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Results for “Candidate pathways”

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PubMed2005

Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke.

The aim of the present study is to better understand oxygen-sensitive adaptative pathways underlying the hypoxic preconditioning-induced protection of the brain against ischemia. Using oligonucleotide microarrays, we examined the brain genomic response of adult mice following hypoxia preconditioning (8% O2 for 1 or 6 h of hypoxia with reoxygenation 12, 18, 24 h or 72 h) and ischemia (6 h), preceeded (tolerant state) or not, by preconditioning. Real-time PCR was used to validate the results. Most gene expression increases occurred during hypoxia, including those of HIF-1-dependent genes (RTP801, AM, VEGF, p21, GLUT-1), early response genes (IER3) and transcriptional factors (ATF3, C/EBPdelta). A second wave of changes occurred 24 h after reoxygenation (S100A5, TH, Calretinin, PBX3). A third one occurred during ischemia itself, revealing that hypoxic preconditioning modifies the brain genomic response to ischemia. In addition, we show that some identical genes are overexpressed by hypoxia in both neonatal and adult brains (VEGF, EPO, GLUT-1, AM, MTs, C/EBPdelta).

Age Factors↗

PubMed2006

A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway.

TGF-beta-activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMP-activated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1/AMPK signaling axis, an essential governor of cell metabolism.

AMP-Activated Protein Kinases↗

PubMed2006

Does the PGC-1/PPARgamma pathway play a role in Com-1/p8 mediated cell growth inhibition in prostate cancer?

Com-1, candidate of metastasis-1, also known as p8, has been shown to regulate the growth and apoptosis of cancer cells and is associated with the disease progression in human cancers including prostate cancer. In the current study, we investigated a potential mechanism underlying the anticancer action of Com-1/p8 in human prostate cancer. Human prostate cancer cells were used. Full-length Com-1 cDNA was isolated from normal mammary tissues. Ribozyme transgenes that specifically target human Com-1 were constructed using the pEF6/V5-His vector. Com-1 interacting proteins were determined using immunoprecipitation method. Cell growth and invasiveness were investigated using in vitro methods. Using immunoprecipitation and Western blotting, Com-1 was found to be cross-reprecipitated with PGC-1, a coactivator of peroxisome proliferator activated receptor (PPAR)-gamma, but not PPAR-gamma itself. Elimination of Com-1 from prostate cancer cells resulted in a reduced response of the cells to ciglitizone, a PPAR-gamma agonist, whereas forced expression of Com-1 rendered cells more responsive to ciglitizone. We further demonstrated that the overexpression of Com-1/p8 resulted in changes in the expression of the PGC-1 responsive gene, fatty acid synthase (FAS). Com-1 may act as a tumour suppressor in human prostate cancer cells. The potential tumour suppressive effect of Com-1 is at least partly via its interaction with PGC-1, the PPAR-gamma coactivator.

Basic Helix-Loop-Helix Proteins↗

PubMed1981

[Candidal sepsis in nursing infants].

Four observations of Candida sepsis in young infants are described, analysing the pathways for fungus penetration, discussing the organ pathology and features of morphological reactions in infants. In one case primary immunodeficiency of the cellular-humoral type was established.

Autopsy↗

PubMed1985

Eicosanoids in skin UV inflammation.

Several studies have implicated the eicosanoids as mediator substances in different types of UV inflammation. In human UV erythema, various arachidonic acid metabolites--mainly cyclooxygenase products--have been detected, particularly in skin exudates. The concentration and the sequence of release of the various eicosanoids vary in relation to the time course and the various types of UV-induced erythema. UVB, UVC but not UVA erythema at its maximum was only to some extent inhibited by indomethacin despite almost complete inhibition of the synthesis of prostaglandins E2 and F2 alpha. A major issue cannot, as yet, be answered satisfactorily: are one or a number of eicosanoids per se causing the erythema or are they only passive bystanders released by damage to cellular structures? Until further evidence has been provided, the causative role of E and F prostaglandins in relation to development of UV erythema is doubtful. By contrast, PGI2 is a more likely candidate in this respect, being synthesized and released close to the events occurring in the vessel walls. The lipoxygenase pathway is still too unexplored for proper evaluation with regard to a role in the pathogenesis, but the pharmacological properties of leukotrienes and hydroxy-fatty acids may qualify them as potential candidates alone or in a concert of mediator events occurring during the developments of UV inflammation.

