83 results on '"Magesh S"'
Search Results
52. Synthesis, Characterization and Antimicrobial Activity of 4-Phenyl-3-thiopyrimido[4,5-b]quinolines (III).
- Author
-
Suresh, T., primary, Kumar, R. Nandha, additional, Magesh, S., additional, and Mohan, P. S., additional
- Published
- 2003
- Full Text
- View/download PDF
53. Synthesis of Novel Benzopyranopyranopyrimidines and Benzopyranopyranothiopyrimidines.
- Author
-
Kumar, R. Nandha, primary, Suresh, T., additional, Magesh, S., additional, and Mohan, P. S., additional
- Published
- 2003
- Full Text
- View/download PDF
54. A flexible resampling mechanism for parallel particle filters.
- Author
-
Sangjin Hong, Shu-Shin Chin, and Magesh, S.
- Published
- 2003
- Full Text
- View/download PDF
55. Rapid Generation of Multiple Loci-Engineered Marker-free Poxvirus and Characterization of a Clinical-Grade Oncolytic Vaccinia Virus
- Author
-
Zong Sheng Guo, Zuqiang Liu, Magesh Sathaiah, Jiahu Wang, Roshni Ravindranathan, Eun Kim, Shaohua Huang, Thomas W. Kenniston, John C. Bell, Herbert J. Zeh, III, Lisa H. Butterfield, Andrea Gambotto, and David L. Bartlett
- Subjects
vaccinia virus ,oncolytic virus ,vaccine ,cancer ,method ,marker-free poxvirus ,clinical grade ,immunotherapy ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Recombinant poxviruses, utilized as vaccine vectors and oncolytic viruses, often require manipulation at multiple genetic loci in the viral genome. It is essential for viral vectors to possess no adventitious mutations and no (antibiotic) selection marker in the final product for human patients in order to comply with the guidance from the regulatory agencies. Rintoul et al. have previously developed a selectable and excisable marker (SEM) system for the rapid generation of recombinant vaccinia virus. In the current study, we describe an improved methodology for rapid creation and selection of recombinant poxviruses with multiple genetic manipulations solely based on expression of a fluorescent protein and with no requirement for drug selection that can lead to cellular stress and the risk of adventitious mutations throughout the viral genome. Using this improved procedure combined with the SEM system, we have constructed multiple marker-free oncolytic poxviruses expressing different cytokines and other therapeutic genes. The high fidelity of inserted DNA sequences validates the utility of this improved procedure for generation of therapeutic viruses for human patients. We have created an oncolytic poxvirus expressing human chemokine CCL5, designated as vvDD-A34R-hCCL5, with manipulations at two genetic loci in a single virus. Finally, we have produced and purified this virus in clinical grade for its use in a phase I clinical trial and presented data on initial in vitro characterization of the virus.
- Published
- 2017
- Full Text
- View/download PDF
56. Preparation and thermal energy storage behaviour of stearic acid–TiO2 nanofluids as a phase change material for solar heating systems.
- Author
-
Harikrishnan, S., Magesh, S., and Kalaiselvam, S.
- Subjects
- *
HEAT storage , *STEARIC acid , *TITANIUM dioxide , *NANOFLUIDS , *PHASE change materials , *SOLAR heating - Abstract
Highlights: [•] Composite PCMs have exhibited enhanced heat transfer performance during energy storage and release processes. [•] Effective TiO2 nanoparticles dispersed into stearic acid have accelerated the melting and solidification rates of composite PCMs. [•] Higher thermal conductivities were observed in composite PCMs while comparing to base material. [•] Better thermal stability was achieved in composite PCMs for long-term utility period. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
57. An outbreak of food poisoning in Tamil Nadu associated with Yersinia enterocolitica
- Author
-
Abraham, M., Pai, M., Kang, G., Asokan GV, Magesh, S. R., Bhattacharji, S., and Ramakrishna, B. S.
58. A Fatal Case of Nafcillin-Induced Hepatotoxicity: A Case Report and the Literature Review
- Author
-
Mian Bilal Alam, Amin Kadoura, and Magesh Sathaiah
- Subjects
Medicine - Abstract
Background. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8 mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative.
- Published
- 2012
- Full Text
- View/download PDF
59. Co-zorbs: Motile, multispecies biofilms aid transport of diverse bacterial species.
- Author
-
Magesh S, Schrope JH, Soto NM, Li C, Hurley AI, Huttenlocher A, Beebe DJ, and Handelsman J
- Abstract
Biofilms are three-dimensional structures containing one or more bacterial species embedded in extracellular polymeric substances. Although most biofilms are stationary, Flavobacterium johnsoniae forms a motile spherical biofilm called a zorb, which is propelled by its base cells and contains a polysaccharide core. Here, we report formation of spatially organized, motile, multispecies biofilms, designated "co-zorbs," that are distinguished by a core-shell structure. F. johnsoniae forms zorbs whose cells collect other bacterial species and transport them to the zorb core, forming a co-zorb. Live imaging revealed that co-zorbs also form in zebrafish, thereby demonstrating a new type of bacterial movement in vivo. This discovery opens new avenues for understanding community behaviors, the role of biofilms in bulk bacterial transport, and collective strategies for microbial success in various environments.
- Published
- 2024
- Full Text
- View/download PDF
60. The intratumor microbiome varies by geographical location and anatomical site in head and neck squamous cell carcinoma.
