categorized by its clinical variants., Objective: To evaluate disease associations of localized and generalized granuloma annulare., Methods: In total, 407 granuloma annulare patients from 1989 to 2019 were retrospectively reviewed, categorized by clinical variant (localized or generalized), age (pediatric or adult), and diagnostic method (clinical or histologic). Descriptive statistical analyses and multivariate logistic regression analysis were performed. Fisher's exact tests were conducted to produce unbiased probability values., Results: Overall, 75.2% of the study sample was female, 47.2% had dyslipidemia, 24.8% were diabetic, and 24.6% had thyroid disease. Dyslipidemia (OR 2.15, CI 1.95-2.35, P < .001), diabetes (OR 1.16, CI 1.01-1.31, P = .041), and histologic diagnosis (OR 2.08, CI 1.21-3.52, P = .007) were associated with increased risk of GGA compared to LGA. When stratified by adult versus pediatric cases, dyslipidemia and diagnostic method remained significant, but diabetes did not., Conclusions: Evaluating granuloma annulare by its clinical variants may help to determine disease associations with each variant.

TIA-1 is an RNA-binding protein that sequesters target RNA into stress granules under conditions of cellular stress. Promotion of stress granule formation by TIA-1 depends upon self-association of its prion-like domain that facilitates liquid-liquid phase separation and is thought to be enhanced via RNA binding. However, the mechanisms underlying the influence of RNA on TIA-1 self-association have not been previously demonstrated. Here we have investigated the self-associating properties of full-length TIA-1 in the presence of designed and native TIA-1 nucleic acid binding sites in vitro, monitoring phase separation, fibril formation and shape. We show that single stranded RNA and DNA induce liquid-liquid phase separation of TIA-1 in a multisite, sequence-specific manner and also efficiently promote formation of amyloid-like fibrils. Although RNA binding to a single site induces a small conformational change in TIA-1, this alone does not enhance phase separation of TIA-1. Tandem binding sites are required to enhance phase separation of TIA-1 and this is finely tuned by the protein:binding site stoichiometry rather than nucleic acid length. Native tandem TIA-1 binding sites within the 3' UTR of p53 mRNA also efficiently enhance phase separation of TIA-1 and thus may potentially act as potent nucleation sites for stress granule assembly., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This study employed mesophilic Bacillus subtilis RTS strain isolated from soil with high xylanolytic activity. A 642 bp (xyn) xylanase gene (GenBank accession number MT677937) was extracted from Bacillus subtilis RTS and cloned in Escherichia coli BL21 cells using pET21c expression system. The cloned gene belongs to glycoside hydrolase family 11 with protein size of approximately 23 KDa. The recombinant xylanase showed optimal enzyme activity at 60 °C and at pH 6.5. Thermostability of recombinant xylanase was observed between the temperature range of 30-60 °C. Xylanase also remained stable in different concentration of various organic solvents (ethanol, butanol). This might be due to the formation of protein/organic solvent interface which prevents stripping of essential water molecules from enzyme, thus enzyme conformation and activity remained stable. Finally, the molecular docking analysis through AutoDock Vina showed the involvement of Tyr 108, Arg140 and Pro144 in protein-ligand interaction, which stabilizes this complex. The observed stability of recombinant xylanase at higher temperature and in the presence of organic solvent (ethanol, butanol) suggested possible application of this enzyme in biofuel and other industrial applications., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Eyelid basal cell carcinoma (BCC) is the most common eyelid malignancy. Metabolic reprogramming is critical in tumorigenesis, but the metabolic feature of eyelid BCC remains elusive. In this study, we aim to reveal the metabolic profile in eyelid BCC using targeted metabolomics. Eyelid samples were collected from patients who had removal of BCC and from control patients who underwent blepharoplasty. Multivariate analysis of metabolomics data distinguished the two groups, indicating that eyelid BCC has significantly different metabolome than the healthy tissue. We found 16 increased and 11 decreased metabolites in the BCC tissues. These metabolites were highly enriched in the metabolism of nicotinamide adenine dinucleotide (NAD), glutathione metabolism, polyamine metabolism, and the metabolism of glycine, serine, threonine, arginine and proline. amino acid metabolism. Metabolites from NAD metabolism (Nicotinamide; Nicotinamide riboside; N1-Methylnicotinamide) had the highest sensitivity, specificity, and prediction accuracy in a prediction model for eyelid BCC. In conclusion, eyelid BCC has a signature change of cell metabolome. Metabolites in NAD metabolic pathways could potentially be biomarkers or therapeutic targets for eyelid BCC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Increased tendency of cancer patients to develop venous thromboembolism (VTE) is associated with high rates of mortality. Elevation of procoagulant proteins and down regulation of naturally occurring coagulation inhibitors appears to form the basis of high risk of VTE in malignancy. A reduced level of anticoagulant protein like antithrombin (AT) will influence both coagulation and angiogenesis, as its cleaved and latent conformations show potent antiangiogenic activity. We show a concentration dependent perturbation in the secondary and tertiary structures of AT conformers exposed to hypochlorous acid (HOCl). Modulated under a very narrow concentration range of HOCl, native AT undergoes oligomerization, aggregation and fragmentation based on spectroscopic, SDS and native-PAGE studies. Factor Xa inhibition assay demonstrated a progressive decrease in inhibition activity of AT on modification by HOCl. Bis-ANS result showed that hydrophobic patches were more exposed in the case of HOCl-modified AT when assessed fluorometrically. Dosage of HOCl-modified AT in experimental animals induced high titer antibodies showing more specificity towards modified forms in comparison to unmodified forms. Auto-antibodies isolated from cancer patients also showed enhanced binding with HOCl-modified AT in comparison to native counterpart. Compared to normal AT, structurally and functionally altered conformation of HOCl-modified AT showed increased immunogenic sensitivity. HOCl modified AT can contribute to prothrombotic and angiogenic environment during cancer progression/development., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acetaldehyde is a toxic, mutagenic and carcinogenic metabolite of alcohol which can bind to proteins, DNA and several other cellular macromolecules. Chronic alcohol consumption increases intracellular acetaldehyde levels which enhances the generation of reactive oxygen and nitrogen species (ROS and RNS). In this study, we have examined the effect of acetaldehyde on human erythrocytes under in vitro conditions. Treatment of human erythrocytes with different concentrations of acetaldehyde (0.05-2 mM) for 24 h at 37 °C increased intracellular generation of ROS and RNS. It also increased oxidation of proteins and lipids but decreased glutathione, total sulphhydryl and free amino group content. Methemoglobin level was increased accompanied by a decrease in methemoglobin reductase activity. Acetaldehyde impaired the antioxidant defence system and lowered the total antioxidant capacity of the cell. It decreased the activity of metabolic and membrane-bound enzymes and altered erythrocyte morphology. Our results show that acetaldehyde enhances the generation of ROS and RNS that results in oxidative modification of cellular components. This will lower the oxygen transporting ability of blood and shorten erythrocyte lifespan (red cell senescence).