Animals↗

PubMed2002

Light induction of a vertebrate clock gene involves signaling through blue-light receptors and MAP kinases.

The signaling pathways that couple light photoreception to entrainment of the circadian clock have yet to be deciphered. Two prominent groups of candidates for the circadian photoreceptors are opsins (e.g., melanopsin) and blue-light photoreceptors (e.g., cryptochromes). We have previously showed that the zebrafish is an ideal model organism in which to study circadian regulation and light response in peripheral tissues. Here, we used the light-responsive zebrafish cell line Z3 to dissect the response of the clock gene zPer2 to light. We show that the MAPK (mitogen-activated protein kinase) pathway is essential for this response, although other signaling pathways may also play a role. Moreover, action spectrum analyses of zPer2 transcriptional response to monochromatic light demonstrate the involvement of a blue-light photoreceptor. The Cry1b and Cry3 cryptochromes constitute attractive candidates as photoreceptors in this setting. Our results establish a link between blue-light photoreceptors, probably cryptochromes, and the MAPK pathway to elicit light-induced transcriptional activation of clock genes.

Adaptation, Ocular↗

PubMed1989

Middle-latency responses. I. Electrical and acoustic excitation.

The electrically evoked auditory brain-stem response has been used in the past to assess auditory system function with regard to cochlear prosthesis application. The brief latency of the response makes it susceptible to electrical artifact contamination, and waveform identification is often difficult. As a possible alternative for a noninvasive measure of system excitability, the middle-latency response (MLR), elicited by electrical stimulation, was investigated. Middle-latency responses were recorded in response to acoustic and round-window electrical stimulation in albino guinea pigs. Acoustic and electrically evoked MLR waveforms were similar, as were their respective latency/intensity functions. Amplitude/intensity functions for the electric MLR showed greater variability than acoustically evoked MLR functions. The electric MLR is readily evoked and relatively insensitive to electrical artifact in the guinea pig. It is potentially a useful tool in assessing the integrity of auditory pathways and consequently in the development of diagnostic tests for cochlear implant candidates.

Acoustic Stimulation↗

PubMed2026

T2T Genome Assembly and Multi-Omics Data Reveal Terrestrial Adaptation and Mucus Biosynthesis in Tropical Leatherleaf Slug (Laevicaulis alte).

Laevichaulis alte is a slug in the order Systellommatophora that evolved from aquatic ancestors and now faces strong challenges from desiccation, respiration on land, and novel pathogens. Its mucus is essential for water retention, locomotion, and defense. To link terrestrial adaptation with mucus biosynthesis, we generated a gap-free genome assembly of L. alte using PacBio HiFi reads, Oxford Nanopore ultra-long reads, and Hi-C data. The genome shows low heterozygosity and holocentromeric chromosomes. Functional metabolomics revealed marked metabolic shifts between L. alte and the closely related aquatic species Peronia verruculata. In L. alte, differential metabolites were enriched in lipid metabolism, immune regulation, and stress response pathways, consistent with life in a dry and microbe-rich terrestrial environment. Comparative genomics and transcriptomics identified candidate genes linked to mucus secretion and physiological adaptation, including VEGF, ASGR2, and COL6A6. Further analyses highlighted the vascular endothelial growth factor (VEGF) gene family as a key regulator connecting angiogenesis, tissue remodeling, and mucus production pathways in L. alte. Together, this gap-free genome and multi-omics dataset establish a molecular framework that links genomic innovation, mucus biology, and terrestrial adaptation in Systellommatophora, and they offer a basis for understanding ecological niche specialization in land molluscs.

