Publications by authors named "Balakrishnan Arun"

29 Publications

  • Page 1 of 1

Prioritizing Delivery of Cancer Treatment During a COVID-19 Lockdown: The Experience of a Clinical Oncology Service in India.

JCO Glob Oncol 2021 01;7:99-107

Department of Radiation Oncology, Tata Medical Center, Kolkata, India.

Purpose: A COVID-19 lockdown in India posed significant challenges to the continuation of radiotherapy (RT) and systemic therapy services. Although several COVID-19 service guidelines have been promulgated, implementation data are yet unavailable. We performed a comprehensive audit of the implementation of services in a clinical oncology department.

Methods: A departmental protocol of priority-based treatment guidance was developed, and a departmental staff rotation policy was implemented. Data were collected for the period of lockdown on outpatient visits, starting, and delivery of RT and systemic therapy. Adherence to protocol was audited, and factors affecting change from pre-COVID standards analyzed by multivariate logistic regression.

Results: Outpatient consults dropped by 58%. Planned RT starts were implemented in 90%, 100%, 92%, 90%, and 75% of priority level 1-5 patients. Although 17% had a deferred start, the median time to start of adjuvant RT and overall treatment times were maintained. Concurrent chemotherapy was administered in 89% of those eligible. Systemic therapy was administered to 84.5% of planned patients. However, 33% and 57% of curative and palliative patients had modifications in cycle duration or deferrals. The patient's inability to come was the most common reason for RT or ST deviation. Factors independently associated with a change from pre-COVID practice was priority-level allocation for RT and age and palliative intent for systemic therapy.

Conclusion: Despite significant access limitations, a planned priority-based system of delivery of treatment could be implemented.
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http://dx.doi.org/10.1200/GO.20.00433DOI Listing
January 2021

Robot Assisted Laparoscopic Adrenalectomy: Does Size Matter?

Cureus 2020 Aug 20;12(8):e9887. Epub 2020 Aug 20.

Urology, Apollo Hospitals, Chennai, IND.

Objective:  Open adrenalectomy (OA) is considered to be the standard care for large adrenal tumors. Minimally invasive surgery (MIS) using laparoscopic technique is considered for many patients in the modern era. Robot assisted laparoscopic adrenalectomy (RALA) can be an extremely useful tool which will negate the disadvantage of laparoscopic method. The aim of the present study is to determine whether adrenal tumor size and laterality have an impact on patients undergoing RALA with respect to perioperative and postoperative outcomes.  Methods: During the study period, 38 patients who underwent RALA in a tertiary care center were considered for retrospectively analysis. The study populations were subdivided into distinctive groups based on the tumor size (<5 cm and ≥5 cm, <8 cm and ≥8 cm), and side (right and left side). For all the subgroups, perioperative and postoperative outcomes were analyzed. Perioperative and postoperative outcomes were assessed between patient groups, group a) <5 cm and ≥5 cm tumor, group b) <8 cm and ≥8 cm, and group c) laterality (right vs left).

Results:  None of the patients showed any differences. In the current study, the conversion rate, readmission, and mortality were not observed. No major complications were noted.

Conclusion:  RALA appears to be an extremely viable alternative to MIS using laparoscopic technique. The operative time, console time, blood loss, complication rates, and stay were extremely minimal irrespective of the size or laterality of the adrenal tumor.
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http://dx.doi.org/10.7759/cureus.9887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502421PMC
August 2020

Setting up a lung stereotactic body radiotherapy service in a tertiary center in Eastern India: The process, quality assurance, and early experience.

J Cancer Res Ther 2020 Jul-Sep;16(4):888-899

Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Context: Stereotactic body radiotherapy (SBRT) is increasingly being used for early-stage lung cancer and lung oligometastases.

Aims: To report our experience of setting up lung SBRT and early clinical outcomes.

Settings And Design: This was a retrospective, interventional, cohort study.

Subjects And Methods: Patients were identified from multidisciplinary tumor board meetings. They underwent four-dimensional computed tomography-based planning. The ROSEL trial protocol, the Radiation Therapy Oncology Group (RTOG) 0236, and the UK-Stereotactic Ablative Body Radiotherapy Consortium guidelines were used for target volume and organs-at-risks (OARs) delineation, dosimetry, and plan quality assessment. Each SBRT plan underwent patient-specific quality assurance (QA). Daily online image guidance using KVCT or MVCT was done to ensure accurate treatment delivery.

Statistical Analysis Used: Microsoft Excel 2010 was used for data analysis.

Results: Fifteen patients were treated to one or more lung tumors. One patient received helical tomotherapy in view of bilateral lung oligometastases at similar axial levels. All the remaining patients received volumetric modulated arc therapy (VMAT)-based treatment. The prescription dose varied from 40 to 60 Gy in 5-8 fractions with alternate-day treatment. The mean and median lung V20 was 5.24% and 5.16%, respectively (range, 1.66%-9.10%). The mean and median conformity indexes were 1.02 and 1.06, respectively (range, 0.70-1.18). After a median follow-up of 17 months, the locoregional control rate was 93.3%.