- Author
-
Yalamarty R, Magesh S, John D, Chakladar J, Li WT, Brumund KT, Wang-Rodriguez J, and Ongkeko WM
- Subjects
- Humans, Tumor Microenvironment, Squamous Cell Carcinoma of Head and Neck microbiology, Squamous Cell Carcinoma of Head and Neck pathology, Head and Neck Neoplasms microbiology, Head and Neck Neoplasms pathology, Microbiota
- Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly heterogeneous cancer that is characterized by distinct phenotypes based on anatomical site and etiological agents. Recently, the intratumor microbiome has been implicated in cancer pathogenesis and progression. Although it is well established that the gut microbiome varies with geographical location and is highly influenced by factors such as diet, environment, and genetics, the intratumor microbiome is not very well characterized. In this review, we aim to characterize the HNSCC intratumor microbiome by geographical location and anatomical site. We conducted a review of primary literature from PubMed and assessed studies based on relevancy and recency. To the best of our knowledge, we are the first to comprehensively examine the tumor microenvironment of HNSCC with respect to these two primary factors on a large scale. Our results suggest that there are unique bacterial and fungal biomarkers for HNSCC for each of the following geographical locations: North America, Asia, Europe, Australia, and Africa. We also identified a panel of microbial biomarkers that are unique to two primary HNSCC anatomic sites, as well as microbial biomarkers associated with various etiological agents of HNSCC. Future study of these microbes may improve HNSCC diagnostic and therapeutic modalities by accounting for differences based on geographic regions and anatomical sites., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was funded by the University of California Academic Senate San Diego Division [RG104647] to Weg M. Ongkeko., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
61. Surface colonization by Flavobacterium johnsoniae promotes its survival in a model microbial community.
- Author
-
Magesh S, Hurley AI, Nepper JF, Chevrette MG, Schrope JH, Li C, Beebe DJ, and Handelsman J
- Subjects
- Humans, Sand, Flavobacterium genetics, Bacterial Proteins metabolism, Health Promotion, Microbiota
- Abstract
Flavobacterium johnsoniae is a ubiquitous soil and rhizosphere bacterium, but despite its abundance, the factors contributing to its success in communities are poorly understood. Using a model microbial community, T he H itchhikers o f the R hizosphere (THOR), we determined the effects of colonization on the fitness of F. johnsoniae in the community. Insertion sequencing, a massively parallel transposon mutant screen, on sterile sand identified 25 genes likely to be important for surface colonization. We constructed in-frame deletions of candidate genes predicted to be involved in cell membrane biogenesis, motility, signal transduction, and transport of amino acids and lipids. All mutants poorly colonized sand, glass, and polystyrene and produced less biofilm than the wild type, indicating the importance of the targeted genes in surface colonization. Eight of the nine colonization-defective mutants were also unable to form motile biofilms or zorbs, thereby suggesting that the affected genes play a role in group movement and linking stationary and motile biofilm formation genetically. Furthermore, we showed that the deletion of colonization genes in F. johnsoniae affected its behavior and survival in THOR on surfaces, suggesting that the same traits are required for success in a multispecies microbial community. Our results provide insight into the mechanisms of surface colonization by F. johnsoniae and form the basis for further understanding its ecology in the rhizosphere., Importance: Microbial communities direct key environmental processes through multispecies interactions. Understanding these interactions is vital for manipulating microbiomes to promote health in human, environmental, and agricultural systems. However, microbiome complexity can hinder our understanding of the underlying mechanisms in microbial community interactions. As a first step toward unraveling these interactions, we explored the role of surface colonization in microbial community interactions using T he H itchhikers O f the R hizosphere (THOR), a genetically tractable model community of three bacterial species, Flavobacterium johnsoniae , Pseudomonas koreensis , and Bacillus cereus . We identified F. johnsoniae genes important for surface colonization in solitary conditions and in the THOR community. Understanding the mechanisms that promote the success of bacteria in microbial communities brings us closer to targeted manipulations to achieve outcomes that benefit agriculture, the environment, and human health., Competing Interests: David J. Beebe holds equity in Bellbrook Labs LLC, Tasso Inc., Salus Discovery LLC, Lynx Biosciences Inc., Stacks to the Future LLC, Flambeau Diagnostics LLC, and Onexio Biosystems LLC. Jo Handelsman holds equity in Wacasa Inc. and Ascribe, Inc.
- Published
- 2024
- Full Text
- View/download PDF
62. Antioxidant and Antidiabetic Potential of Ormocarpum cochinchinense (Lour.) Merr. Leaf: An Integrated In vitro and In silico Approach.