Animals↗

PubMed2006

A rapid, high content, in vivo model of glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is a major clinical problem given the widespread use of steroids and limited efficacy of biphosphonates. Existing animal models of GIOP are both slow and expensive. Hence, there is a need both for adjunctive modelling systems, as well as more efficacious therapies for the treatment of GIOP. We have addressed this issue through the creation of a zebrafish model of GIOP, which can be used for 96-well plate in vivo screening with an assay time of 5 days. The model demonstrates key similarities to human GIOP including a partial response to bisphosphonates. The ability to extract detailed pharmacological data, including concentration-response analyses, enables the screening and ranking of candidate therapeutic compounds. In addition, the zebrafish model is highly relevant for pathway dissection through genetic knockdown and overexpression studies.

Animals↗

PubMed1994

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives.

Unlike herpes viruses, human immunodeficiency virus and other retroviruses do not encode specific enzymes required for the metabolism of the purine or pyrimidine nucleotides to their corresponding 5'-triphosphates. Therefore, 2',3'-dideoxynucleosides and acyclic nucleoside phosphonates must be phosphorylated and metabolized by host cell kinases and other enzymes of purine and/or pyrimidine metabolism. Different animal species (or even different cell types within one animal species) may differ in the efficiency of conversion of these drugs to their antivirally active metabolite(s). Three 2',3'-dideoxynucleosides are officially licensed for clinical use [i.e., zidovudine (3'-azido-2',3'-dideoxythymidine, AZT), didanosine (2',3'-dideoxyinosine, DDI) and zalcitabine (2',3'-dideoxycytidine, DDC)]. A number of other 2',3'-dideoxynucleoside analogues [among them stavudine (2',3'-didehydro-2',3'-dideoxythymidine, D4T), 2',3'-dideoxy-3'-thiacytidine (3TC), 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA)] are currently under clinical investigation and are candidate compounds for eventual licensing as anti-AIDS drugs. The metabolic pathways, antimetabolic effects and mechanism of antiviral action of these nucleoside analogues will be discussed.

Animals↗

PubMed2006

Current topics in human SLE genetics.

Susceptibility to systemic lupus erythematosus (SLE) depends on genetic and environmental factors. Genome scan studies have identified eight chromosomal regions with significant linkage to SLE that are confirmed by individual cohorts, suggesting that susceptibility genes may be identified within each of these loci. Linkage studies and single nucleotide polymorphisms (SNPs) have led to the identification of positional candidate genes, and their functional allelic variants have demonstrated molecular pathogenesis of the disease. The discovery of positional candidate genes that are associated with various autoimmune diseases signifies a common pathway in the mechanism of these diseases. Copy polymorphisms in susceptibility genes provide evidence in how genetic plasticity affects complex phenotypes as seen in SLE.

Genetic Linkage↗

PubMed2000

Update on inflammatory bowel disease genetics.

The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.

Base Sequence↗

PubMed1994

DET1, a negative regulator of light-mediated development and gene expression in arabidopsis, encodes a novel nuclear-localized protein.

The mechanisms by which plants integrate light signals to modify endogenous developmental programs are largely unknown. One candidate for a signal transduction component that may integrate light with developmental pathways is the Arabidopsis DET1 gene product. Here we report the positional cloning of the DET1 locus and show that DET1 is a unique nuclear-localized protein. An analysis of a number of det1 mutants indicates that mutants with partial DET1 activity develop as light-grown plants in the dark. det1 null mutants share this phenotype, but also display severe defects in temporal and spatial regulation of gene expression. These results suggest that DET1 acts in the nucleus to control the cell type-specific expression of light-regulated promoters.

Amino Acid Sequence↗

PubMed1981

Effect of chronic ipsilateral or contralateral intrauterine infusion of prostaglandin E2 (PGE2) on luteal function of unilaterally ovariectomized ewes.

The relationship between the chronic intrauterine injection of PGE2 every four hours adjacent or opposite to the corpus luteum on luteal function was studied. Intrauterine infusions every four hours of PGE2 (500 mug) from days 10 to 17 postestrus maintained luteal function only when infused into a uterine horn adjacent to a luteal-bearing ovary of unilaterally ovariectomized sheep with surgically separated uterine cornua. These data are compatible with the hypothesis that PGE2 is a good candidate for the antiluteolysin since it works only through a similar local pathway as the embryo during early pregnancy to sustain the corpus luteum.