Conclusions: SBRT was implemented using careful evaluation of OAR dose constraints, dosimetric accuracy and plan quality, patient-specific QA, and online image guidance for accurate treatment delivery. It was safe and effective for early-stage nonsmall cell lung cancer and lung metastases. Prospective data were collected to audit our outcomes.
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http://dx.doi.org/10.4103/jcrt.JCRT_427_18DOI Listing
November 2020

Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

Oncotarget 2016 Jan;7(3):3217-32

Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.

Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.
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http://dx.doi.org/10.18632/oncotarget.6560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823101PMC
January 2016

High Expression of Three-Gene Signature Improves Prediction of Relapse-Free Survival in Estrogen Receptor-Positive and Node-Positive Breast Tumors.

Biomark Insights 2015 30;10:103-12. Epub 2015 Nov 30.

Piramal Life Sciences Ltd, Nirlon Complex, Goregaon (E), Mumbai, India.

The objective of the present study was to validate prognostic gene signature for estrogen receptor alpha-positive (ER03B1+) and lymph node (+) breast cancer for improved selection of patients for adjuvant therapy. In our previous study, we identified a group of seven genes (GATA3, NTN4, SLC7A8, ENPP1, MLPH, LAMB2, and PLAT) that show elevated messenger RNA (mRNA) expression levels in ERα (+) breast cancer patient samples. The prognostic values of these genes were evaluated using gene expression data from three public data sets of breast cancer patients (n = 395). Analysis of ERα (+) breast cancer cohort (n = 195) showed high expression of GATA3, NTN4, and MLPH genes significantly associated with longer relapse-free survival (RFS). Next cohort of ERα (+) and node (+) samples (n = 109) revealed high mRNA expression of GATA3, SLC7A8, and MLPH significantly associated with longer RFS. Multivariate analysis of combined three-gene signature for ERα (+) cohort, and ERα (+) and node (+) cohorts showed better hazard ratio than individual genes. The validated three-gene signature sets for ERα (+) cohort, and ERα (+) and node (+) cohort may have potential clinical utility since they demonstrated predictive and prognostic ability in three independent public data sets.
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http://dx.doi.org/10.4137/BMI.S30559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666521PMC
December 2015

Anticancer activity of koningic acid and semisynthetic derivatives.

Bioorg Med Chem 2015 Jul 9;23(13):3712-21. Epub 2015 Apr 9.

Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France. Electronic address:

A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential.
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http://dx.doi.org/10.1016/j.bmc.2015.04.004DOI Listing
July 2015

Evaluation to determine the caries remineralization potential of three dentifrices: An in vitro study.

J Conserv Dent 2013 Jul;16(4):375-9

Department of Conservative Dentistry and Endodontics, Rajas Dental College, Tirunelveli, Tamil Nadu, India.

Aim: The aim of this study was to evaluate the remineralizing potential of three different remineralizing agents (GC tooth Mousse, Clinpro tooth crθme and SHY-NM) on demineralized tooth surfaces using micro CT and microhardness.

Materials And Methods: Forty five freshly extracted mandibular premolars were collected and enamel specimens were prepared. The samples were assigned to three groups with fifteen specimens in each group. The specimens were then demineralized using McInne's demineralizing solution in two cycles. After that, remineralization was carried out in two cycles for 30 days using Casein phosphopeptide - Amorphous calcium phosphate (CPP - ACP), 0.21% sodium fluoride - Tricalcium phosphate (f-TCP) and Calcium Sodium Phosphosilicate (CSP) containing tooth pastes for groups I, II, III respectively. The specimens were evaluated for Linear attenuation co-efficient using micro CT (Scanco™) and Vicker's Micro Hardness (Schimadzu™) testing at different time periods. The results were tabulated and statistically analysed.

Results: It was observed that all the three remineralizing agents used in the study significantly increased the Linear Attenuation Co-efficient and Vicker's hardness number values of the enamel specimens following 15 days and 30 days application.

Conclusion: CPP - ACP showed the better remineralizing potential than the other two agents and there was no statistical significant difference between f-TCP and CSP groups.
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http://dx.doi.org/10.4103/0972-0707.114347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740654PMC
July 2013

The role of feedback in improving the effectiveness of workplace based assessments: a systematic review.

BMC Med Educ 2012 May 2;12:25. Epub 2012 May 2.

Department of Ophthalmology, Heart of England NHS Foundation Trust, Birmingham, UK.

Background: With recent emphasis placed on workplace based assessment (WBA) as a method of formative performance assessment, there is limited evidence in the current literature regarding the role of feedback in improving the effectiveness of WBA. The aim of this systematic review was to elucidate the impact of feedback on the effectiveness of WBA in postgraduate medical training.