- Author
-
Katturajan R, Shivaji P, Nithiyanandam S, Parthasarathy M, Magesh S, Vashishth R, Radhakrishnan V, and Prince SE
- Subjects
- Glycoside Hydrolase Inhibitors pharmacology, Glycoside Hydrolase Inhibitors chemistry, alpha-Glucosidases metabolism, Methanol, Molecular Docking Simulation, Plant Extracts chemistry, alpha-Amylases metabolism, Plant Leaves metabolism, Inositol pharmacology, Hypoglycemic Agents pharmacology, Hypoglycemic Agents chemistry, Antioxidants pharmacology, Antioxidants chemistry
- Abstract
Diabetes is a prevalent metabolic disorder associated with various complications. Inhibition of α-glucosidase and α-amylase enzymes is an effective strategy for managing non-insulin-dependent diabetes mellitus. This study aimed to investigate the antioxidant and antidiabetic potential of Ormocarpum cochinchinense leaf through in vitro and in silico approaches. The methanol extract exhibited the highest phenolic and flavonoid content over solvent extracts aqueous, acetone, hexane, and chloroform, the same has been correlating with strong antioxidant activity. Furthermore, the methanol extract demonstrated significant inhibitory effects on α-amylase and α-glucosidase enzymes, indicating its potential as an antidiabetic agent. Molecular docking analysis identified compounds, including myo-inositol, with favorable binding energies comparable to the standard drug metformin. The selected compounds displayed strong binding affinity towards α-amylase and α-glucosidase enzymes. Structural dynamics analysis revealed that myo-inositol formed a more stable complex with the enzymes. These findings suggest that O. cochinchinense leaf possesses antioxidant and antidiabetic properties, making it a potential source for developing therapeutic agents., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)
- Published
- 2024
- Full Text
- View/download PDF
63. Characterization of tRNA-Derived Fragments in Lung Squamous Cell Carcinoma with Respect to Tobacco Smoke.
- Author
-
Magesh S, Gande P, Yalamarty R, John D, Chakladar J, Li WT, and Ongkeko WM
- Subjects
- Humans, RNA, Transfer genetics, Lung, Tobacco Smoke Pollution, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell genetics, Lung Neoplasms genetics
- Abstract
Lung squamous cell carcinoma (LUSC) is a highly heterogeneous cancer that is influenced by etiological agents such as tobacco smoke. Accordingly, transfer RNA-derived fragments (tRFs) are implicated in both cancer onset and development and demonstrate the potential to act as targets for cancer treatments and therapies. Therefore, we aimed to characterize tRF expression with respect to LUSC pathogenesis and clinical outcomes. Specifically, we analyzed the effect of tobacco smoke on tRF expression. In order to do so, we extracted tRF read counts from MINTbase v2.0 for 425 primary tumor samples and 36 adjacent normal samples. We analyzed the data in three primary cohorts: (1) all primary tumor samples (425 samples), (2) smoking-induced LUSC primary tumor samples (134 samples), and (3) non-smoking-induced LUSC primary tumor samples (18 samples). Differential expression analysis was performed to examine tRF expression in each of the three cohorts. tRF expression was correlated to clinical variables and patient survival outcomes. We identified unique tRFs in primary tumor samples, smoking-induced LUSC primary tumor samples, and non-smoking-induced LUSC primary tumor samples. In addition, many of these tRFs demonstrated correlations to worse patient survival outcomes. Notably, tRFs in the smoking-induced LUSC and non-smoking-induced LUSC primary tumor cohorts were significantly correlated to clinical variables pertaining to cancer stage and treatment efficacy. We hope that our results will be used to better inform future LUSC diagnostic and therapeutic modalities.
- Published
- 2023
- Full Text
- View/download PDF
64. The Intratumor Bacterial and Fungal Microbiome Is Characterized by HPV, Smoking, and Alcohol Consumption in Head and Neck Squamous Cell Carcinoma.
- Author
-
Chakladar J, John D, Magesh S, Uzelac M, Li WT, Dereschuk K, Apostol L, Brumund KT, Rodriguez JW, and Ongkeko WM
- Subjects
- Humans, Squamous Cell Carcinoma of Head and Neck complications, Papillomaviridae genetics, Smoking adverse effects, Alcohol Drinking adverse effects, Papillomavirus Infections, Head and Neck Neoplasms complications, Mycobiome
- Abstract
Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.
- Published
- 2022
- Full Text
- View/download PDF
65. Microbiome composition modulates secondary metabolism in a multispecies bacterial community.
- Author
-
Chevrette MG, Thomas CS, Hurley A, Rosario-Meléndez N, Sankaran K, Tu Y, Hall A, Magesh S, and Handelsman J
- Subjects
- Anti-Bacterial Agents, Benzamides, Humans, Secondary Metabolism, Microbiota, Siderophores genetics, Siderophores metabolism
- Abstract
Bacterial secondary metabolites are a major source of antibiotics and other bioactive compounds. In microbial communities, these molecules can mediate interspecies interactions and responses to environmental change. Despite the importance of secondary metabolites in human health and microbial ecology, little is known about their roles and regulation in the context of multispecies communities. In a simplified model of the rhizosphere composed of Bacillus cereus , Flavobacterium johnsoniae , and Pseudomonas koreensis , we show that the dynamics of secondary metabolism depend on community species composition and interspecies interactions. Comparative metatranscriptomics and metametabolomics reveal that the abundance of transcripts of biosynthetic gene clusters (BGCs) and metabolomic molecular features differ between monocultures or dual cultures and a tripartite community. In both two- and three-member cocultures, P. koreensis modified expression of BGCs for zwittermicin, petrobactin, and other secondary metabolites in B. cereus and F. johnsoniae, whereas the BGC transcriptional response to the community in P. koreensis itself was minimal. Pairwise and tripartite cocultures with P. koreensis displayed unique molecular features that appear to be derivatives of lokisin, suggesting metabolic handoffs between species. Deleting the BGC for koreenceine, another P. koreensis metabolite, altered transcript and metabolite profiles across the community, including substantial up-regulation of the petrobactin and bacillibactin BGCs in B. cereus , suggesting that koreenceine represses siderophore production. Results from this model community show that bacterial BGC expression and chemical output depend on the identity and biosynthetic capacity of coculture partners, suggesting community composition and microbiome interactions may shape the regulation of secondary metabolism in nature.