Acetaldehyde is a metabolite of ethanol, an important constituent of tobacco pyrolysis and the aldehydic product of lipid peroxidation. Acetaldehyde induced toxicity is mainly due to its binding to cellular macromolecules resulting in the formation of stable adducts accompanied by oxidative stress. The aim of this study was to characterize structural and immunological alterations in human immunoglobulin G (IgG) modified with acetaldehyde in the presence of sodium borohydride, a reducing agent. The IgG modifications were studied by various physicochemical techniques such as fluorescence and CD spectroscopy, free amino group estimation, 2,2-azobis 2-amidinopropane (AAPH) induced red blood cell hemolysis as well as transmission electron microscopy. Molecular docking was also employed to predict the preferential binding of acetaldehyde to IgG. The immunogenicity of native and acetaldehyde-modified IgG was investigated by immunizing female New Zealand white rabbits using native and modified IgG as antigens. Binding specificity and cross reactivity of rabbit antibodies was screened by competitive inhibition ELISA and band shift assays. The modification of human IgG with acetaldehyde results in quenching of the fluorescence of tyrosine residues, decrease in free amino group content, a change in the antioxidant property as well as formation of cross-linked structures in human IgG. Molecular docking reveals strong binding of IgG to acetaldehyde. Moreover, acetaldehyde modified IgG induced high titer antibodies (>1:12800) in the experimental animals. The antibodies exhibited high specificity in competitive binding assay toward acetaldehyde modified human IgG. The results indicate that acetaldehyde induces alterations in secondary and tertiary structure of IgG molecule that leads to formation of neo-epitopes on IgG that enhances its immunogenicity., (© 2019 International Union of Biochemistry and Molecular Biology.)

