Publications by authors named "Benjamin Simms"

12 Publications

  • Page 1 of 1

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences.

J Nutr Biochem 2014 Oct 6;25(10):1011-8. Epub 2014 Jun 6.

Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. Electronic address:

Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes that may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets.
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http://dx.doi.org/10.1016/j.jnutbio.2014.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157943PMC
October 2014

Hookworm infection among school age children in Kintampo north municipality, Ghana: nutritional risk factors and response to albendazole treatment.

Am J Trop Med Hyg 2013 Sep 8;89(3):540-8. Epub 2013 Jul 8.

Program in International Child Health, Department of Pediatrics and School of Public Health, Yale School of Medicine, New Haven, CT 06520, USA.

Children (n = 812) 6-11 years of age attending 16 schools in the Kintampo North Municipality of Ghana were screened for participation in a study on hookworm infection, nutrition, and response to albendazole. The prevalence of Necator americanus hookworm infection (n = 286) was 39.1%, and significant predictors of infection included age, malaria parasitemia, lack of health care, school area, levels of antibodies against hookworm, and low consumption of animal foods. The cure rate after a single dose (400 mg) albendazole was 43%, and the mean fecal egg count reduction rate was 87.3%. Data for an in vitro egg hatch assay showed a trend toward reduced albendazole susceptibility in post-treatment hookworm isolates (P = 0.06). In summary, hookworm infection is prevalent among school age children in the Kintampo North Municipality and animal food intake inversely correlates with infection status. Modest cure rates and fecal egg count reduction rates reinforce the need for further investigation of potential benzimidazole resistance in Ghana.
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http://dx.doi.org/10.4269/ajtmh.12-0605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771297PMC
September 2013

Biodiversity of small molecules--a new perspective in screening set selection.

Drug Discov Today 2013 Jul 20;18(13-14):674-80. Epub 2013 Feb 20.

Cheminformatics and Statistics, Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland.

How is the 'diversity' of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound-target diversity. Biodiverse compound subsets outperform chemically diverse libraries regarding hit rate and the total number of unique chemical scaffolds present among hits. Specifically, by screening ~19% of a HTS collection, we expect to discover ~50-80% of all desired bioactive compounds.
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http://dx.doi.org/10.1016/j.drudis.2013.02.005DOI Listing
July 2013

Frequency and intensity of exposure mediate resistance to experimental infection with the hookworm, Ancylostoma ceylanicum.

Exp Parasitol 2013 Mar 8;133(3):243-9. Epub 2012 Dec 8.

Program in International Child Health, Department of Pediatrics, Yale School of Medicine, New Haven, CT 06520, USA.

Hookworms are bloodfeeding intestinal nematodes that are a major cause of anemia in resource-limited countries. Despite repeated exposure beginning in early childhood, humans retain lifelong susceptibility to infection without evidence of sterilizing immunity. In contrast, experimental infection of laboratory animals is typically characterized by varying degrees of resistance following primary infection, although the mechanisms underlying this phenomenon remain unknown. In this study, hamsters subjected to a single drug-terminated infection with 100 third stage hookworm larvae were confirmed to be resistant to pathological effects following a subsequent challenge. In a second experiment, hamsters infected twice-weekly with 10 third stage larvae (low inoculum) exhibited clinical and parasitological evidence of continued susceptibility, while those given 100 L3 (high inoculum) developed apparent resistance within 3 days following the initial exposure. The kinetics of parasite-specific IgA, IgM, and IgG antibody production varied by group, which suggests that the humoral immune response to hookworm infection is stimulated by the nature (frequency and intensity) of larval exposure. These results suggest that intermittent low-inoculum larval exposure, which is characterized by prolonged susceptibility to infection, may serve as a more representative model of human hookworm disease for studies of pathogenesis, as well as drug and vaccine development.
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http://dx.doi.org/10.1016/j.exppara.2012.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580025PMC
March 2013

Rethinking molecular similarity: comparing compounds on the basis of biological activity.

ACS Chem Biol 2012 Aug 31;7(8):1399-409. Epub 2012 May 31.

Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

Since the advent of high-throughput screening (HTS), there has been an urgent need for methods that facilitate the interrogation of large-scale chemical biology data to build a mode of action (MoA) hypothesis. This can be done either prior to the HTS by subset design of compounds with known MoA or post HTS by data annotation and mining. To enable this process, we developed a tool that compares compounds solely on the basis of their bioactivity: the chemical biological descriptor "high-throughput screening fingerprint" (HTS-FP). In the current embodiment, data are aggregated from 195 biochemical and cell-based assays developed at Novartis and can be used to identify bioactivity relationships among the in-house collection comprising ~1.5 million compounds. We demonstrate the value of the HTS-FP for virtual screening and in particular scaffold hopping. HTS-FP outperforms state of the art methods in several aspects, retrieving bioactive compounds with remarkable chemical dissimilarity to a probe structure. We also apply HTS-FP for the design of screening subsets in HTS. Using retrospective data, we show that a biodiverse selection of plates performs significantly better than a chemically diverse selection of plates, both in terms of number of hits and diversity of chemotypes retrieved. This is also true in the case of hit expansion predictions using HTS-FP similarity. Sets of compounds clustered with HTS-FP are biologically meaningful, in the sense that these clusters enrich for genes and gene ontology (GO) terms, showing that compounds that are bioactively similar also tend to target proteins that operate together in the cell. HTS-FP are valuable not only because of their predictive power but mainly because they relate compounds solely on the basis of bioactivity, harnessing the accumulated knowledge of a high-throughput screening facility toward the understanding of how compounds interact with the proteome.
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http://dx.doi.org/10.1021/cb3001028DOI Listing
August 2012

From in silico target prediction to multi-target drug design: current databases, methods and applications.

J Proteomics 2011 Nov 18;74(12):2554-74. Epub 2011 May 18.

Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.

Given the tremendous growth of bioactivity databases, the use of computational tools to predict protein targets of small molecules has been gaining importance in recent years. Applications span a wide range, from the 'designed polypharmacology' of compounds to mode-of-action analysis. In this review, we firstly survey databases that can be used for ligand-based target prediction and which have grown tremendously in size in the past. We furthermore outline methods for target prediction that exist, both based on the knowledge of bioactivities from the ligand side and methods that can be applied in situations when a protein structure is known. Applications of successful in silico target identification attempts are discussed in detail, which were based partly or in whole on computational target predictions in the first instance. This includes the authors' own experience using target prediction tools, in this case considering phenotypic antibacterial screens and the analysis of high-throughput screening data. Finally, we will conclude with the prospective application of databases to not only predict, retrospectively, the protein targets of a small molecule, but also how to design ligands with desired polypharmacology in a prospective manner.
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http://dx.doi.org/10.1016/j.jprot.2011.05.011DOI Listing
November 2011

Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia.

Am J Respir Cell Mol Biol 2008 Jun 10;38(6):699-706. Epub 2008 Jan 10.

Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.

While signal transducer and activator of transcription (STAT) 3 signaling has been linked to multiple pathways influencing immune function and cell survival, the direct influence of this transcription factor on innate immunity and tissue homeostasis during pneumonia is unknown. Human patients with dominant-negative mutations in the Stat3 gene develop recurrent pneumonias, suggesting a role for STAT3 in pulmonary host defense. We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram-negative bacterial pneumonia. STAT3 phosphorylation was increased in pneumonic mouse lungs and in murine lung epithelial (MLE)-15 cells stimulated with pneumonic bronchoalveolar lavage fluid (BALF) through 48 hours of Escherichia coli pneumonia. Mice lacking active STAT3 in alveolar epithelial cells (Stat3(Delta/Delta)) had fewer alveolar neutrophils and more viable bacteria than control mice early after intratracheal E. coli. By 48 hours after E. coli infection, however, lung injury was increased in Stat3(Delta/Delta) mice. Bacteria were cleared from lungs of both genotypes, albeit more slowly in Stat3(Delta/Delta) mice. Of the IL-6 family cytokines measured in lungs from infected C57BL/6 mice, IL-6, oncostatin M, leukemia inhibitory factor (LIF), and IL-11 were significantly elevated. Neutralization studies demonstrated that LIF and IL-6 mediated BALF-induced STAT3 activation in MLE-15 cells. Together, these results indicate that during E. coli pneumonia, select IL-6 family members activate alveolar epithelial STAT3, which functions to promote neutrophil recruitment and to limit both infection and lung injury.
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http://dx.doi.org/10.1165/rcmb.2007-0365OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2396249PMC
June 2008

Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia.

J Immunol 2007 Feb;178(3):1896-903

Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA 02115, USA.

Eradication of bacteria in the lower respiratory tract depends on the coordinated expression of proinflammatory cytokines and consequent neutrophilic inflammation. To determine the roles of the NF-kappaB subunit RelA in facilitating these events, we infected RelA-deficient mice (generated on a TNFR1-deficient background) with Streptococcus pneumoniae. RelA deficiency decreased cytokine expression, alveolar neutrophil emigration, and lung bacterial killing. S. pneumoniae killing was also diminished in the lungs of mice expressing a dominant-negative form of IkappaBalpha in airway epithelial cells, implicating this cell type as an important locus of NF-kappaB activation during pneumonia. To study mechanisms of epithelial RelA activation, we stimulated a murine alveolar epithelial cell line (MLE-15) with bronchoalveolar lavage fluid (BALF) harvested from mice infected with S. pneumoniae. Pneumonic BALF, but not S. pneumoniae, induced degradation of IkappaBalpha and IkappaBbeta and rapid nuclear accumulation of RelA. Moreover, BALF-induced RelA activity was completely abolished following combined but not individual neutralization of TNF and IL-1 signaling, suggesting either cytokine is sufficient and necessary for alveolar epithelial RelA activation during pneumonia. Our results demonstrate that RelA is essential for the host defense response to pneumococcus in the lungs and that RelA in airway epithelial cells is primarily activated by TNF and IL-1.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674289PMC
http://dx.doi.org/10.4049/jimmunol.178.3.1896DOI Listing
February 2007

Tumor suppressor PTEN is a physiologic suppressor of chemoattractant-mediated neutrophil functions.