- Published
- 2022
- Full Text
- View/download PDF
66. Roles of YAP/TAZ in ferroptosis.
- Author
-
Magesh S and Cai D
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Humans, Phosphoproteins metabolism, Signal Transduction, Trans-Activators metabolism, Transcriptional Coactivator with PDZ-Binding Motif Proteins, YAP-Signaling Proteins, Ferroptosis
- Abstract
Ferroptosis is a unique iron-dependent form of regulated cell death. Recently, researchers found that ferroptosis was sensitive to cell density, regulated by Hippo signaling. This article summarizes the roles of the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in ferroptosis and the therapeutic potential of activating ferroptosis in cancer., Competing Interests: Declaration of interests D.C. is a consultant of Faze Medicines Inc., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
67. Disparities in COVID-19 Outcomes by Race, Ethnicity, and Socioeconomic Status: A Systematic-Review and Meta-analysis.
- Author
-
Magesh S, John D, Li WT, Li Y, Mattingly-App A, Jain S, Chang EY, and Ongkeko WM
- Subjects
- COVID-19 epidemiology, Humans, Outcome Assessment, Health Care methods, Prevalence, Racial Groups ethnology, Racial Groups statistics & numerical data, United States epidemiology, United States ethnology, COVID-19 ethnology, COVID-19 mortality, Outcome Assessment, Health Care statistics & numerical data, Social Class
- Abstract
Importance: COVID-19 has disproportionately affected racial and ethnic minority groups, and race and ethnicity have been associated with disease severity. However, the association of socioeconomic determinants with racial disparities in COVID-19 outcomes remains unclear., Objective: To evaluate the association of race and ethnicity with COVID-19 outcomes and to examine the association between race, ethnicity, COVID-19 outcomes, and socioeconomic determinants., Data Sources: A systematic search of PubMed, medRxiv, bioRxiv, Embase, and the World Health Organization COVID-19 databases was performed for studies published from January 1, 2020, to January 6, 2021., Study Selection: Studies that reported data on associations between race and ethnicity and COVID-19 positivity, disease severity, and socioeconomic status were included and screened by 2 independent reviewers. Studies that did not have a satisfactory quality score were excluded. Overall, less than 1% (0.47%) of initially identified studies met selection criteria., Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Associations were assessed using adjusted and unadjusted risk ratios (RRs) and odds ratios (ORs), combined prevalence, and metaregression. Data were pooled using a random-effects model., Main Outcomes and Measures: The main measures were RRs, ORs, and combined prevalence values., Results: A total of 4 318 929 patients from 68 studies were included in this meta-analysis. Overall, 370 933 patients (8.6%) were African American, 9082 (0.2%) were American Indian or Alaska Native, 101 793 (2.4%) were Asian American, 851 392 identified as Hispanic/Latino (19.7%), 7417 (0.2%) were Pacific Islander, 1 037 996 (24.0%) were White, and 269 040 (6.2%) identified as multiracial and another race or ethnicity. In age- and sex-adjusted analyses, African American individuals (RR, 3.54; 95% CI, 1.38-9.07; P = .008) and Hispanic individuals (RR, 4.68; 95% CI, 1.28-17.20; P = .02) were the most likely to test positive for COVID-19. Asian American individuals had the highest risk of intensive care unit admission (RR, 1.93; 95% CI, 1.60-2.34, P < .001). The area deprivation index was positively correlated with mortality rates in Asian American and Hispanic individuals (P < .001). Decreased access to clinical care was positively correlated with COVID-19 positivity in Hispanic individuals (P < .001) and African American individuals (P < .001)., Conclusions and Relevance: In this study, members of racial and ethnic minority groups had higher risks of COVID-19 positivity and disease severity. Furthermore, socioeconomic determinants were strongly associated with COVID-19 outcomes in racial and ethnic minority populations.
- Published
- 2021
- Full Text
- View/download PDF
68. Tobacco Smoke and Electronic Cigarette Vapor Alter Enhancer RNA Expression That Can Regulate the Pathogenesis of Lung Squamous Cell Carcinoma.
- Author
-
Tsai JC, Saad OA, Magesh S, Xu J, Lee AC, Li WT, Chakladar J, Fuster MM, Chang EY, Wang-Rodriguez J, and Ongkeko WM
- Abstract
Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level.
