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At least 1,477 records · Page 82Linked to original sources
PubMed2004

Synergistic effect of vitamin E and selenium in human prostate cancer cell lines.

Vitamin E and selenium are the two most popular dietary supplements used to prevent prostate cancer. The hypothesis that these antioxidants reduce prostate risk is being tested in the selenium and vitamin E chemoprevention trial (SELECT). We hypothesize that selenium potentiates vitamin E-induced inhibition of prostate cancer cell growth in vitro. Prostate cancer cell populations growing asynchronously were treated with a combination of vitamin E and selenium and processed for flow cytometric analysis. Prostate cancer cells treated with a combination of the antioxidants revealed that selenium potentiates vitamin E-induced inhibition of LNCaP cells in vitro. This was demonstrated by a reduction in the percentage of cells in the S phase. This crucial finding confirms our previous observations that antioxidant molecules act via distinct mechanistic pathways. These independent biological effects can be exploited in order to augment the anticancer properties of individual agents. These data also validate the two factorial design of the SELECT trial, permitting pairwise comparisons between agents in combination and alone.

Antioxidants↗
PubMed2006

Dynamic single cell culture array.

It is important to quantify the distribution of behavior amongst a population of individual cells to reach a more complete quantitative understanding of cellular processes. Improved high-throughput analysis of single cell behavior requires uniform conditions for individual cells with controllable cell-cell interactions, including diffusible and contact elements. Uniform cell arrays for static culture of adherent cells have previously been constructed using protein micropatterning techniques but lack the ability to control diffusible secretions. Here we present a microfluidic-based dynamic single cell culture array that allows both arrayed culture of individual adherent cells and dynamic control of fluid perfusion with uniform environments for individual cells. In our device no surface modification is required and cell loading is done in less than 30 seconds. The device consists of arrays of physical U-shaped hydrodynamic trapping structures with geometries that are biased to trap only single cells. HeLa cells were shown to adhere at a similar rate in the trapping array as on a control glass substrate. Additionally, rates of cell death and division were comparable to the control experiment. Approximately 100 individual isolated cells were observed growing and adhering in a field of view spanning approximately 1 mm(2) with greater than 85% of cells maintained within the primary trapping site after 24 hours. Also, greater than 90% of cells were adherent and only 5% had undergone apoptosis after 24 hours of perfusion culture within the trapping array. We anticipate uses in single cell analysis of drug toxicity with physiologically relevant perfused dosages as well as investigation of cell signaling pathways and systems biology.

Cell Adhesion↗
PubMed2004

Getting to grips with the granulocyte: manipulation of granulocyte behaviour and apoptosis by protein transduction methods.

Human granulocytes clearly play an important role in host defence against invading organisms, however they have also been implicated in the pathogenesis and progression of many chronic inflammatory diseases. In addition, these cells have been paramount in gaining a better understanding of many key-signalling pathways regulating fundamental biological processes. Since granulocytes are terminally differentiated and undergo relatively rapid constitutive apoptosis it has been difficult to manipulate intracellular events by transfection or transduction procedures. It has been shown in recent years that the HIV-TAT protein transduction system can be successfully used in granulocytes to manipulate key signalling mechanisms regulating functional responsiveness and survival. In this paper, we review recent literature highlighting important developments using this system in isolated human granulocytes and in inflammatory process in vivo where these cells play a prominent role.

Apoptosis↗
PubMed2003

Progress and new technologies for developing vaccines against gastrointestinal nematode parasites of sheep.

Despite the identification of highly effective native antigens for vaccination against Haemonchus contortus, particularly 'hidden' antigens derived from the intestine of adult worms, to date similar efficacy has not been shown with recombinant antigens. In addition, progress towards identification of protective antigens from other sheep gastrointestinal (GI) nematode species is limited. Coupled with this is an incomplete understanding of the mechanism of natural immunity to GI nematodes, making selection of appropriate immunization strategies and adjuvants for evaluation of candidate 'natural' antigens problematic. The current explosion in new high-throughput technologies, arising from human studies, for analysis of the genome, transcriptome, proteome and glycome offers the opportunity to gain a better understanding of the molecular pathways underlying pathogen biology, the host immune system and the host-pathogen interaction. An overview is provided on how these technologies can be applied to parasite research and how they may aid in overcoming some of the current problems in development of commercial vaccines against GI nematode parasites.