Methods: Searches were conducted using the following bibliographic databases to identify original published studies related to WBA and the role of feedback: Medline (1950-December 2010), Embase (1980-December 2010) and Journals@Ovid (English language only, 1996-December 2010). Studies which attempted to evaluate the role of feedback in WBA involving postgraduate doctors were included.

Results: 15 identified studies met the inclusion criteria and minimum quality threshold. They were heterogeneous in methodological design. 7 studies focused on multi source feedback, 3 studies were based on mini-clinical evaluation exercise, 2 looked at procedural based assessment, one study looked at workplace based assessments in general and 2 studies looked at a combination of 3 to 6 workplace based assessments. 7 studies originated from the United Kingdom. Others were from Canada, the United States and New Zealand. Study populations were doctors in various grades of training from a wide range of specialties including general practice, general medicine, general surgery, dermatology, paediatrics and anaesthetics. All studies were prospective in design, and non-comparative descriptive or observational studies using a variety of methods including questionnaires, one to one interviews and focus groups.

Conclusions: The evidence base contains few high quality conclusive studies and more studies are required to provide further evidence for the effect of feedback from workplace based assessment on subsequent performance. There is, however, good evidence that if well implemented, feedback from workplace based assessments, particularly multisource feedback, leads to a perceived positive effect on practice.
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http://dx.doi.org/10.1186/1472-6920-12-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432628PMC
May 2012

CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis.

Mol Cancer Ther 2012 Jul 24;11(7):1598-608. Epub 2012 Apr 24.

Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G(2)/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and gemcitabine resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392497PMC
July 2012

Spatiotemporal aspects of real-time PM(2.5): low- and middle-income neighborhoods in Bangalore, India.

Environ Sci Technol 2011 Jul 14;45(13):5629-36. Epub 2011 Jun 14.

Department of Civil Engineering, University of Minnesota, Minneapolis, Minnesota, United States.

We measured outdoor fine particulate matter (PM(2.5)) concentrations in a low- and a nearby middle-income neighborhood in Bangalore, India. Each neighborhood included sampling locations near and not near a major road. One-minute average concentrations were recorded for 168 days during September 2008 to May 2009 using a gravimetric-corrected nephelometer. We also measured wind speed and direction, and PM(2.5) concentration as a function of distance from road. Average concentrations are 21-46% higher in the low- than in the middle-income neighborhood, and exhibit differing spatiotemporal patterns. For example, in the middle-income neighborhood, median concentrations are higher near-road than not near-road (56 versus 50 μg m(-3)); in the low-income neighborhood, the reverse holds (68 μg m(-3) near-road, 74 μg m(-3) not near-road), likely because of within-neighborhood residential emissions (e.g., cooking; trash combustion). A moving-average subtraction method used to infer local- versus urban-scale emissions confirms that local emissions are greater in the low-income neighborhood than in the middle-income neighborhood; however, relative contributions from local sources vary by time-of-day. Real-time relative humidity correction factors are important for accurately interpreting real-time nephelometer data.
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http://dx.doi.org/10.1021/es104331wDOI Listing
July 2011

Molecular basis of the anti-inflammatory property exhibited by cyclo-pentano phenanthrenol isolated from Lippia nodiflora.

Immunol Invest 2010 ;39(7):713-39

Centre for Biotechnology, Anna University, Chennai, India.

The objective of this study was to assess the anti-inflammatory potential of the active molecule isolated from Lippia nodiflora and to understand its molecular dynamics in Vitro inflammation models. Human Peripheral Blood Mononuclear Cells were used as models to study mitogen induced lymphocyte proliferation, cytokine mRNA expression (TNF-α, IL-1β and IL-6) and intracellular protein levels of pro-inflammatory mediators (MAPK and NF-κB). The NO release levels, on treatment with the extract and molecule, were correlated with the underlying iNOS mRNA expression in the murine macrophage cell line RAW 264.7. RT-PCR for COX-2, MMP2 and MMP9 were also performed in the cell line. The rat basophilic leukemia cell line RBL-2H3 was used as an in Vitro model for PLA2 activity. Then, 20 μg/ml of Lippia nodiflora crude methanol extract and 10 μg/ml of the purified CPP were used for subsequent studies based on the IC50 values obtained in the proliferation assay. Results demonstrate that the isolated Cyclo-pentano phenanthrenol inhibits TNF-α, IL-1β and IL-6 expression, NO release via iNOS suppression, prostaglandin biosynthesis via PLA2 and COX-2 inhibition and the activation of intracellular targets, MAPK and NF-κB. We conclude, cyclo-pentano phenanthrenol exerts its anti-inflammatory effect via inhibition of MAPK phosphorylation and NF-κB translocation.
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http://dx.doi.org/10.3109/08820139.2010.493190DOI Listing
May 2011

Identification of gene expression signature in estrogen receptor positive breast carcinoma.

Biomark Cancer 2010 11;2:1-15. Epub 2010 Feb 11.

Department of Biomarker Discovery, Piramal Life Sciences Limited, Mumbai, Maharashtra, India.

