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At least 631 records · Page 35Linked to original sources
PubMed2005

Functional characterization of full-length TLR3, IRAK-4, and TRAF6 in zebrafish (Danio rerio).

Recently, the zebrafish, Danio rerio, has been recognized as a useful model for infectious disease and immunity. The Toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system that responds to specific pathogen-associated molecular patterns (PAMPs) during an infection. This study reports the identification and characterization of a full-length orthologue of mammalian TLR3, and the key TLR pathway signaling molecules IRAK-4 and TRAF6 in the zebrafish. Sequence analysis of zebrafish TLR3 (zfTLR3), IRAK-4 (zfIRAK-4), and TRAF6 (zfTRAF6) revealed conserved domains shared with insect and mammalian genes. Quantitative real-time PCR showed that all three genes are expressed in a variety of adult tissues and during embryonic development. In in situ hybridization, we showed that zfTLR3, zfIRAK-4, and zfTRAF6 are present in distinct regions of the developing brain at 22hpf and that zfTRAF6 was observed in the developing medial neural tube. Overexpression of zfIRAK-4, zfTRAF6, or a mutant zfTLR3 construct was able to stimulate NF-kappaB activation in ZFL cells as measured by a cotransfected NF-kappaB-luciferase reporter plasmid. Messenger RNA expression profiles of each gene in zebrafish embryos and adults were examined by quantitative real-time PCR following infection with snakehead rhabdovirus (SHRV) or Edwardsiella tarda. Following exposure to SHRV, only zfTLR3 and zfTRAF6 mRNA transcripts were upregulated. Interestingly, exposure of fish to E. tarda resulted in an unexpected increase in mRNA expression of zfTLR3, as well as the anticipated upregulation of zfIRAK-4 and zfTRAF6 mRNA transcripts. These results demonstrate that zebrafish possess conserved TLR-signaling pathways, further emphasizing the utility of the zebrafish as a model for vertebrate immunology.

Amino Acid Sequence↗
PubMed2005

Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton.

Osteoporosis is a common, increasingly prevalent and potentially debilitating condition of men and women. Genetic factors are major determinants of bone mass and the risk of fracture, but few genes have been definitively demonstrated to be involved. The identification of these factors will provide novel insights into the processes of bone formation and loss and thus the pathogenesis of osteoporosis, enabling the rational development of novel therapies. In this article, we present the extensive genetic and functional data indicating that the LRP5 gene and the Wnt signalling pathway are key players in bone formation and the risk of osteoporosis, and that LRP5 signalling is essential for normal morphology, developmental processes and bone health.

Animals↗
PubMed2004

Changes in expression level of genes as a function of time of day in the liver of rats.

Daily, rhythmic variation in various biochemical, physiological, and behavioral events is a fundamental property of biological organization. Here, we report analysis of relative levels of gene expression in the liver of 16 Fischer 344 rats as a function of time of day. Expression levels were determined for 3906 genes using high-density oligonucleotide microarrays. Of the 3906 genes, 1171 (30%) were clearly expressed while 2735 (70%) were not expressed or the expression was too low to distinguish from background levels. The maximum estimated changes observed for most genes (1029, 88%) were less than 1.5-fold. Analysis of variance and the Kruskal-Wallis tests were used to identify 67 genes whose expression was significantly altered as a function of time of day. These significantly altered genes were classified according to their functions and fall into key cellular pathways including drug metabolism, ion transport, signal transduction, DNA binding and regulation of transcription, and immune response.

Animals↗
PubMed2006

In vivo mapping of functional connectivity in neurotransmitter systems using pharmacological MRI.

Pharmacological MRI (phMRI) methods map the hemodynamic response to drug challenge as a surrogate for changes in neuronal activity. However, the central effects of drugs can be complex and include activity at the primary site of action, downstream effects in other brain regions and direct effects on vasculature and neurovascular coupling. Univariate analysis, normally applied to phMRI data, does not discriminate between these effects, and can result in anatomically non-specific activation patterns. We analysed inter-subject correlations in the amplitude of the slow phMRI response to map functionally connected brain regions recruited in response to pharmacological challenge. Application of D-amphetamine and fluoxetine revealed well-defined functional structure underlying the widespread signal changes detected via standard methods. Correlated responses were found to delineate key neurotransmitter pathways selectively targeted by these drugs, corroborating a tight correspondence between the phMRI response and changes in neurotransmitter systems specific to the pharmacological action. In vivo mapping of correlated responses in this way greatly extends the range of information available from phMRI studies and provides a new window into the function of neurotransmitter systems in the active state. This approach may provide new important insights regarding the central systems underlying pharmacological action.