- Published
- 2021
- Full Text
- View/download PDF
69. The intratumor microbiome predicts prognosis across gender and subtypes in papillary thyroid carcinoma.
- Author
-
Gnanasekar A, Castaneda G, Iyangar A, Magesh S, Perez D, Chakladar J, Li WT, Bouvet M, Chang EY, and Ongkeko WM
- Abstract
While the intratumor microbiome has become increasingly implicated in cancer development, the microbial landscape of papillary thyroid carcinoma (PTC) is essentially uninvestigated. PTC is characterized by varied prognosis between gender and cancer subtype, but the cause for gender and subtype-based dissimilarities is unclear. Women are more frequently diagnosed with PTC, while men suffer more advanced-staged PTC. In addition, tall cell variants are more aggressive than classical and follicular variants of PTC. We hypothesized that intratumor microbiome composition distinctly alters the immune landscape and predicts clinical outcome between PTC subtypes and between patient genders. Raw whole-transcriptome RNA-sequencing, Level 3 normalized mRNA expression read counts, and DNA methylation 450 k sequencing data for untreated, nonirradiated tumor, and adjacent normal tissue were downloaded from the Genomic Data Commons (GDC) legacy archive for 563 thyroid carcinoma patients. Microbe counts were extracted using Pathoscope 2.0 software. We correlated microbe abundance to clinical variables and immune-associated gene expression. Gene-set enrichment, mutation, and methylation analyses were conducted to correlate microbe abundance to characterize microbes' roles. Overall, PTC tumor tissue significantly lacked microbes that are populated in adjacent normal tissue, which suggests presence of microbes may be critical in controlling immune cell expression and regulating immune and cancer pathways to mitigate cancer growth. In contrast, we also found that microbes distinctly abundant in tall cell and male patient cohorts were also correlated with higher mutation expression and methylation of tumor suppressors. Microbe dysbiosis in specific PTC types may explain observable differences in PTC progression and pathogenesis. These microbes provide a basis for developing specialized prebiotic and probiotic treatments for varied PTC tumors., Competing Interests: 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., (© 2021 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)
- Published
- 2021
- Full Text
- View/download PDF
70. Antioxidant Potential of Naringenin Helps to Protect Liver Tissue from Streptozotocin-Induced Damage.
- Author
-
Rashmi R, Bojan Magesh S, Mohanram Ramkumar K, Suryanarayanan S, and Venkata SubbaRao M
- Abstract
Background: Naringenin is a bioactive flavonoid found in grapes and citrus fruits including tangelo, blood orange, lemons, and tangerines. The aims of this study were to investigate the ability of naringenin to scavenge free radicals and determine its ability to protect animals from streptozotocin (STZ) -induced liver damage., Methods: The free radical-scavenging activity of naringenin was evaluated by in vitro cell-free assay systems. In animals, the antioxidant potential of orally administered 50 and 100 mg/kg body weight naringenin for 45 days was assessed by measuring TBARS, lipid hydroperoxides, SOD, catalase, GST, GPx, and glutathione levels in liver homogenates prepared from animals injected intraperitoneally with multiple low dose streptozotocin at 50 mg/kg for five consecutive days. The extent of cellular damage caused by STZ administration was analyzed using H & E staining., Results: Naringenin showed potent free radical scavenging activity in vitro. Naringenin effectively neutralized (a) hydroxyl radicals, (b) superoxide, (c) hydrogen peroxide, (d) nitric oxide radical, (e) DPPH, and (f) lipid peroxidation. In animals, administration of naringenin reduced lipid peroxidation and increased antioxidant levels. Analysis of liver sections showed the restoration of normal morphology upon treatment with naringenin., Conclusion: Naringenin helps to mitigate STZ-induced liver complications by promoting antioxidant defence enzyme activities and increasing glutathione levels.
- Published
- 2018
71. Enantiomeric characterization and structure elucidation of LH601A using vibrational circular dichroism spectroscopy.
- Author
-
Shen J, Magesh S, Chen L, Hu L, and He Y
- Abstract
LH601A is a novel non-reactive chiral molecule inhibiting Keap1-Nrf2 protein-protein interaction. The absolute configuration (AC) was independently determined in this study using vibrational circular dichroism (VCD) spectroscopy. Because of band overlapping and broadening in the IR spectrum, a direct VCD spectrum comparison method is devised without the conventional IR band alignment. Being an unbiased AC inquiry, all possible chiralities are evaluated based on the statistical analysis of VCD similarity, S
v . The AC of three-center stereoisomer LH601A is unambiguously assigned to (S,R,S). A comparative study was also carried out to investigate the structural and energy differences of calculated conformers using the polarized continuum model of dimethyl sulfoxide., (Copyright © 2017. Published by Elsevier B.V.)- Published
- 2018
- Full Text
- View/download PDF
72. The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo.
- Author
-
Hyun SW, Liu A, Liu Z, Cross AS, Verceles AC, Magesh S, Kommagalla Y, Kona C, Ando H, Luzina IG, Atamas SP, Piepenbrink KH, Sundberg EJ, Guang W, Ishida H, Lillehoj EP, and Goldblum SE
- Subjects
- Animals, Bacterial Proteins genetics, Bacterial Proteins metabolism, Cathepsin A genetics, Cathepsin A metabolism, Cell Movement drug effects, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells enzymology, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Endothelium, Vascular enzymology, Epithelial Cells cytology, Epithelial Cells drug effects, Epithelial Cells enzymology, Fibroblasts cytology, Fibroblasts drug effects, Fibroblasts enzymology, Flagellin antagonists & inhibitors, Flagellin pharmacology, Gene Expression Regulation, Humans, Hydrolysis, Isoenzymes antagonists & inhibitors, Isoenzymes genetics, Isoenzymes metabolism, Lung cytology, Lung enzymology, Mice, Models, Molecular, Mucin-1 genetics, Mucin-1 metabolism, N-Acetylneuraminic Acid analogs & derivatives, N-Acetylneuraminic Acid chemistry, Neuraminidase genetics, Neuraminidase metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Domains, Protein Interaction Domains and Motifs, Pseudomonas aeruginosa chemistry, Enzyme Inhibitors pharmacology, Lung drug effects, Mucin-1 chemistry, N-Acetylneuraminic Acid pharmacology, Neuraminidase antagonists & inhibitors
- Abstract
Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the β-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
73. A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1-N9 Neuraminidases: Insight into Neuraminidase-Inhibitor Interactions.