A significant group of patient with estrogen receptor (ER) α positive breast tumors fails to appreciably respond to endocrine therapy. An increased understanding of the molecular basis of estrogen-mediated signal transduction and resultant gene expression may lead to novel strategies for treating breast cancer. In this study, we sought to identify the dysregulated genes in breast tumors related to ERα status. Microarray analyses of 31 tumor samples showed 108 genes differentially expressed in ERα (+) and ERα (-) primary breast tumors. Further analyses of gene lists indicated that a significant number of dysregulated genes were involved in mRNA transcription and cellular differentiation. The majority of these genes were found to have promoter-binding sites for E74-like factor 5 (ELF5; 54.6% genes), E2F transcription factor 1 (E2F1; 22.2% genes), and nuclear transcription factor Y alpha (NFYA; 32.4% genes). Six candidate genes (NTN4, SLC7A8, MLPH, ENPP1, LAMB2, and PLAT) with differential expression were selected for further validation studies using RT-qPCR (76 clinical specimen) and immunohistochemistry (48 clinical specimen). Our studies indicate significant over-expression of all the six genes in ERα (+) breast tumors as compared to ERα (-) breast tumors. In vitro studies using T-47D breast cancer cell line confirmed the estrogen dependant expression of four of the above six genes (SLC7A8, ENPP1, LAMB2, and PLAT). Collectively, our study provides further insights into the molecular basis of estrogen-dependent breast cancer and identifies "candidate biomarkers" that could be useful for predicting endocrine responsiveness.
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http://dx.doi.org/10.4137/BIC.S3793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783308PMC
November 2013

3beta-taraxerol of Mangifera indica, a PI3K dependent dual activator of glucose transport and glycogen synthesis in 3T3-L1 adipocytes.

Biochim Biophys Acta 2010 Mar 21;1800(3):359-66. Epub 2009 Dec 21.

Centre for Biotechnology, Anna University, India.

Background: The present study focuses on identifying and developing an anti-diabetic molecule from plant sources that would effectively combat insulin resistance through proper channeling of glucose metabolism involving glucose transport and storage.

Methods: Insulin-stimulated glucose uptake formed the basis for isolation of a bioactive molecule through column chromatography followed by its characterization using NMR and mass spectroscopic analysis. Mechanism of glucose transport and storage was evaluated based on the expression profiling of signaling molecules involved in the process.

Results: The study reports (i) the isolation of a bioactive compound 3beta-taraxerol from the ethyl acetate extract (EAE) of the leaves of Mangifera indica (ii) the bioactive compound exhibited insulin-stimulated glucose uptake through translocation and activation of the glucose transporter (GLUT4) in an IRTK and PI3K dependent fashion. (iii) the fate of glucose following insulin-stimulated glucose uptake was ascertained through glycogen synthesis assay that involved the activation of PKB and suppression of GSK3beta.

General Significance: This study demonstrates the dual activity of 3beta-taraxerol and the ethyl acetate extract of Mangifera indica as a glucose transport activator and stimulator of glycogen synthesis. 3beta-taraxerol can be validated as a potent candidate for managing the hyperglycemic state.
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http://dx.doi.org/10.1016/j.bbagen.2009.12.002DOI Listing
March 2010

Anti-inflammatory and anticancer activity of ergoflavin isolated from an endophytic fungus.

Chem Biodivers 2009 May;6(5):784-9

Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Near NSE Complex, Goregaon (East), Mumbai, India.

Biodiversity is a major resource for identification of new molecules with specific therapeutic activities. To identify such an active resource, high throughput screening (HTS) of the extracts prepared from such diversity are examined on specific functional assays. Based on such HTS studies and bioactivity-based fractionation, we have isolated ergoflavin, a pigment from an endophytic fungus, growing on the leaves of an Indian medicinal plant Mimosops elengi (bakul). We report here the isolation, structure elucidation, and biological properties of this compound, which showed good anti-inflammatory and anticancer activities.
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http://dx.doi.org/10.1002/cbdv.200800103DOI Listing
May 2009

Tackling multiple antibiotic resistance in enteropathogenic Escherichia coli (EPEC) clinical isolates: a diarylheptanoid from Alpinia officinarum shows promising antibacterial and immunomodulatory activity against EPEC and its lipopolysaccharide-induced inflammation.

Int J Antimicrob Agents 2009 Mar 17;33(3):244-50. Epub 2008 Dec 17.

Centre for Biotechnology, Anna University, Chennai, India.

Antibiotic treatment for infectious diseases commonly leads to host inflammatory responses. Molecules with bifunctional antibacterial and anti-inflammatory properties could provide a solution for such clinical manifestations. Here we report such bifunctional activity for a diarylheptanoid (5-hydroxy-7-(4''-hydroxy-3-methoxyphenyl)-1-phenyl-3-heptanone) isolated from Alpinia officinarum, a medicinal plant belonging to the Zingiberaceae family, against enteropathogenic Escherichia coli (EPEC). The diarylheptanoid showed inhibitory and bactericidal activity against EPEC clinical isolates and efficiently suppressed EPEC lipopolysaccharide-induced inflammation in human peripheral blood mononuclear cells. In silico docking analysis revealed that the diarylheptanoid could interact with subunit A of E. coli DNA gyrase. Such molecules with bifunctional activity may be potential therapeutics for infectious diseases.
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http://dx.doi.org/10.1016/j.ijantimicag.2008.08.032DOI Listing
March 2009

Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists.