Animals↗
PubMedDate not supplied

The impact of genetic polymorphisms on the protein composition of ruminant milks.

The purpose of this review is to give an overview of our current knowledge on the polymorphisms occurring in genes coding for milk proteins and responsible for quantitative variability in their expression, thus influencing the protein composition of livestock ruminant milk. The overall genomic organisation of the 6 main ruminant milk protein genes: alpha-lactalbumin, beta-lactoglobulin and the four caseins (alpha(s1), alpha(s2), beta and kappa), their chromosomal location and their expression pattern are first summarised before presenting general mechanisms controlling gene expression both at the transcriptional and the post-transcriptional levels. Polymorphisms found in cis-regulatory elements, mainly within the 5'-flanking region of the genes encoding beta-lactoglobulin and alpha(s1)- and alpha(s2)-caseins, have been found, in cattle, to influence their transcription rate. In addition, polymorphisms found in the transcription unit, within intron as well as exon sequences, have been shown to be responsible for defects in the processing of primary transcripts and/or the export of messenger RNA to the cytoplasm. Mutations responsible for the occurrence of premature stop codons in alpha(s1)- and beta-casein mRNAs have been shown to be associated both with a decrease in the level of the relevant transcripts and the existence of multiple forms of messengers due to alternative splicing (exon skipping, usage of cryptic splice sites). Such a situation, well-exemplified by the gene encoding alpha(s1)-casein in the goat, may have dramatic biological consequences (secretion pathway, casein micelle structure, fat content, etc.) by modifying the message and accordingly the primary structure of the protein as well as its expression. Since some of these polymorphisms dramatically affect technological properties of milk, including cheese yields and organoleptic characteristics, methods mainly based on the PCR technique have been designed and applied in selection and breeding programmes to improve milk protein quality.

Animals↗
PubMed2004

Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo.

There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOs, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.

Animals↗
PubMed2003

Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model.

Epidemiological studies support a link between melanoma risk and UV exposure early in life, yet the molecular targets of UV's mutagenic actions are not known. By using well characterized murine models of melanoma, we provide genetic and molecular evidence that identifies components of the Rb pathway as the principal targets of UV mutagenesis in murine melanoma development. In a melanoma model driven by H-RAS activation and loss of p19(ARF) function, UV exposure resulted in a marked acceleration in melanoma genesis, with nearly half of these tumors harboring amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification. Moreover, UV-induced melanomas showed a strict reciprocal relationship between cdk6 amplification and p16(INK4a) loss, which is consistent with the actions of UV along the Rb pathway. Most significantly, UV exposure had no impact on the kinetics of melanoma driven by H-RAS activation and p16(INK4a) deficiency. Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo.

Animals↗
PubMed1997

Benzo[a]pyrene diol epoxide-DNA cis adduct formation through a trans chlorohydrin intermediate.

Alkylation of DNA by 7r,8t-dihydroxy,9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) forms mainly trans adducts (with respect to the C-9/10 positions). We recently described a halide-catalyzed pathway that preferentially generates cis adducts and now report that the trans chlorohydrin of anti-BPDE (trans-BPDCH) is an intermediate in the chloride-catalyzed reaction. trans-BPDCH was synthesized, and both it and anti-BPDE were reacted with deoxyadenosine as a model DNA nucleophile. The stereochemistry and yields of deoxyadenosine adducts were determined as a function of chloride concentration. In the absence of salt, the fraction of cis adducts obtained from anti-BPDE and trans-BPDCH are 0.33 and 0.67, respectively. Adding sodium chloride increases the fraction of cis adducts (and consequently decreases the fraction of trans adducts), with the midpoint of the increase for both substrates at approximately 35-40 mM chloride. The chloride-dependent curves for BPDE and BPDCH converge at 1 M chloride, where the fraction of cis adducts is 0.88. Chloride also increases the total yield of cis adducts with either substrate, whereas the yield of trans adducts from the chlorohydrin is not significantly changed. These results support a mechanism by which chloride ion undergoes nucleophilic addition to the benzylic C-10 position of anti-BPDE. This generates a trans halohydrin that alkylates DNA with inversion of configuration to form a cis adduct. This pathway may have biological significance because chlorohydrins could form in serum or in cells with relatively high intracellular concentrations of chloride.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase.