Segmental mandibular defects secondary to infectious, traumatic, and pathologic conditions can be debilitating because of their impact on function and facial esthetics. Several reconstructive techniques are available, with vascularized flaps commonly used for the reconstruction of large bony or composite segmental defects. The free fibular flap for mandibular reconstruction is well documented and remains a commonly used flap because of its bone length, versatility, distant location from the head and neck region that allows for a 2-team approach, and ability to simultaneously place endosseous implants. Virtual surgical planning (VSP) and guided resection and reconstruction of maxillofacial defects have facilitated complex 3-dimensional (3D) reconstruction. The accuracy and fidelity of VSP are dependent on the intraoperative execution of the VSP, with computer-aided design and computer-aided modeling of patient-specific cutting guides and hardware providing a template for its execution. The goal of this report is to describe the authors' experience with the use of a novel 3D printed fixation tray designed from the VSP data. It provides dual functionality by aiding in alignment and stabilization of the fibular segments and concomitantly providing patient-specific anatomic references for indexing of bony and soft tissue components. This tray enables rapid ex vivo configuration of the fibula segment(s) with the reconstruction bar relative to the native mandibular segments and allows the compiled construct to be transferred to the head and neck for insetting as a precisely configured single unit., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Acetaldehyde is a reactive aldehyde produced as an intermediate of alcohol metabolism and tobacco pyrolysis. It has the potential to interact with different biomolecules in various tissues which results in the formation of stable, unstable and covalent adducts. This causes structural and functional modifications that may lead to severe complications such as cancer. This study has probed the structural modifications in human immunoglobulin G (IgG) as a function of different concentrations of acetaldehyde in the presence of reducing agent, sodium borohydride. Acetaldehyde mediated modifications in IgG have been characterised by various physicochemical techniques. UV-spectrophotometry showed that acetaldehyde modified IgG exhibited marked increase in hyperchromicity. Fluorescence studies revealed a significant quenching of tryptophan fluorescence which resulted in loss of β-sheet secondary structure that was confirmed by circular dichroic analysis. Gross structural changes in the morphology of IgG were confirmed by increase in mass and hydrodynamic radius of this glycoprotein along with the appearance of fibrillar structures in modified IgG, when compared to the granular structure of the native form of IgG observed by scanning electron microscope. The results indicate that acetaldehyde causes alterations in the secondary and tertiary structure of the protein leading to diminution of normal function of IgG molecule., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease and mortality. Uncontrolled type 2 diabetes mellitus results in a systemic milieu of increased circulating glucose and fatty acids. The development of insulin resistance in cardiac tissue decreases cellular glucose import and enhances mitochondrial fatty acid uptake. While triacylglycerol and cytotoxic lipid species begin to accumulate in the cardiomyocyte, the energy substrate utilization ratio of free fatty acids to glucose changes to almost entirely free fatty acids. Accumulating evidence suggests a role of miRNA in mediating this metabolic transition. Energy substrate metabolism, apoptosis, and the production and response to excess reactive oxygen species are regulated by miRNA expression. The current momentum for understanding the dynamics of miRNA expression is limited by a lack of understanding of how miRNA expression is controlled. While miRNAs are important regulators in both normal and pathological states, an additional layer of complexity is added when regulation of miRNA regulators is considered. miRNA expression is known to be regulated through a number of mechanisms, which include, but are not limited to, epigenetics, exosomal transport, processing, and posttranscriptional sequestration. The purpose of this review is to outline how mitochondrial processes are regulated by miRNAs in the diabetic heart. Furthermore, we will highlight the regulatory mechanisms, such as epigenetics, exosomal transport, miRNA processing, and posttranslational sequestration, that participate as regulators of miRNA expression. Additionally, current and future treatment strategies targeting dysfunctional mitochondrial processes in the diseased myocardium, as well as emerging miRNA-based therapies, will be summarized.