- Author
-
Sriwilaijaroen N, Magesh S, Imamura A, Ando H, Ishida H, Sakai M, Ishitsubo E, Hori T, Moriya S, Ishikawa T, Kuwata K, Odagiri T, Tashiro M, Hiramatsu H, Tsukamoto K, Miyagi T, Tokiwa H, Kiso M, and Suzuki Y
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Chickens, Dogs, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Madin Darby Canine Kidney Cells, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Neuraminidase metabolism, Orthomyxoviridae growth & development, Structure-Activity Relationship, Virus Replication drug effects, Antiviral Agents pharmacology, Enzyme Inhibitors pharmacology, Neuraminidase antagonists & inhibitors, Orthomyxoviridae drug effects
- Abstract
People throughout the world continue to be at risk for death from influenza A virus, which is always creating a new variant. Here we present a new effective and specific anti-influenza viral neuraminidase (viNA) inhibitor, 9-cyclopropylcarbonylamino-4-guanidino-Neu5Ac2en (cPro-GUN). Like zanamivir, it is highly effective against N1-N9 avian and N1-N2 human viNAs, including H274Y oseltamivir-resistant N1 viNA, due to its C-6 portion still being anchored in the active site, different from the disruption of oseltamivir's C-6 anchoring by H274Y mutation. Unlike zanamivir, no sialidase inhibitory activity has been observed for cPro-GUN against huNeu1-huNeu4 enzymes. Broad efficacy of cPro-GUN against avian and human influenza viruses in cell cultures comparable to its sialidase inhibitory activities makes cPro-GUN ideal for further development for safe therapeutic or prophylactic use against both seasonal and pandemic influenza.
- Published
- 2016
- Full Text
- View/download PDF
74. Insilico docking study of compounds elucidated from helicteres isora fruits with ampkinase- insulin receptor.
- Author
-
Vennila S, Bupesh G, Saravanamurali K, SenthilKumar V, SenthilRaja R, Saran N, and Magesh S
- Abstract
Insulin receptor (IR) proteins were essential intracellular signaling peptides in the insulin action cascade. Insulin receptor substrate proteins (IRS-1and IRS-2) serve and regulate the insulin level in the normal insulin action. The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing. Such type of proteins were cyclic adenosine monophosphate-activated protein kinase, this proteins play a key role in the insulin response and regulation. Type -2 Diabetes mellitus occurs during prolonged periods of peripheral insulin resistance due to inactivation of IRS proteins. The compounds isolated from the medicinal plants were safer than synthetic drugs and possess high bio activity. In the present study, four compounds were elucidated from fruits of Helicteres isora. The elucidated compounds were evaluated for the antidiabetic activity using in silico docking study. The receptor was analyzed for the active site and pocket finder tools. The aminoacids such as Phenylalanine, Lysine, Glutamic acid and Asparigine were predicted as active site binding residues. Docking studies were done through Autodock 4 software. All the compounds from fruits of Helicteres isora showed good docking profiles with AMP Kinase, except compound-3 (1,2,3,4-tetrahydro-1,5,6,8-tetramethyl-7-(2-methylprop-1-enylnaphthalene-4-ylpivalate). Finally the result from the study demonstrates that the HS-1, HS-2 and HS-4 posses potent anti diabetic activity against type-2 diabetes mellitus through drug action on AMP kinase cascade system.
- Published
- 2014
- Full Text
- View/download PDF
75. Design and synthesis of novel iminothiazinylbutadienols and divinylpyrimidinethiones as ARE inducers.
- Author
-
Chen L, Magesh S, Wang H, Yang CS, Kong AN, and Hu L
- Subjects
- Curcumin chemistry, Curcumin metabolism, Isothiocyanates chemistry, Isothiocyanates pharmacology, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Pyrimidines pharmacology, Structure-Activity Relationship, Sulfoxides, Thiadiazines chemical synthesis, Thiadiazines chemistry, Thiadiazines pharmacology, Thiones chemical synthesis, Thiones pharmacology, Thiourea chemistry, Thiourea metabolism, Antioxidant Response Elements drug effects, Drug Design, Thiones chemistry
- Abstract
Novel iminothiazinylbutadienols and divinylpyrimidinethiones were designed and synthesized as analogues of curcumin with its diketone moiety masked as a heterocyclic adduct with thiourea. The chemical stability of these novel heterocyclic compounds was improved as compared to curcumin. They exhibit longer half-lives and do not react with nucleophilic thiols under physiological conditions. In an ARE-luciferase reporter assay, some of these new curcumin analogues are more effective ARE activators than curcumin and isothiocyanates., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