Animals↗
PubMed2006

Crosstalk between abiotic and biotic stress responses: a current view from the points of convergence in the stress signaling networks.

Plants have evolved a wide range of mechanisms to cope with biotic and abiotic stresses. To date, the molecular mechanisms that are involved in each stress has been revealed comparatively independently, and so our understanding of convergence points between biotic and abiotic stress signaling pathways remain rudimentary. However, recent studies have revealed several molecules, including transcription factors and kinases, as promising candidates for common players that are involved in crosstalk between stress signaling pathways. Emerging evidence suggests that hormone signaling pathways regulated by abscisic acid, salicylic acid, jasmonic acid and ethylene, as well as ROS signaling pathways, play key roles in the crosstalk between biotic and abiotic stress signaling.

Plant Diseases↗
PubMed2005

Melanocortin-4 receptors, beta-MSH and leptin: key elements in the satiety pathway.

This paper reviews aspects of our research, focusing on the role of the melanocortin system in the central regulation of feeding and energy balance, which was begun in 1997. It describes data from successive physiological studies, concerning the identity of the appetite-regulating melanocortin receptor, melanocortin-4 receptor (MC4R) regulation with altered nutritional status, the role of MC4R in dietary obesity and the identity of the endogenous MC4R ligand.

Animals↗
PubMed2006

Antipsychotic drugs disrupt normal development in Caenorhabditis elegans via additional mechanisms besides dopamine and serotonin receptors.

Antipsychotic drugs may produce adverse effects during development in humans and rodents. However, the extent of these effects has not been systematically characterized nor have molecular mechanisms been identified. Consequently, we sought to evaluate the effects of an extensive panel of antipsychotic drugs in a model organism, Caenorhabditis elegans, whose development is well characterized and which offers the possibility of identifying novel molecular targets. For these studies, animals were grown from hatching in the presence of vehicle (control) or antipsychotic drugs over a range of concentrations (20-160microM) and growth was analyzed by measuring head-to-tail length at various intervals. First-generation antipsychotics (e.g., fluphenazine) generally slowed growth and maturation more than second-generation drugs such as quetiapine and olanzapine. This is consistent with in vitro effects on human neuronal cell lines. Clozapine, a second-generation drug, produced similar growth deficits as haloperidol. Converging lines of evidence, including the failure to rescue growth with high concentrations of agonists, suggested that the drug-induced delay in development was not mediated by the major neurotransmitter receptors recognized by the antipsychotic drugs. Moreover, in serotonin-deficient tph-1 mutants, the drugs dramatically slowed development and led to larval arrest (including dauer formation) and neuronal abnormalities. Evaluation of alternative targets of the antipsychotics revealed a potential role for calmodulin and underscored the significance of Ca(2+)-calmodulin signaling in development. These findings suggest that antipsychotic drugs may interfere with normal developmental processes and provide a tool for investigating the key signaling pathways involved.

Animals↗
PubMed2005

Stereoselective synthesis of monomeric flavonoids.

Polyphenolic compounds have recently attracted considerable interest in the field of nutrition, health and medicine. This is the result of the growing body of evidence suggesting that these compounds may act as potent antioxidants and/or modulate key biological pathways in vivo in mammals. Studies aimed at comprehending the intricate principles that govern the chemistry of these important natural products have thus accelerated over the past decade. Prominent amongst these is the ability to synthesize monomeric prototypes with and without 13C- and radio-labeling. Endeavors exploiting the stereoselective syntheses of representative classes of flavonoid monomers are reviewed here.

Flavonoids↗
PubMed2004

Roles of mitogen activated protein kinases and EGF receptor in arsenite-stimulated matrix metalloproteinase-9 production.