Sphingomyelinase (SMase) activation and ceramide generation have emerged as an important signaling pathway transducing diverse biological effects of cytokine receptors like p55 tumor necrosis factor (TNF) receptor or Fas. Here we describe the TNF-dependent activation of acid SMase (A-SMase) through the p55 TNF receptor-associated proteins TRADD and FADD. Overexpression of TRADD and FADD in 293 cells did not change basal activity of A-SMase but enhanced TNF-induced stimulation of A-SMase. Other TNF R55-associated proteins like TRAF2 and RIP, which were reported to mediate TNF R55-mediated activation of nuclear factor kappaB, did not affect activation of A-SMase. Caspase inhibitors markedly reduced A-SMase activity, suggesting the involvement of an ICE-like protease in TRADD/FADD-mediated activation of A-SMase. Overexpression of caspase-8/a (FLICE/MACH) or caspase-10/b (FLICE2) did not change A-SMase activity, suggesting that TRADD/FADD-mediated activation of A-SMase involves a yet to be defined caspase-like protease distinct from caspase-8/a or -10/b.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho.

Small GTP-binding proteins of the Rho family play a critical role in signal transduction. However, there is still very limited information on how they are activated by cell surface receptors. Here, we used a consensus sequence for Dbl domains of Rho guanine nucleotide exchange factors (GEFs) to search DNA data bases, and identified a novel human GEF for Rho-related GTPases harboring structural features indicative of its possible regulatory mechanism(s). This protein contained a tandem DH/PH domain closely related to those of Rho-specific GEFs, a PDZ domain, a proline-rich domain, and an area of homology to Lsc, p115-RhoGEF, and a Drosophila RhoGEF that was termed Lsc-homology (LH) domain. This novel molecule, designated PDZ-RhoGEF, activated biological and biochemical pathways specific for Rho, and activation of these pathways required an intact DH and PH domain. However, the PDZ domain was dispensable for these functions, and mutants lacking the LH domain were more active, suggesting a negative regulatory role for the LH domain. A search for additional molecules exhibiting an LH domain revealed a limited homology with the catalytic region of a newly identified GTPase-activating protein for heterotrimeric G proteins, RGS14. This prompted us to investigate whether PDZ-RhoGEF could interact with representative members of each G protein family. We found that PDZ-RhoGEF was able to form, in vivo, stable complexes with two members of the Galpha12 family, Galpha12 and Galpha13, and that this interaction was mediated by the LH domain. Furthermore, we obtained evidence to suggest that PDZ-RhoGEF mediates the activation of Rho by Galpha12 and Galpha13. Together, these findings suggest the existence of a novel mechanism whereby the large family of cell surface receptors that transmit signals through heterotrimeric G proteins activate Rho-dependent pathways: by stimulating the activity of members of the Galpha12 family which, in turn, activate an exchange factor acting on Rho.

Amino Acid Sequence↗
PubMed2001

Conditional expression of RNase P in the cyanobacterium Synechocystis sp. PCC6803 allows detection of precursor RNAs. Insight in the in vivo maturation pathway of transfer and other stable RNAs.

We have constructed a strain (CT1) that expresses RNase P conditionally with the aim to analyze the in vivo tRNA processing pathway and the biological role that RNase P plays in Synechocystis 6803. In this strain, the rnpB gene, coding for the RNA subunit of RNase P, has been placed under the control of the petJ gene promoter (P(petJ)), which is repressed by copper, cell growth, and accumulation of RNase P RNA is inhibited in CT1 after the addition of copper, indicating that the regulation by copper is maintained in the chimerical P(petJ)-rnpB gene and that RNase P is essential for growth in Synechocystis. We have analyzed several RNAs by Northern blot and primer extension in CT1. Upon addition of copper to the culture medium, precursors of the mature tRNAs are detected. Furthermore, our results indicate that there is a preferred order in the action of RNase P when it processes a dimeric tRNA precursor. The precursors detected are 3'-processed, indicating that 3' processing can occur before 5' processing by RNase P. The size of the precursors suggests that the terminal CCA sequence is already present before RNase P processing. We have also analyzed other potential RNase P substrates, such as the precursors of tmRNA and 4.5 S RNA. In both cases, accumulation of larger than mature size RNAs is observed after transferring the cells to a copper-containing medium.

Base Sequence↗
PubMed2006

The low density lipoprotein receptor-related protein functions as an endocytic receptor for decorin.