Bioorg Med Chem Lett 2008 Dec 1;18(24):6357-61. Epub 2008 Nov 1.

Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400063, India.

In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 microM (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%.
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http://dx.doi.org/10.1016/j.bmcl.2008.10.085DOI Listing
December 2008

Activation of apoptosis by 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde, a novel compound from Aegle marmelos.

Cancer Res 2008 Oct;68(20):8573-81

Department of Medicine, OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.

We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-alpha (TNF-alpha), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G(1) cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-alpha, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-alpha-mediated activation and translocation of nuclear factor-kappaB (NF-kappaB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-kappaB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G(1) phase of the cell cycle and could be a potential chemotherapeutic candidate.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-2372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692325PMC
October 2008

Outer membrane proteins of wild-type and intimin-deficient enteropathogenic Escherichia coli induce Hep-2 cell death through intrinsic and extrinsic pathways of apoptosis.

Int J Med Microbiol 2009 Feb 3;299(2):121-32. Epub 2008 Sep 3.

Centre for Biotechnology, Anna University, Chennai, India.

Enteropathogenic Escherichia coli cause protracted diarrhoea and malnutrition in infants by cytoskeletal depolymerisation and effacement of enterocyte microvilli. In this study, outer membrane proteins of wild-type enteropathogenic E. coli and an intimin-deficient mutant are shown to induce apoptosis by up-regulation of tumour necrosis factor alpha and activation of c-jun N-terminal kinase. Fluorescence-activated cell sorter analysis revealed apoptosis of cells treated with outer membrane proteins of wild-type and intimin-deficient strains. Proteinase K treatment of outer membrane proteins reduced apoptosis significantly, as did neutralising tumour necrosis factor alpha with specific antibodies. Elevated tumour necrosis factor receptor 1-associated death domain and caspase-3 expression were also observed on treatment with both types of outer membrane proteins. Furthermore, apoptosis was associated with suppression of Bcl-2 protein expression, up-regulation of Bax mRNA levels and increased cytochrome c release from mitochondria. Elevated phospho-c-jun N-terminal kinase, c-jun mRNA and activator protein-1 expression were observed, and phosphorylation of activator protein-1 was also observed by DNA-binding assays. Inhibition of c-jun N-terminal kinase, but not inhibition of p38 mitogen-activated protein kinase, resulted in reduction of tumour necrosis factor alpha mRNA levels and caspase-3 protein levels, and a reduction in apoptosis as observed by fluorescence-activated cell sorter analysis. From the host point of view, this study suggests a possible interplay between the death receptor and mitochondrial pathways when cell-free bacterial outer membrane preparations are used to trigger apoptosis.
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http://dx.doi.org/10.1016/j.ijmm.2008.07.005DOI Listing
February 2009

Varicose veins.

J Perioper Pract 2008 Aug;18(8):346-53

University Hospital of North Tees, Hardwick Road, Stockton-on-Tees, Cleveland TS19 8PE.

Varicose veins are common and often asymptomatic. A variety of treatment methods are available for those who develop symptoms or complications. The traditional open surgical treatment still forms the mainstay of treatment. Endovenous treatment methods offer a new alternative but have their own limitations. Foam sclerotherapy holds much promise as it can be done in an outpatient setting under local anesthesia, but it needs to be tested over a longer time period.
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http://dx.doi.org/10.1177/175045890801800805DOI Listing
August 2008

Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-alpha and IL-6 inhibitors.

Bioorg Med Chem 2008 Aug 26;16(15):7167-76. Epub 2008 Jun 26.

Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1, Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400063, India.

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl-D-glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-alpha and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60-65% inhibition at 10 microM concentration. Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC(50)'s of 0.2, 0.3 and 0.16 microM, respectively. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 microM.
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http://dx.doi.org/10.1016/j.bmc.2008.06.042DOI Listing
August 2008

Novel leads from Heliotropium ovalifolium, 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde show specific IL-6 inhibitory activity in THP-1 cells and primary human monocytes.

Phytomedicine 2008 Dec 25;15(12):1079-86. Epub 2008 Jun 25.

Screening and Biotechnology, Department of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Mumbai 400063, India.