The dermatotoxicity of arsenic is well established and epidemiological studies identify an increased incidence of keratinocytic tumors (basal cell and squamous cell carcinoma) associated with arsenic exposure. Little is known about the underlying mechanisms of arsenic-mediated skin carcinogenesis, but activation of mitogen-activated protein (MAP) kinases and subsequent regulation of downstream target genes may contribute to tumor promotion and progression. In this study, we investigated activation of the extracellular signal regulated kinase (ERK) and the stress-associated kinase p38 by arsenite in HaCat cells, a spontaneously immortalized human keratinocyte cell line. Arsenite concentrations > or =100 microM stimulate rapid activation of p38 and ERK MAP kinases. However, upon extended exposure (24 h), persistent stimulation of p38 and ERK MAP kinases was detected at low micromolar concentrations of arsenite. Although ERK and p38 were activated with similar time and concentration dependence, the mechanism of activation differed for these two MAP kinases. ERK activation by arsenite was fully dependent on the catalytic activity of the epidermal growth factor (EGF) receptor and partially dependent on Src-family kinase activity. In contrast, p38 activation was independent of EGF receptor or Src-family kinase activity. Arsenite-stimulated MAP kinase signal transduction resulted in increased production of matrix metalloproteinase (MMP)-9, an AP-1 regulated gene product. MMP-9 induction by arsenite was prevented when EGF receptor or MAP kinase signaling was inhibited. These studies indicate that EGF receptor activation is a component of arsenite-mediated signal transduction and gene expression in keratinocytes and that low micromolar concentrations of arsenite stimulate key signaling pathways upon extended exposure. Stimulation of MAP kinase cascades by arsenic and subsequent regulation of genes including c-fos, c-jun, and the matrix degrading proteases may play an important role in arsenic-induced skin carcinogenesis.

Arsenites↗
PubMed2005

Developmental decisions in Dictyostelium discoideum.

Dictyostelium discoideum is an excellent system in which to study developmental decisions. Synchronous development is triggered by starvation and rapidly generates a limited number of cell types. Genetic and image analyses have revealed the elegant intricacies associated with this simple development system. Key signaling pathways identified as regulating cell fate decisions are likely to be conserved with metazoa and are providing insight into differentiation decisions under circumstances where considerable cell movement takes place during development.

Animals↗
PubMed2006

Chromatin modifications in the germinal vesicle (GV) of mammalian oocytes.

The nucleus of eukaryotic cells is organized into functionally specialized compartments that are essential for the control of gene expression, chromosome architecture and cellular differentiation. The mouse oocyte nucleus or germinal vesicle (GV) exhibits a unique chromatin configuration that is subject to dynamic modifications during oogenesis. This process of 'epigenetic maturation' is critical to confer the female gamete with meiotic as well as developmental competence. In spite of its biological significance, little is known concerning the cellular and molecular mechanisms regulating large-scale chromatin structure in mammalian oocytes. Here, recent findings that provide mechanistic insight into the complex relationship between large-scale chromatin structure and global transcriptional repression in pre-ovulatory oocytes will be discussed. Post-translational modifications of histone proteins such as acetylation and methylation are crucial for heterochromatin formation and thus play a key role in remodeling the oocyte genome. This strategy involves multiple and hierarchical chromatin modifications that regulate nuclear dynamics in response to a developmentally programmed signal(s), presumably of paracrine origin, before the resumption of meiosis. Models for the experimental manipulation of large-scale chromatin structure in vivo and in vitro will be instrumental to determine the key cellular pathways and oocyte-derived factors involved in genome-wide chromatin modifications. Importantly, analysis of the functional differentiation of chromatin structure in the oocyte genome with high resolution and in real time will have wide-ranging implications to understand the role of nuclear organization in meiosis, the events of nuclear reprogramming and the spatio-temporal regulation of gene expression during development and differentiation.

Animals↗
PubMed2005

Skeletal muscle stem and progenitor cells: reconciling genetics and lineage.

Skeletal muscle provides a unique paradigm for studying stem to differentiated cell transitions, as well as the acquisition of cellular identity. Embryological and genetic studies over the last decades have unveiled key signaling pathways and regulatory genes which are involved in this process. In the adult, regeneration from fiber-associated satellite cells as well as non-muscle cells have opened the perspective for cell therapy studies. Paradoxically, however, the lineage has remained largely elusive. Recent studies have provided clues regarding the cellular organization in this lineage. Furthermore, the complexity of the genetic networks regulating global and local myogenic programs can be correlated with location and lineage. Finally, prenatal and postnatal developmental strategies have similarities and differences which will also be highlighted.

Animals↗
PubMed2026

Comprehensive analysis of metabolomics and transcriptomics of radiation-induced rectal injury.

