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Teng C.-H.,National Cheng Kung University | Tseng Y.-T.,National Cheng Kung University | Maruvada R.,Johns Hopkins University | Pearce D.,Johns Hopkins University | And 3 more authors.
Infection and Immunity | Year: 2010

Escherichia coli K1 is the most common Gram-negative bacillary organism causing neonatal meningitis. E. coli K1 binding to and invasion of human brain microvascular endothelial cells (HBMECs) is a prerequisite for its traversal of the blood-brain barrier (BBB) and penetration into the brain. In the present study, we identified NlpI as a novel bacterial determinant contributing to E. coli K1 interaction with HBMECs. The deletion of nlpI did not affect the expression of the known bacterial determinants involved in E. coli K1-HBMEC interaction, such as type 1 fimbriae, flagella, and OmpA, and the contribution of NlpI to HBMECs binding and invasion was independent of those bacterial determinants. Previous reports have shown that the nlpI mutant of E. coli K-12 exhibits growth defect at 42°C at low osmolarity, and its thermosensitive phenotype can be suppressed by a mutation on the spr gene. The nlpI mutant of strain RS218 exhibited similar thermosensitive phenotype, but additional spr mutation did not restore the ability of the nlpI mutant to interact with HBMECs. These findings suggest the decreased ability of the nlpI mutant to interact with HBMECs is not associated with the thermosensitive phenotype. NlpI was determined as an outer membrane-anchored protein in E. coli, and the nlpI mutant was defective in cytosolic phospholipase A2α (cPLA 2α) phosphorylation compared to the parent strain. These findings illustrate the first demonstration of NlpI's contribution to E. coli K1 binding to and invasion of HBMECs, and its contribution is likely to involve cPLA2α. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Rajakumar P.,University of Madras | Padmanabhan R.,Orchid Chemicals and Pharmaceuticals Ltd | Rajesh N.,Orchid Research Laboratories Ltd
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A series of bis-oxy cyclophane diamides with bis(aminomethyl)m-terphenyl as spacer have been synthesized and characterized from spectral and analytical data. All the cyclophane diamides exhibit better anti-arthritic activity than the reference drug viz. diclofenac sodium. Some of the cyclophane diamides exhibit good anti-inflammatory activity. The cyclophane amide 4 and 5 do not show any evidence of mutagenicity and cytotoxicity. © 2012 Elsevier Ltd. All rights reserved.

Ebrahim A.S.,Mayo Medical School | Kulathingal J.,Mayo Medical School | Kulathingal J.,Orchid Research Laboratories Ltd | Murray M.E.,Mayo Medical School | And 4 more authors.
Acta Neuropathologica | Year: 2011

Clinical and pathological evidence supports the notion that corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are distinct, but overlapping neurodegenerative tauopathies. Although both disorders are characterized by abnormal accumulation of 4-repeat tau, they display distinct proteolytic profiles of tau species and they have distinct astrocytic lesions, astrocytic plaques in CBD and tufted astrocytes in PSP. To investigate other differences between these two disorders at the molecular level, we compared the profiles of proteins from caudate nucleus of CBD and PSP by quantitative two-dimensional difference gel electrophoresis. Twenty-one protein spots differentially expressed in CBD and PSP were dissected for mass spectrometry (MS). One of the spots was identified by MS to contain light chain (LC) ferritin. Western blot analysis verified the presence of LC ferritin in this spot and showed that this protein was two-fold higher in caudate of CBD than that of PSP samples. These results were confirmed by LC ferritin immunohistochemistry. Co-labeling of caudate nucleus with tau and LC ferritin antibodies showed the presence of LC ferritin immunoreactivity in astrocytic plaques of CBD, but minimal labeling of tufted astrocytes in PSP. This difference did not reflect the extent of gliosis. Analysis of other brain regions in CBD and PSP showed no difference in LC ferritin levels. Together the data suggest that LC ferritin is a unique marker of astrocytic lesions in CBD, adding further support to the notion that CBD and PSP are distinct clinicopathologic entities. © 2011 Springer-Verlag.

Bhonde M.R.,Charite - Medical University of Berlin | Bhonde M.R.,Orchid Research Laboratories Ltd | Hanski M.-L.,Charite - Medical University of Berlin | Stehr J.,Charite - Medical University of Berlin | And 7 more authors.
International Journal of Cancer | Year: 2010

The role of the mismatch repair (MMR) system in correcting base-base mismatches is well established; its involvement in the response to DNA double strand breaks, however, is less clear. We investigated the influence of the essential component of MMR, the hMLH1 protein, on the cellular response to DNA-double strand breaks induced by treatment with SN-38, the active metabolite of topoisomerase I inhibitor irinotecan, in a strictly isogenic cell system (p53wt, hMLH1+/p53wt, hMLH1-). By using hMLH1 expressing clones or cells transduced with the hMLH1-expressing adenovirus as well as siRNA technology, we show that in response to SN-38-induced DNA damage the MMR proficient (MMR+) cells make: (i) a stronger G2/M arrest, (ii) a subsequent longer tetraploid G1 arrest, (iii) a stronger activation of Chk1 and Chk2 kinases than the MMR deficient (MMR -) counterparts. Both Cdk2 and Cdk4 kinases contribute to the basal tetraploid G1 arrest in MMR+ and MMR- cells. Although the Chk1 kinase is involved in the G2/M arrest, neither Chk1 nor Chk2 are involved in the enhancement of the tetraploid G1 arrest. The long-lasting tetraploid G1 arrest of MMR+ cells is associated with their lower clonogenic survival after SN-38 treatment, the abrogation of the tetraploid G1 arrest resulted in their better clonogenic survival. These data show that the stabilization of the tetraploid G1 arrest in response to double strand breaks is a novel function of the MMR system that contributes to the lesser survival of MMR+ cells. © 2009 UICC.

Murugan R.,Orchid Research Laboratories Ltd | Raghunathan R.,University of Madras | Narayanan S.S.,University of Madras
Synthetic Communications | Year: 2010

Triarylideneacetylacetone undergoes regioselective 1,3-dipolar cycloaddition reactions with azomethine ylide derived from isatin and L-proline/sarcosine/octahydro-1H-indole-2-carboxylic acid by decarboxylation, affording a series of spiroheterocycles. This one-pot, three-component tandem reaction is efficient and yields novel spiroheterocylic compounds in good yields. The structure and stereochemistry of the cycloadduct have been established by single-crystal X-ray and spectroscopic techniques. Copyright © Taylor & Francis Group, LLC.

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