Hypochlorous acid (HOCl) is generated by activated phagocytes at the site of inflammation. Exposure of DNA to HOCl results in base and nucleotide modifications causing DNA damage, which is one of the leading causes of various pathological conditions including carcinogenesis. In the present work, various biophysical techniques were used to study HOCl induced structural and conformational changes in human placental DNA. The HOCl modified DNA showed hyperchromicity, reduced fluorescence and decrease in melting temperature. Circular dichorism (CD) and Fourier transform infra-red (FT-IR) studies exhibited conformational changes and shift in band positions of DNA, respectively, suggesting structural changes. Agarose gel electrophoresis and scanning electron microscopy showed strand breakage and decreased aggregation. These results suggest that HOCl causes conformational and structural perturbations in mammalian DNA, which may consequentially lead to DNA mutations resulting in perturbation of epigenetic signals leading to cancer and autoimmune diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

TIA-1 (T-cell restricted intracellular antigen-1) is an RNA-binding protein involved in splicing and translational repression. It mainly interacts with RNA via its second and third RNA recognition motifs (RRMs), with specificity for U-rich sequences directed by RRM2. It has recently been shown that RRM3 also contributes to binding, with preferential binding for C-rich sequences. Here we designed UC-rich and CU-rich 10-nt sequences for engagement of both RRM2 and RRM3 and demonstrated that the TIA-1 RRM23 construct preferentially binds the UC-rich RNA ligand (5΄-UUUUUACUCC-3΄). Interestingly, this binding depends on the presence of Lys274 that is C-terminal to RRM3 and binding to equivalent DNA sequences occurs with similar affinity. Small-angle X-ray scattering was used to demonstrate that, upon complex formation with target RNA or DNA, TIA-1 RRM23 adopts a compact structure, showing that both RRMs engage with the target 10-nt sequences to form the complex. We also report the crystal structure of TIA-1 RRM2 in complex with DNA to 2.3 Å resolution providing the first atomic resolution structure of any TIA protein RRM in complex with oligonucleotide. Together our data support a specific mode of TIA-1 RRM23 interaction with target oligonucleotides consistent with the role of TIA-1 in binding RNA to regulate gene expression., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastric cancer is generally associated with poor survival rates and accounts for a remarkable proportion of global cancer mortality. The prevalence of gastric carcinoma varies in different regions of world and across teh various ethnic groups. On the basis of pathological assessment, gastric cancer can be categorized as intestinal and diffuse carcinomas. The etiology is diverse, including chemical carcinogen exposure, and high salt intake Helicobacter pylori also plays a vital role in the pathogenesis of certain gastric carcinomas. The development of gastric cancer involves various alterations in mRNAs, genes (GOLPH3, MTA2) and proteins (Coronins). miRNAs, Hsamir135b, MiR21, miR106b, miR17, miR18a, MiR21, miR106b, miR17, miR18a and MiRNA375, miRNA1955p are the latest diagnostic biomarkers which can facilitate the early diagnosis of gastric carcinomas. Recent development in the treatment strategies for gastric carcinoma include the introduction of monoclonal antibodies, TKI inhibitors, inhibitors of PDGFR β, VEGFR1, VEGFR2, AntiEGFR and antiHER2 agents which can be applied along with conventional therapies.

Aim: The aim of this study was to assess the changes of markers of DNA damage by glycation and oxidation in patients with type 2 diabetes and the association with diabetic nephropathy., Methodology: DNA oxidation and glycation adducts were analysed in plasma and urine by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. DNA markers analysed were as follows: the oxidation adduct 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OxodG) and glycation adducts of glyoxal and methylglyoxal--imidazopurinones GdG, MGdG, and N2-(1,R/S-carboxyethyl)deoxyguanosine (CEdG)., Results: Plasma 8-OxodG and GdG were increased 2-fold and 6-fold, respectively, in patients with type 2 diabetes, with respect to healthy volunteers. Median urinary excretion rates of 8-OxodG, GdG, MGdG, and CEdG were increased 28-fold, 10-fold, 2-fold, and 2-fold, respectively, in patients with type 2 diabetes with respect to healthy controls. In patients with type 2 diabetes, nephropathy was associated with increased plasma 8-OxodG and increased urinary GdG and CEdG. In a multiple logistic regression model for diabetic nephropathy, diabetic nephropathy was linked to systolic blood pressure and urinary CEdG., Conclusion: DNA oxidative and glycation damage-derived nucleoside adducts are increased in plasma and urine of patients with type 2 diabetes and further increased in patients with diabetic nephropathy.