From our screening program, we identified the anti-inflammatory effects of the extracts of Heliotropium ovalifolium in its ability to inhibit specific cytokines. The H. ovalifolium extract was found to be moderately active with an IC(50) equaling 10 microg/ml for inhibition of interleukin-6 (IL-6) in a human monocytic cell line. Interleukin-6 is a pleiotropic cytokine with implications in the regulation of the immune response, inflammation and hematopoiesis. This prompted us to examine and identify the active molecules that are responsible for the bioactivity in THP-1 cells. Bioassay guided fractionation identified two compounds 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde with an IC(50) of 2.4 and 2.0 microM for IL-6 inhibition and an IC(50) of 15.6 and 7.0 microM for tumor necrosis factor-alpha (TNF-alpha) inhibition in THP-1 cells. The protein expression data were supported by the inhibitory effect on mRNA gene expression. The compounds isolated from H. ovalifolium were also non-toxic in human peripheral blood monocytes from normal donors and the activity profile was similar to that obtained on THP-1 cells. Thus, we believe that these scaffolds may be of interest to develop leads for treating rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and other inflammatory disorders. However, more detailed investigations need to be carried out to explain the efficacy of these compounds as drugs.
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http://dx.doi.org/10.1016/j.phymed.2008.04.013DOI Listing
December 2008

Tannins present in Cichorium intybus enhance glucose uptake and inhibit adipogenesis in 3T3-L1 adipocytes through PTP1B inhibition.

Chem Biol Interact 2008 Jul 24;174(1):69-78. Epub 2008 Apr 24.

Centre for Biotechnology, Tissue Culture and Drug Discovery Lab, Anna University, Chennai 600025, Tamilnadu, India.

Insulin resistance is a fundamental aspect for the etiology of non-insulin dependent diabetes mellitus (NIDDM) and has links with a wide array of secondary disorders including weight gain and obesity. The present study analyzes the effect of Cichorium intybus methanolic (CME) extract on glucose transport and adipocyte differentiation in 3T3-L1 cells by studying the radiolabelled glucose uptake and lipid accumulation assays, respectively. By performing detannification (CME/DT), the role of tannins present in CME on both the activities was evaluated. CME and CME/DT exhibited significant glucose uptake in 3T3-L1 adipocytes with a dose-dependent response. Glucose uptake profile in the presence of PI3K and IRTK inhibitors (Wortmannin and Genistein) substantiates the mechanism used by both the extracts. CME inhibited the differentiation of 3T3-L1 preadipocytes but failed to show glucose uptake in inhibitor treated cells. The activity exhibited by CME/DT is exactly vice versa to CME. Furthermore, the findings from PTP1B inhibition assay, mRNA and protein expression analysis revealed the unique behavior of CME and CME/DT. The duality exhibited by C. intybus through adipogenesis inhibition and PPARgamma up regulation is of interest. Current observation concludes that the activities possessed by C. intybus are highly desirable for the treatment of NIDDM because it reduces blood glucose levels without inducing adipogenesis in 3T3-L1 adipocytes.
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http://dx.doi.org/10.1016/j.cbi.2008.04.016DOI Listing
July 2008

Modulation of tight junction barrier function by outer membrane proteins of enteropathogenic Escherichia coli: role of F-actin and junctional adhesion molecule-1.

Cell Biol Int 2007 Aug 12;31(8):836-44. Epub 2007 Feb 12.

Centre for Biotechnology, Anna University, Chennai 600 025, Tamil Nadu, India.

Enteropathogenic Escherichia coli (EPEC) is a major cause of infantile diarrhea. In this work we investigated the effect of outer membrane proteins (OMP) of EPEC on barrier integrity and the role of actin, junctional adhesion molecule (JAM) and signaling pathways contributing to these changes. Barrier function was assessed by transepithelial electrical resistance (TER). OMP of wild type EPEC, eaeA and maltoporin mutants decreased TER levels of Caco-2 cells. The OMP of espB mutant was deficient in decreasing TER of Caco-2 cells. The proteinase K-digested wild type OMP and EAF mutant OMP did not cause any change in barrier function. Our previous studies have demonstrated that EPEC OMP induced changes in cadherin junctions of Caco-2 cells. Immunofluorescence revealed disruption in actin cytoskeleton by EPEC OMP. However, no change in expression of junctional adhesion molecule-1 was observed. NF-kappaB inhibitor slightly blocked the decrease in TER and protected against actin disruption while ERK1/2 inhibitor had no effect in blocking these changes. In conclusion, our data suggest that the OMP of EPEC alter intestinal barrier function by disrupting actin cytoskeleton and signaling pathways like NF-kappaB may have a role in regulating barrier changes.
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http://dx.doi.org/10.1016/j.cellbi.2007.01.036DOI Listing
August 2007

Enteropathogenic Escherichia coli outer membrane proteins induce iNOS by activation of NF-kappaB and MAP kinases.

Inflammation 2004 Dec;28(6):345-53

Centre for Biotechnology, Anna University, Chennai 600 025, India.