Blood 2007 May 3;109(9):4028-37. Epub 2007 Jan 3.

Department of Pathology, Harvard Medical School, Boston, MA, USA.

The recruitment and activation of neutrophils at infected tissues is essential for host defense against invading microorganisms. However, excessive neutrophil recruitment or activation can also damage the surrounding tissues and cause unwanted inflammation. Hence, the responsiveness of neutrophils needs to be tightly regulated. In this study, we have investigated the functional role of tumor suppressor PTEN in neutrophils by using a mouse line in which PTEN is disrupted only in myeloid-derived cells. Chemoattractant-stimulated PTEN(-/-) neutrophils displayed significantly higher Akt phosphorylation and actin polymerization. A larger fraction of these neutrophils displayed membrane ruffles in response to chemoattractant stimulation. In addition, chemoattractant-induced transwell migration and superoxide production were also augmented. Single-cell chemotaxis assays showed that PTEN(-/-) neutrophils have a small (yet statistically significant) defect in directionality. However, these neutrophils also showed an increase in cell speed. As a result, overall chemotaxis, which depends on speed and directionality, was not affected. Consistent with the increased responsiveness of PTEN(-/-) neutrophils, the in vivo recruitment of these cells to the inflamed peritoneal cavity was significantly enhanced. Thus, as a physiologic-negative regulator, PTEN should be a promising therapeutic target for modulating neutrophil functions in various infectious and inflammatory diseases.
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http://dx.doi.org/10.1182/blood-2006-10-055319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874585PMC
May 2007

Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality.

J Exp Med 2006 Jun 15;203(6):1447-58. Epub 2006 May 15.

Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.
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http://dx.doi.org/10.1084/jem.20060375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118329PMC
June 2006

Roles of interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli pneumonia.

J Infect Dis 2006 Feb 27;193(3):360-9. Epub 2005 Dec 27.

Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA.

Interleukin (IL)-6 concentrations are positively associated with the severity of pneumonia, and this cytokine is essential to surviving experimental pneumococcal pneumonia. The role that IL-6 plays during pneumonia and its impact during gram-negative bacterial pneumonia remain to be determined. During Escherichia coli pneumonia, IL-6-deficient mice had increased bacterial burdens in their lungs, indicating compromised host defenses. Decreased neutrophil counts in alveolar air spaces, despite normal blood neutrophil counts and survival of emigrated neutrophils, suggested that defective neutrophil recruitment was responsible for exacerbating the infection. Neutrophil recruitment requires nuclear factor (NF)- kappa B, but IL-6 was neither sufficient nor essential to induce NF- kappa B-mediated gene expression in the lungs. In contrast, IL-6 induced the phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3 in the lungs, and STAT1 and STAT3 phosphorylation during E. coli pneumonia was decreased by IL-6 deficiency. Thus, IL-6 plays essential roles in activating STAT transcription factors, enhancing neutrophil recruitment, and decreasing bacterial burdens during E. coli pneumonia.
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http://dx.doi.org/10.1086/499312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674298PMC
February 2006

Lung NF-kappaB activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia.

J Immunol 2005 Dec;175(11):7530-5

Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA.

Pulmonary inflammation is an essential component of the host defense against Streptococcus pneumoniae infection of the lungs. The early response cytokines, TNF-alpha and IL-1, are rapidly induced upon microbial exposure. Mice deficient in all TNF- and IL-1-dependent signaling receptors were used to determine the roles of these cytokines during pneumococcal pneumonia. The deficiency of signaling receptors for TNF and IL-1 decreased bacterial clearance. Neutrophil recruitment to alveolar air spaces was impaired by receptor deficiency, as was pulmonary expression of the neutrophil chemokines KC and MIP-2. Because NF-kappaB mediates the expression of both chemokines, we assessed NF-kappaB activation in the lungs. During pneumococcal pneumonia, NF-kappaB proteins translocate to the nucleus and activate gene expression; these functions were largely abrogated by the deficiency of receptors for TNF-alpha and IL-1. Thus, the combined deficiency of TNF and IL-1 signaling reduces innate immune responses to S. pneumoniae in the lungs, probably due to essential roles for these receptors in activating NF-kappaB.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723739PMC
http://dx.doi.org/10.4049/jimmunol.175.11.7530DOI Listing
December 2005