Stress granule (SG) formation is a primary mechanism through which gene expression is rapidly modulated when the eukaryotic cell undergoes cellular stresses (including heat, oxidative, viral infection, starvation). In particular, the sequestration of specifically targeted translationally stalled mRNAs into SGs limits the expression of a subset of genes, but allows the expression of heatshock proteins that have a protective effect in the cell. The importance of SGs is seen in several disease states in which SG function is disrupted. Fundamental to SG formation are the T cell restricted intracellular antigen (TIA) proteins (TIA-1 and TIA-1 related protein (TIAR)), that both directly bind to target RNA and self-associate to seed the formation of SGs. Here a summary is provided of the current understanding of the way in which TIA proteins target specific mRNA, and how TIA self-association is triggered under conditions of cellular stress.

The spindle assembly checkpoint (SAC) is a conserved mechanism that ensures the fidelity of chromosome distribution in mitosis by preventing anaphase onset until the correct bipolar microtubule-kinetochore attachments are formed. Errors in SAC function may contribute to tumorigenesis by inducing numerical chromosome anomalies (aneuploidy). On the other hand, total disruption of SAC can lead to massive genomic imbalance followed by cell death, a phenomena that has therapeutic potency. We performed a cell-based high-throughput screen with a compound library of 2000 bioactives for novel SAC inhibitors and discovered a plant-derived phenolic compound eupatorin (3',5-dihydroxy-4',6,7-trimethoxyflavone) as an anti-mitotic flavonoid. The premature override of the microtubule drug-imposed mitotic arrest by eupatorin is dependent on microtubule-kinetochore attachments but not interkinetochore tension. Aurora B kinase activity, which is essential for maintenance of normal SAC signaling, is diminished by eupatorin in cells and in vitro providing a mechanistic explanation for the observed forced mitotic exit. Eupatorin likely has additional targets since eupatorin treatment of pre-mitotic cells causes spindle anomalies triggering a transient M phase delay followed by impaired cytokinesis and polyploidy. Finally, eupatorin potently induces apoptosis in multiple cancer cell lines and suppresses cancer cell proliferation in organotypic 3D cell culture model., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Glyoxal and methylglyoxal are reactive dicarbonyl metabolites formed and metabolized in physiological systems. Increased exposure to these dicarbonyls is linked to mutagenesis and cytotoxicity and enhanced dicarbonyl metabolism by overexpression of glyoxalase 1 is linked to tumour multidrug resistance in cancer chemotherapy. We report herein that glycation of DNA by glyoxal and methylglyoxal produces a quantitatively important class of nucleotide adduct in physiological systems-imidazopurinones. The adduct derived from methylglyoxal-3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one isomers-was the major quantitative adduct detected in mononuclear leukocytes in vivo and tumour cell lines in vitro. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell permeable glyoxalase 1 inhibitor. Unexpectedly, the DNA content of methylglyoxal-derived imidazopurinone and oxidative marker 7,8-dihydro-8-oxo-2'-deoxyguanosine were increased moderately in glyoxalase 1-linked multidrug resistant tumour cell lines. Together these findings suggest that imidazopurinones are a major type of endogenous DNA damage and glyoxalase 1 overexpression in tumour cells strives to counter increased imidazopurinone formation in tumour cells likely linked to their high glycolytic activity.