Enteropathogenic Escherichia coli (EPEC) infects the human intestinal epithelium and is a major cause of infantile diarrhea in developing countries. Nitric oxide (NO) is an important modulator of intestinal inflammatory response. The aim of the present study was to investigate whether EPEC outer membrane proteins (OMPs) up regulate epithelial cell expression of inducible nitric oxide synthase (iNOS) and to examine the role of NF-kappaB and MAP kinases (MAPK) on nitrite production. iNOS mRNA expression was assessed by RT-PCR. Nitrite levels were measured by Griess reaction. NF-kappaB activation by OMPs was evaluated by EMSA and immunoblotting was done to detect MAPK activation. EPEC OMP up regulated iNOS, induced nitrite production and NF-kappaB and MAPK were activated in caco-2 cells. The nitrite levels decreased when NF-kappaB and MAPK inhibitors were used. Thus, EPEC OMPs induce iNOS expression and NO production through activation of NF-kappaB and MAPK.
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http://dx.doi.org/10.1007/s10753-004-6645-8DOI Listing
December 2004

Upregulation of Glut-4 and PPAR gamma by an isoflavone from Pterocarpus marsupium on L6 myotubes: a possible mechanism of action.

J Ethnopharmacol 2005 Feb 13;97(2):253-60. Epub 2005 Jan 13.

Centre For Biotechnology, Anna University, Chennai 600025, Tamil Nadu, India.

The purpose of the present study is to analyse the influence of Pterocarpus marsupium methanolic extract and isolated Pterocarpus marsupium isoflavone on a battery of cellular targets Glut-4, PPAR gamma and PI3 kinase. Pterocarpus marsupium is an anti-diabetic plant indigenous to South India. Sequential extraction performed with different solvents were analysed for glucose uptake activity at each step. Fraction-9 showing maximum glucose activity on glucose uptake was purified by column chromatography and the structure was elucidated as 7-O-alpha-L-rhamnopyranosyl oxy-4'-methoxy-5-hydroxy isoflavone using NMR and mass spectroscopy. The significant glucose uptake showed by Pterocarpus marsupium crude and pure was comparable with insulin and rosiglitazone. Elevation of Glut-4 and PPARgamma gene expression in parallel with glucose uptake supported the in vitro glucose uptake activity of Pterocarpus marsupium methanolic extract and Pterocarpus marsupium isoflavone. The inhibitory effect of cycloheximide on Pterocarpus marsupium methanolic extract and Pterocarpus marsupium isoflavone-mediated glucose uptake suggested that new protein synthesis is required for elevated Glut-4 protein expression. PI3 kinase plays an important role in glucose transport and activated by Pterocarpus marsupium methanolic extract but not the isolated pure isoflavone. Therefore, we postulate that the isoflavone from Pterocarpus marsupium may activate glucose transport by a PI3 kinase independent pathway, which require further analysis.
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http://dx.doi.org/10.1016/j.jep.2004.11.023DOI Listing
February 2005

Enteropathogenic Escherichia coli outer membrane proteins induce changes in cadherin junctions of Caco-2 cells through activation of PKCalpha.

Microbes Infect 2004 Jan;6(1):38-50

Centre for Biotechnology, Anna University, 600 025, Chennai, India.

Enteropathogenic Escherichia coli (EPEC) is a Gram-negative bacterial pathogen that adheres to human intestinal epithelial cells, resulting in watery, persistent diarrhoea. Despite the advances made in understanding EPEC-host cell interactions, the molecular mechanisms underlying watery diarrhoea have not been understood fully. Loss of transepithelial resistance and increased monolayer permeability by disruption of tight junctions has been implicated in this process. Apart from disruption of tight junctions, an important factor known to regulate monolayer permeability is E-cadherin and its interaction with beta-catenin, both of which constitute the adherens junctions. Our previous studies using HEp-2 cells demonstrated the morphological and cytoskeletal changes caused by cell-free outer membrane preparations (OMPs) of EPEC. In this study, we have shown that EPEC and its OMP induce significant changes in the adherens junctions of Caco-2 monolayers. We also observed significant phosphorylation of protein kinase Calpha (PKCalpha) in cells treated with either whole EPEC or its OMP. Immunoprecipitation of cell lysates with anti-E-cadherin and probing with phospho-PKCalpha monoclonal antibodies and anti-beta-catenins revealed that in these cells, phosphorylated PKCalpha is associated with cadherins, leading to the dissociation of the cadherin/beta-catenin complex. Immunofluorescence showed beta-catenins dissociated from the membrane-bound cadherins and redistributed into the cytoplasm. Expression of dominant negative PKCalpha reversed these effects caused by either whole EPEC or its OMP and also reduced the associated increase in monolayer permeability. It is possible that this mechanism may complement the earlier known pathways for loss of barrier function involving myosin light chain kinase activation and also may play a role in causing host cell death by apoptosis.
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http://dx.doi.org/10.1016/j.micinf.2003.09.022DOI Listing
January 2004

Targeting apoptotic signalling pathway and pro-inflammatory cytokine expression as therapeutic intervention in TPE induced lung damage.

Cell Biol Int 2003 ;27(4):375-82

Centre for Biotechnology, Anna University, Chennai 600025, India.