76. In vitro and in vivo anti-inflammatory effects of a novel 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione.
- Author
-
Lee JH, Lee KR, Su ZY, Boyanapalli SS, Barman DN, Huang MT, Chen L, Magesh S, Hu L, and Kong AN
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Cyclooxygenase 2 metabolism, Dose-Response Relationship, Drug, Female, Hep G2 Cells, Humans, Inflammation chemically induced, Inflammation drug therapy, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Mice, Molecular Structure, Nitric Oxide Synthase Type II antagonists & inhibitors, Nitric Oxide Synthase Type II metabolism, Pyrimidines chemistry, Structure-Activity Relationship, Tetradecanoylphorbol Acetate analogs & derivatives, Tetradecanoylphorbol Acetate antagonists & inhibitors, Thiones chemistry, Tumor Cells, Cultured, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Pyrimidines pharmacology, Thiones pharmacology
- Abstract
Inflammation plays a critical defensive role in the human body. However, uncontrolled or aberrant inflammatory responses contribute to various acute and chronic diseases. The Nrf2-ARE pathway plays a pivotal role in the regulation of inflammatory markers, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). On the basis of this concept, we synthesized a novel anti-inflammatory 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione (HPT), and in vitro experiments using HepG2-C8 ARE-luciferase-transfected cells demonstrated the induction of Nrf2-ARE activity. In lipopolysaccharide (LPS)-induced RAW 264.7 cells, HPT treatment reduced the production of nitric oxide (NO) as well as the protein and mRNA expression levels of COX-2 and iNOS, in a dose-dependent manner. In addition, HPT suppressed the mRNA expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In LPS-induced macrophages, HPT inhibited COX-2 and iNOS by blocking the activation of p38 and c-Jun NH2-terminal kinase (JNK) but not extracellular signal-regulated kinase (ERK1/2). Furthermore, an in vivo anti-inflammatory study was performed using a TPA-induced skin inflammation mouse model, and the results showed that HPT reduced TPA-induced inflammation and attenuated the expression of COX-2 and iNOS in TPA-induced mouse skin tissue. Thus, HPT demonstrated anti-inflammatory activity both in LPS-induced RAW 264.7 cells and TPA-stimulated mouse skin and may therefore serve as a potential anti-inflammatory agent.
- Published
- 2014
- Full Text
- View/download PDF
77. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
- Author
-
Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, Shen J, Kerrigan JE, Kong AN, Dandapani S, Palmer M, Schreiber SL, and Munoz B
- Subjects
- Crystallography, X-Ray, Dose-Response Relationship, Drug, Fluorescence Polarization, High-Throughput Screening Assays, Humans, Isoquinolines chemistry, Kelch-Like ECH-Associated Protein 1, Models, Molecular, Molecular Probes chemistry, Molecular Structure, Phthalimides chemistry, Protein Binding drug effects, Small Molecule Libraries chemistry, Structure-Activity Relationship, Drug Discovery, Intracellular Signaling Peptides and Proteins metabolism, Isoquinolines pharmacology, Molecular Imaging, Molecular Probes pharmacology, NF-E2-Related Factor 2 metabolism, Phthalimides pharmacology, Small Molecule Libraries pharmacology
- Abstract
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
78. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents.
- Author
-
Magesh S, Chen Y, and Hu L
- Subjects
- Animals, Anti-Inflammatory Agents therapeutic use, Antineoplastic Agents therapeutic use, Antioxidants therapeutic use, Humans, Hypoglycemic Agents therapeutic use, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, NF-E2-Related Factor 2 antagonists & inhibitors, Neuroprotective Agents therapeutic use, Oxidative Stress, Response Elements, Antioxidants metabolism, Intracellular Signaling Peptides and Proteins metabolism, NF-E2-Related Factor 2 metabolism, Signal Transduction
- Abstract
Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction., (© 2012 Wiley Periodicals, Inc.)
- Published
- 2012
- Full Text
- View/download PDF
79. Evaluation of a Set of C9 N-acyl Neu5Ac2en Mimetics as Viral Sialidase Selective Inhibitors.
- Author
-
Magesh S, Sriwilaijaroen N, Moriya S, Ando H, Miyagi T, Suzuki Y, Ishida H, and Kiso M
- Abstract
Identification of selective influenza viral sialidase inhibitors is highly desirable in order to minimize or avoid the adverse effects due to the possible inhibition of endogenous human sialidases. We recently reported the evaluation of C9 N-acyl Neu5Ac2en mimetics as probes for human sialidases. Herein, we describe the in vitro activity of the same set of C9 N-acyl Neu5Ac2en mimetics against sialidases expressed by influenza virus A/PR/8/34 (H1N1), A/Memphis/1/72 (H3N2), and A/Duck/313/78 (H5N3) strains. Compound 8 is identified as a promising starting point for the development of viral sialidase selective inhibitors. Multiple sequence alignment and molecular docking techniques are also performed to explore the plausible interaction of compound 8 with viral sialidases.
- Published
- 2011
- Full Text
- View/download PDF
80. Human sialidase inhibitors: design, synthesis, and biological evaluation of 4-acetamido-5-acylamido-2-fluoro benzoic acids.