To identify a novel amplified cancer gene a systematic screen of 975 human cancer DNA samples, 750 cell lines and 225 primary tumors, using the Affymetrix 10K SNP microarray was undertaken. The screen identified 193 amplicons. A previously uncharacterized amplicon located on 6p21.2 whose 1 Mb minimal common amplified region contained eight genes (GLO1, DNAH8, GLP1R, C6orf64, KCNK5, KCNK17, KCNK16, and C6orf102) was further investigated to determine which gene(s) are the biological targets of this amplicon. Real time quantitative PCR (qPCR) analysis of all amplicon 6p21.2 genes in 618 human cancer cell lines identified GLO1, encoding glyoxalase 1, to be the most frequently amplified gene [twofold or greater amplification in 8.4% (49/536) of cancers]. Also the association between amplification and overexpression was greatest for GLO1. RNAi knockdown of GLO1 had the greatest and most consistent impact on cell accumulation and apoptosis. Cell lines with GLO1 amplification were more sensitive to inhibition of GLO1 by bromobenzylglutathione cyclopentyl diester (BBGC). Subsequent qPCR of 520 primary tumor samples identified twofold and greater amplification of GLO1 in 8/37 (22%) of breast, 12/71 (17%) of sarcomas, 6/53 (11.3%) of nonsmall cell lung, 2/23 (8.7%) of bladder, 6/93 (6.5%) of renal and 5/83 (6%) of gastric cancers. Amplification of GLO1 was rare in colon cancer (1/35) and glioma (1/94). Collectively the results indicate that GLO1 is at least one of the targets of gene amplification on 6p21.2 and may represent a useful target for therapy in cancers with GLO1 amplification.

Nucleobases and DNA react non-enzymatically with sugars, and generate DNA-advanced glycation end products (DNA-AGEs). Incubation of plasmid pBr322 with ribose for 3-7 days caused the transformation of the supercoiled plasmid to the open circular and linear forms. Removal of sugar after an initial 24 h incubation resulted in marked enhancement in the transformation rate. Enhancement in transformation was also observed when bovine serum albumin (BSA) exposed to ribose for short durations was incubated with plasmid in absence of the sugar. The effect on DNA was attenuated when excess ribose remained in the incubation mixture of ribose and protein. The data suggested that an increase in ribose concentration in the vicinity of DNA could be damaging and the damage exacerbated, if sugar levels fell subsequently. Incubation of herring sperm DNA with ribose resulted in a concentration and time-dependent increase of N2-carboxyethyl-2'-deoxyguanosine (CEdGA,B). The concentration of CEdGA,B, however, did not increase further when ribose was removed from the reaction mixture.

Objective: To confirm or refute the validity of the fear associated with anal sphincterotomy for anal fissure, particularly when performed with other anorectal procedures., Design: Descriptive study., Place and Duration of Study: Surgical Wings - Medicare Hospital and Fatima Medical Center, Multan, over a period of 8 years from January 1994 to December 2001., Subjects and Methods: Records of 112 anal fissure patients, 46 (41.0%) males and 66 (58.9%) females, ranging in age from 12-95 years (mean 39) were studied. All patients with acute or chronic anal fissures with or without other anorectal pathologies were included. Seventeen patients who had anal dilatation and 2 recurrent fissures were excluded. Open technique of anal sphincterotomy was employed in all cases. Results were recorded and analyzed., Results: Fissures were acute in 16 (14.2 %) and chronic in 96 (85.7 %) patients. Anterior fissure was present in 20 (17.8%), posterior in 80 (71.4%), both in 9 (8.0%) and lateral or multiple fissures in 3 (2.6%) cases. Commonest associated pathology was haemorrhoids; encountered in 64 (57.1%) patients. Minor complications, taken together, occurred in 20 (17.8%) patients. Urinary retention was seen in 3 (2.6%) with lateral internal anal sphincterotomy (LIAS), and in 6 (5.3%) where haemorrhoidectomy was added. Haemorrhage in 2 (1.7%), temporary loss of flatus control in 3(2.6%) and soiling of clothes in 2 (1.7%) patients was encountered. No permanent loss of flatus or faecal control and recurrence has been reported to-date., Conclusion: Anal sphincterotomy with or without other anorectal procedures can be safely practiced in properly selected patients. Postoperatively, ablution with mild antiseptic added to plain water is adequate in maintaining hygiene to promote healing.