Decorin is a small leucine-rich proteoglycan that modulates the activity of transforming growth factor type beta and other growth factors and thereby influences the processes of proliferation and differentiation in a wide array of physiological and pathological reactions. Hence, understanding the regulatory mechanisms of decorin activity has broad implications. Here we report that the extracellular levels of decorin are controlled by receptor-mediated catabolism, involving the low density lipoprotein receptor family member, low density lipoprotein receptor-related protein (LRP). We show that decorin is endocytosed and degraded by C2C12 myoblast cells and that both processes are blocked by suppressing LRP expression using short interfering RNA. The same occurs with CHO cells, but not with CHO cells genetically deficient in LRP. Finally, we show that LRP-null CHO cells, transfected to express mini-LRP polypeptides containing either the second or fourth LRP ligand-binding domains, carry out decorin endocytosis and lysosomal degradation. These findings point to LRP-mediated catabolism as a new control pathway for the biological activities of decorin, specifically for its ability to influence extracellular matrix signaling.

Animals↗
PubMed2006

Mutations of TGFbeta signaling molecules in human disease.

The transforming growth factor beta (TGFbeta) signaling pathway regulates several biological processes including cellular proliferation, differentiation, apoptosis, migration, and extracellular matrix deposition. Ligand and receptor family members signal through two main Smad signaling branches, TGFbeta/activin to Smad2/3 (Sma and MAD-related proteins) and bone morphogenetic protein (BMP) to Smad1/5. At the molecular level, TGFbeta acts by modifying cytoskeletal organization and ultimately regulating expression of specific target genes. Germline disruption of TGFbeta signaling leads to several types of hereditary congenital malformation or dysfunction of the skeletal, muscular and/or cardiovascular systems, and to cancer predisposition syndromes. In this review, the molecular etiology of TGFbeta-associated disorders is examined, together with a discussion of clinical overlap between syndromes and possible biological explanations underlying the variable penetrance and expressivity of clinical characteristics. Increasing our understanding of the molecular etiology underlying genotype-phenotype correlations will ultimately provide a molecular-based approach that should result in better prognostic tools, smart therapeutics and individualized disease management, not only for these rare syndromes, but for more generalized disorders of the cardiovascular and musculoskeletal systems and cancer. The clinical consequence of TGFbeta signaling mutations appears to depend on environmental factors and on the basal levels of ongoing signaling transduction networks specific to each individual. In this respect, genetic background might be a central factor in determining disease outcome and treatment strategy for TGFbeta-associated diseases.

Genetic Diseases, Inborn↗
PubMed2005

Class prediction in toxicogenomics.

The intent of this article is to discuss some of the complexities of toxicogenomics data and the statistical design and analysis issues that arise in the course of conducting a toxicogenomics study. We also describe a procedure for classifying compounds into various hepatotoxicity classes based on gene expression data. The methodology involves first classifying a compound as toxic or nontoxic and subsequently classifying the toxic compounds into the hepatotoxicity classes, based on votes by binary classifiers. The binary classifiers are constructed by using genes selected to best elicit differences between the two classes. We show that the gene selection strategy improves the misclassification error rates and also delivers gene pathways that exhibit biological relevance.

Algorithms↗
PubMed2006

Establishment of a discriminant mathematical model for diagnosis of deficiency-cold syndrome using gene expression profiling.

OBJECTIVE: To screen diagnostic markers of Deficiency-Cold syndrome by gene expression profile and to establish a discriminant mathematical milliliters model for the clinical diagnosis of this syndrome based on a support vector machine (SVM). METHODS: A family suffering from Deficiency-Cold syndrome is chosen for this study. This family has 5 patients with Deficiency-Cold syndrome and 10 normal members. The peripheral blood samples for these 5 patients and 5 normal members are tested by using cDNA microarray with 18,816 clones to get their differential expression genes. These genes are further explored to understand their biological functions and pathways through existing databases. A SVM model for clinical diagnosis is then developed based on these differential expression genes. RESULTS: A total of 83 differential expression genes were identified between patients and normal members, in which 21 genes were recorded in the FATIGO database and 16 genes were related to metabolism. Eight (8) pathways were sorted out in the KEGG database, and half pathways were associated with human metabolism. A discriminant mathematical model based on a support vector machine successfully predicted a normal person and a patient with heavy Deficiency-Cold syndrome based on their gene differential expression profiles. Thus, this model may classify the Deficiency-Cold syndrome. CONCLUSION: This work demonstrates that the differential expression genes can be used to identify normal persons and patients with Deficiency-Cold syndrome. Deficiency-Cold syndrome is mainly associated with the metabolism-related gene regulations. In addition, the discriminant mathematical model based on a support vector machine is applicable to the clinical diagnosis for Deficiency-Cold syndrome.