Tropical pulmonary eosinophilia (TPE) is an occult manifestation of filariasis, brought about by helminth parasites Wuchereria bancrofti and Brugia malayi. Treatment of patients suffering from TPE involves the administration of diethyl carbamazine and Ivermectin. Although the drugs are able to block acute inflammation, they are not able to alleviate chronic basal inflammation. We have attempted to examine the disease by targeting two important components; namely filarial parasitic sheath proteins (FPP) induced apoptosis and pro-inflammatory cytokine response in human laryngeal carcinoma cells of epithelial origin (HEp-2) cells an epithelial cell line. Earlier studies by us have shown that FPP exposure induced apoptosis in these cells. In this study with hydrocortisone, calpain inhibitor (ALLN) and phorbol myristate acetate (PMA) treatments we demonstrate that apoptosis is inhibited as shown by [3H] thymidine incorporation studies, propidium iodide staining and Annexin V staining. Hydrocortisone at a dose, which inhibits cell death also down regulated, the expression of pro-inflammatory cytokines IL-6 and IL-8. These findings give us insights into the multifaceted approach one may adopt to target critical signalling molecules using appropriate inhibitors, which could eventually be used to reduce lung damage in TPE.
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http://dx.doi.org/10.1016/s1065-6995(03)00014-3DOI Listing
December 2003

CD14-dependent activation of NF-kappaB by filarial parasitic sheath proteins.

Cell Biol Int 2002 ;26(1):43-54

Center for Biotechnology, Anna University, Chennai, 600 025, India.

Tropical pulmonary eosinophilia is in part caused by the hyperimmune responsiveness of the lung tissue against the antigens of degenerating microfilariae. We have previously shown that the activation of the transcription factor NF-kappaB is essential for the synthesis and release of multiple pro-inflammatory cytokines in HEp-2 human airway epithelial cells following exposure to filarial parasitic sheath proteins (FPS). Neither the antigenic component nor the receptor involved in this activation is known. Herein we provide evidence that FPS activation of NF-kappaB can be augmented by the cell surface expression of CD14. CD14 expression, however, is not sufficient to transduce FPS signals for NF-kappaB activation, since its expression in different cell types does not always furnish the capacity to respond to FPS. We also show that NF-kappaB activation by FPS treatment can be distinguished from that induced by bacterial lipolysaccharide, an agent that can also activate NF-kappaB in a CD14-dependent fashion. These observations suggest that the capacity of certain lung epithelial cells to interact with microfilarial antigens, activate NF-kappaB in a CD14-dependent manner and produce pro-inflammatory cytokines may be a contributory factor to immune responses manifested by tropical pulmonary eosinophilia.
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http://dx.doi.org/10.1006/cbir.2001.0828DOI Listing
May 2002

Cytopathic effects of outer-membrane preparations of enteropathogenic Escherichia coli and co-expression of maltoporin with secretory virulence factor, EspB.

J Med Microbiol 2001 Jul;50(7):602-612

Centre for Biotechnology, Anna University, Chennai - 600 025, India and *Department of Microbiology and Immunology, University of Leicester, UK.

Enteropathogenic Escherichia coli (EPEC) is an important aetiological agent of persistent infantile diarrhoea. EPEC pathogenicity is not mediated through known toxins and the role played by outer-membrane proteins (OMPs) in the initial adherence of the bacterium, intimate attachment to epithelial cells and ultimately in the effacement of the intestinal epithelium is being pursued vigorously. In this study of the different cellular fractions of the bacterium investigated, only the outer-membrane fraction was able to disrupt HEp-2 cells. The outer-membrane fraction was also found to be cytotoxic and caused actin accumulation around the periphery of the host cells. To understand the role of OMPs in pathogenesis, protein profiles of outer-membrane preparations of wild-type and attenuated mutants lacking either the EPEC adherence factor (EAF) mega-plasmid or EPEC attaching and effacing gene A (eaeA) coding for a 94-kDa OMP, intimin or EPEC secretory protein gene B (espB) coding for a 34-kDa translocated signal transducing protein were compared and correlated with their cytopathic effects. A 43-kDa protein seen along with intimin in the outer membrane of EPEC was identified as maltoporin, an E. coli outer-membrane porin normally expressed only in response to maltose in the growth medium. In the case of EPEC, not only was this regulation lost, but also the expression of maltoporin was found to be tightly coupled to the expression of the secretory virulence factor EspB. Maltoporin per se is not toxic, as evidenced by the treatment of HEp-2 cells with the outer-membrane preparation of E. coli DH5a grown in the presence of maltose and the significance of this pathogenic adaptation is not clear. However, when maltoporin and possibly other unidentified proteins were not present as a component of the outer-membrane preparation, as in the outer-membrane preparation of an espB-negative strain, cellular disruption as well as actin accumulation proceeded at a very slow rate even though the cytotoxic effects were comparable to those of the wild-type EPEC strains.
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http://dx.doi.org/10.1099/0022-1317-50-7-602DOI Listing
July 2001