- Author
-
Magesh S, Savita V, Moriya S, Suzuki T, Miyagi T, Ishida H, and Kiso M
- Subjects
- 4-Aminobenzoic Acid chemical synthesis, 4-Aminobenzoic Acid pharmacology, Cell Line, Drug Design, Humans, Models, Molecular, Molecular Structure, Protein Binding, Structure-Activity Relationship, Acetanilides chemical synthesis, Acetanilides pharmacology, Neuraminidase antagonists & inhibitors, Neuraminidase metabolism, para-Aminobenzoates
- Abstract
Recent advances in the sialidase biology have clarified the role of human sialidases (NEU 1 to NEU4) in the development of various disease states such as cancer, diabetes and arteriosclerosis. Isoform selective human sialidase inhibitors could be a therapeutic tool or molecular probes for the exploration of the specific functions of human sialidases. In the present study, de novo design based virtual screening was performed to find a new class of human sialidase inhibitors using the experimental crystal structure of NEU2 isoform. A few of nitro benzene and fluoro benzoic acid were identified and a series of 4-acetamido-5-acylamido-2-fluoro benzoic acids were synthesized and, the inhibitory activity of all these compounds against all human sialidase enzymes was evaluated. All these compounds were found to have a poor inhibitory activity and only NEU2 showed more sensitivity to this series of compounds as compared to other isoforms. Molecular docking was performed to gain insight regarding the binding mode of these inhibitors and thereby provided valuable information for our study on the design of selective human sialidase inhibitors further.
- Published
- 2009
- Full Text
- View/download PDF
81. Design, synthesis, and biological evaluation of human sialidase inhibitors. Part 1: selective inhibitors of lysosomal sialidase (NEU1).
- Author
-
Magesh S, Moriya S, Suzuki T, Miyagi T, Ishida H, and Kiso M
- Subjects
- Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Humans, Hydrogen Bonding, Models, Molecular, Molecular Structure, Enzyme Inhibitors chemistry, Lysosomes enzymology, Neuraminidase antagonists & inhibitors
- Abstract
We here report the design and synthesis of selective human lysosomal sialidase (NEU1) inhibitors. A series of amide-linked C9 modified DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid) analogues were synthesized and their inhibitory activities against all four human sialidases (NEU1-NEU4) were determined. Structure-based approach was used to investigate the basis of selectivity of the compounds with experimentally observed activity. Results from the present study are found to be informative in a qualitative manner for the further design of isoform selective human sialidase inhibitors for therapeutic value.
- Published
- 2008
- Full Text
- View/download PDF
82. Homology modeling of human sialidase enzymes NEU1, NEU3 and NEU4 based on the crystal structure of NEU2: hints for the design of selective NEU3 inhibitors.
- Author
-
Magesh S, Suzuki T, Miyagi T, Ishida H, and Kiso M
- Subjects
- Amino Acid Sequence, Carbohydrate Conformation, Carbohydrate Sequence, Catalytic Domain genetics, Computer Simulation, Crystallization, Enzyme Inhibitors pharmacology, Gangliosides chemistry, Humans, Molecular Sequence Data, Molecular Structure, Neuraminidase antagonists & inhibitors, Neuraminidase genetics, Protein Binding, Protein Isoforms antagonists & inhibitors, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Structure, Secondary, Sequence Homology, Amino Acid, Structure-Activity Relationship, Drug Design, Enzyme Inhibitors chemistry, Models, Molecular, Neuraminidase chemistry
- Abstract
Four types of human sialidases have been cloned and characterized at the molecular level. They are classified according to their major intracellular location as intralysomal (NEU1), cytosolic (NEU2), plasma membrane (NEU3) and lysosomal or mitochondrial membrane (NEU4) associated sialidases. These human isoforms are distinct from each other in their enzymatic properties as well as their substrate specificity. Altered expression of sialidases has been correlated with malignant transformation of cells and different sialidases have been known to behave differently during carcinogenesis. Particularly, increased expression of NEU3 has been implicated in the survival of various cancer cells and also in the development of insulin resistance. In the present study, we have modeled three-dimensional structures of NEU1, NEU3 and NEU4 based on the crystal structure of NEU2 using the homology modeling program MODELER. The best model in each enzyme case was chosen on the basis of various standard protein analysis programs. Predicted structures and the experimental protein-ligand complex of NEU2 were compared to identify similarities and differences among the active sites. The molecular electrostatic potential (MEP) was calculated for the predicted models to identify the differences in charge distribution around the active site and its vicinity. The primary objective of the present work is to identify the structural differences between the different isoforms of human sialidases, namely NEU1, NEU2, NEU3 and NEU4, thus providing a better insight into the differences in the active sites of these enzymes. This can in turn guide us in the better understanding and rationale of the differential substrate recognition and activity, thereby aiding in the structure-based design of selective NEU3 inhibitors.
- Published
- 2006
- Full Text
- View/download PDF
83. An outbreak of food poisoning in Tamil Nadu associated with Yersinia enterocolitica.
- Author
-
Abraham M, Pai M, Kang G, Asokan GV, Magesh SR, Bhattacharji S, and Ramakrishna BS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Child, Child, Preschool, Humans, India epidemiology, Middle Aged, Milk microbiology, Disease Outbreaks, Foodborne Diseases epidemiology, Yersinia Infections epidemiology, Yersinia enterocolitica
- Abstract
An outbreak of food poisoning in a Tamil Nadu village, affecting 25 of 48 individuals who participated in a feast, was investigated. The risk of developing illness was associated with consumption of buttermilk (relative risk 3.8). None of the food items consumed during the feast was available for analysis. Toxin-producing Y. enterocolitica (serotype 3, biotype 4) was grown from 1 of 11 stool samples from affected individuals, as well as from a water sample from the source used to dilute the buttermilk. High titres of antibody of Yersinia were detected in 2 of 12 patients but in neither of the two groups of controls. Toxin production was noted in buttermilk incubated for 6 h with Y. enterocolitica. This is the first report from India of a food poisoning outbreak associated with this organism.
- Published
- 1997
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.