Adolescent↗
PubMedDate not supplied

Reactive oxygen species as signaling molecules in cardiovascular differentiation of embryonic stem cells and tumor-induced angiogenesis.

Besides the well known pathophysiological impact of oxidative stress in cardiovascular disease, reactive oxygen species (ROS) generated at low concentrations exert a role as signaling molecules that are involved in signal transduction cascades of numerous growth factor-, cytokine-, and hormone-mediated pathways, and regulate biological effects such as apoptosis, cell proliferation, and differentiation. Embryonic stem cells have the capacity to differentiate into the cardiovascular cell lineage. Furthermore, upon confrontation culture with tumor tissue, they form blood vessel-like structures that induce tumor-induced angiogenesis within tumor tissues. The role of ROS in cardiovascular differentiation of embryonic stem cells appears to be antagonistic. Whereas continuous exposure to ROS results in inhibition of cardiomyogenesis and vasculogenesis, pulse chase exposure to low-level ROS enhances differentiation toward the cardiomyogenic as well as vascular cell lineage. This review summarizes the current knowledge of ROS-induced cardiovascular differentiation of embryonic stem cells as well as the role of ROS in tumor-induced angiogenesis.

Animals↗
PubMed2005

Statistical issues in life course epidemiology.

There is growing recognition that the risk of many diseases in later life, such as type 2 diabetes or breast cancer, is affected by adult as well as early-life variables, including those operating prior to conception and during the prenatal period. Most of these risk factors are correlated because of common biologic and/or social pathways, while some are intrinsically ordered over time. The study of how they jointly influence later ("distal") disease outcomes is referred to as life course epidemiology. This area of research raises several issues relevant to the current debate on causal inference in epidemiology. The authors give a brief overview of the main analytical and practical problems and consider a range of modeling approaches, their differences determined by the degree with which associations present (or presumed) among the correlated explanatory variables are explicitly acknowledged. Standard multiple regression (i.e., conditional) models are compared with joint models where more than one outcome is specified. Issues arising from measurement error and missing data are addressed. Examples from two cohorts in the United Kingdom are used to illustrate alternative modeling strategies. The authors conclude that more than one analytical approach should be adopted to gain more insight into the underlying mechanisms.

Causality↗
PubMed2025

Associations on the Fly, a new feature aiming to facilitate exploration of the Open Targets Platform evidence.

MOTIVATION: The Open Targets Platform (https://platform.opentargets.org) is a unique, comprehensive, open-source resource supporting systematic identification and prioritisation of targets for drug discovery. The Platform combines, harmonizes and integrates data from >20 diverse sources to provide target-disease associations, covering evidence derived from genetic associations, somatic mutations, known drugs, differential expression, animal models, pathways and systems biology. An in-house target identification scoring framework weighs the evidence from each data source and type, contributing to an overall score for each of the 7.8M target-disease associations. However, the old infrastructure did not allow user-led dynamic adjustments in the contribution of different evidence types for target prioritisation, a limitation frequently raised by our user community. Furthermore, the previous Platform user interface did not support navigation and exploration of the underlying target-disease evidence on the same page, occasionally making the user journey counterintuitive. RESULTS: Here, we describe 'Associations on the Fly' (AOTF), a new Platform feature-developed with a user-centred vision-that enables the user to formulate more flexible therapeutic hypotheses through dynamic adjustment of the weight of contributing evidence from each source, altering the prioritisation of targets. AVAILABILITY AND IMPLEMENTATION: The codebases that power the Platform-including our pipelines, GraphQL API, and React UI-are all open source and licensed under the APACHE LICENSE, VERSION 2.0. You can find all of our code repositories on GitHub at https://github.com/opentargets and on Zenodo at https://zenodo.org/records/14392214. This tool was implemented using React v18 and its code is accessible here: (https://github.com/opentargets/ot-ui-apps). The tools are accessible through the Open Targets Platform web interface (https://platform.opentargets.org/) and GraphQL API (https://platform-docs.opentargets.org/data-access/graphql-api). Data is available for download here: (https://platform.opentargets.org/downloads) and from the EMBL-EBI FTP: (https://ftp.ebi.ac.uk/pub/databases/opentargets/platform/).

Software↗