Radiation-induced rectal injury (RRI) significantly affects the quality of life in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NCRT). Non-targeted liquid chromatography-mass spectrometry metabolomics analysis and transcriptomic analysis were conducted to explore RRI characteristics. Hematoxylin-eosin and Masson staining confirmed radiation-induced injury in rectal tissue within the radiotherapy target region. Orthogonal partial least squares discriminant analysis identified 823 differentially expressed metabolites (DEMs). Transcriptomic analysis revealed 400 differentially expressed genes (DEGs). Enrichment analysis revealed that DEMs and DEGs were primarily involved in metabolic, immune, and signal transduction pathways. Integrated analysis demonstrated significant enrichment of DEMs and DEGs in the arachidonic acid metabolism pathway. Pearson's correlation and canonical correlation analyses were used to assess the association between DEMs and DEGs within this pathway. In conclusion, this study identified key biological regulatory pathways involved in RRI through a multi-omics approach, offering potential targets for its diagnosis and treatment.

Humans↗
PubMed1989

Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors.

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.

Animals↗
PubMed2003

Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation.

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.

Animals↗
PubMed2002

Sulfur mustard-induced arachidonic acid release is mediated by phospholipase D in human keratinocytes.

Sulfur mustard (2,2(')-dichloroethyl sulfide) is a chemical warfare agent that causes incapacitating skin blisters in humans 12-24h post-exposure following a variable asymptomatic phase. Recent reports demonstrate that inflammation plays a vital role in sulfur mustard toxicity. One of the key biochemical pathways involved in inflammation is the arachidonic acid cascade. In this report, we demonstrate that arachidonic acid is released in response to sulfur mustard and investigate the mechanisms of arachidonic acid release. Exposure to sulfur mustard caused a 5- to 8-fold increase in arachidonic acid release from human keratinocytes that had been radiolabeled with arachidonic acid. Maximal arachidonic acid release occurred between 12 and 24h. Several enzymatic pathways can lead to arachidonic acid release. Treatment with 2.0% (v/v) ethanol, an inhibitor of phospholipase D, decreased sulfur mustard-induced arachidonic acid release 40+/-7%. Additionally, 100 microM (+/-)-propranolol, an inhibitor of phosphatidic acid phosphohydrolase, blocked sulfur mustard-induced arachidonic acid release by 62+/-3%. These findings suggest that arachidonic acid release is mediated by phospholipase D and phosphatidic acid phosphohydrolase in human keratinocytes following sulfur mustard exposure. Due to the 12-24h delay in arachidonic acid release following sulfur mustard exposure, delayed therapeutic intervention may be possible. Indeed, we found that the addition of 100 microM (+/-)-propranolol up to 18 h after sulfur mustard exposure was still able to block arachidonic acid release by 30+/-3%.

Arachidonic Acid↗
PubMed2001

Multi-stage regulation, a key to reliable adaptive biochemical pathways.

A general "multi-stage" regulation model, based on linearly connected regulatory units, is formulated to demonstrate how biochemical pathways may achieve high levels of accuracy. The general mechanism, which is robust to changes in biochemical parameters, such as protein concentration and kinetic rate constants, is incorporated into a mathematical model of the bacterial chemotaxis network and provides a new framework for explaining regulation and adaptiveness in this extensively studied system. Although conventional theories suggest that methylation feedback pathways are responsible for chemotactic regulation, the model, which is deduced from known experimental data, indicates that protein interactions downstream of the bacterial receptor complex, such as CheAs and CheZ, may play a crucial and complementary role.

Bacterial Physiological Phenomena↗
PubMed2002

CD38 ligation plays a direct role in the induction of IL-1beta, IL-6, and IL-10 secretion in resting human monocytes.

CD38 signaling, either induced by ligation with specific agonistic monoclonal antibody (mAb) or after interaction with CD31, its cognate counter-receptor, is involved in release of IL-1beta, IL-6, and IL-10 cytokines in resting human monocytes. CD38 ligation by the F(ab')(2) IB4 mAb did not induce signals relevant for cytokine secretion and the block of the Fcgamma receptor I (FcgammaRI) by anti-CD64 or FcgammaRII by anti-CD32 mAb did not inhibit CD38-mediated IL-1beta release. Dimerization or multimerization of the CD38 molecule by: (i) cross-linking of the receptor ligated by F(ab')(2) or by (ii) increasing CD38 expression by treating monocytes with IFNgamma were able to restore the truncated CD38-mediated signals involved in cytokine secretion. These data indicate that CD38 receptor-mediated signals operate directly suggesting a Fcgamma receptorial surface molecule independent activation pathway. The key element for the receptor mediated signaling is represented by surface density of CD38 on resting monocytes.

ADP-ribosyl Cyclase↗