Animals↗

PubMed1989

1,25-Dihydroxyvitamin D3-mediated vesicular calcium transport in intestine: dose-response studies.

In order to further test the validity of the vesicular transport model of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-stimulated intestinal calcium absorption, dose-response studies were undertaken. Using previously established methodology for subcellular fractionation following 45Ca absorption from in situ ligated duodenal loops, radionuclide levels were found to increase gradually in endocytic vesicles prepared from 1,25(OH)2D3-treated (+D) chicks relative to controls (-D) achieving a plateau at greater than or equal to 260 pmol seco-steroid. By comparison, lysosomal 45Ca levels increased more readily, having +D/-D ratios of 1.88 +/- 0.35, 2.21 +/- 0.05, 2.17 +/- 0.88, 2.31 +/- 0.25, and 2.15 +/- 0.47 after 0.0104, 0.052, 0.26, 1.3, or 6.5 nmol of 1,25(OH)2D3, respectively. Net intestinal calcium absorption, as judged by appearance of 45Ca in the serum for the same range of doses, rose gradually to a plateau value at greater than or equal to 260 pmol. Since lysosomal 45Ca levels were maximally increased at 1,25(OH)2D3 doses lower than those required for fully stimulated transport, it was concluded that lysosomes are still candidates for cellular calcium carriers, but that other elements of the transport pathway are required. Analyses of gradient fractions for calbindin-D28K (the vitamin D-induced calcium binding protein), and potential 1,25(OH)2D3-mediated changes in vesicular ATPase (microtubule motive power for transcellular delivery of calcium) failed to identify the missing components.

Adenosine Triphosphatases↗

PubMed2007

Mtf-1 lymphoma-susceptibility locus affects retention of large thymocytes with high ROS levels in mice after gamma-irradiation.

Mouse strains exhibit different susceptibilities to gamma-ray-induced thymic lymphomas. Our previous study identified Mtf-1 (metal responsive transcription factor-1) as a candidate susceptibility gene, which is involved in the radiation-induced signaling pathway that regulates the cellular reactive oxygen species (ROS). To reveal the mechanism for the increased susceptibility conferred by Mtf-1 locus, we examined early effects of gamma-ray on ROS levels in vivo and its difference between Mtf-1 susceptible and resistant congenic mice. Here, we show the detection of clonally growing thymocytes at 4 weeks after irradiation, indicating the start of clonal expansion at a very early stage. We also show that large thymocytes with higher ROS levels and a proliferation capacity were more numerous in the Mtf-1 susceptible mice than the resistant mice when examined at 7 days after irradiation, although such tendency was not found in mice lacking one allele of Bcl11b tumor suppressor gene. This high retention of the large thymocytes, at a high risk for ROS-induced mutation, is a compensatory proliferation and regeneration response to depletion of the thymocytes after irradiation and the response is likely to augment the development of prelymphoma cells leading to thymic lymphomas.

Animals↗

PubMed2005

The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology.

Yeast vacuoles are very dynamic structures that must respond to changes in extracellular osmolarity by rapidly altering their size, thereby releasing or taking up water and ions. Further, the need to accommodate a constant biosynthetic influx of membrane and to partition vacuoles during cell division necessitates precise regulation of the size and shape of the vacuole. While it is has been shown that the lipid kinase Fab1p and its product phosphatidylinositol 3,5-bisphosphate, and not the mitogen-activated protein kinase Hog1p, are central to this regulatory pathway, key effectors still await identification. Atg18p is the most recently identified candidate for a Fab1p effector mediating the largely uncharacterized processes of vesicle fission and membrane recycling at the vacuole.

Intracellular Membranes↗

PubMed2006

Molecular mechanisms of resistance and toxicity associated with platinating agents.

Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been used clinically for nearly 30years as part of the treatment of many types of cancers, including head and neck, testicular, ovarian, cervical, lung, colorectal and relapsed lymphoma. The cytotoxic lesion of platinating agents is thought to be the platinum intrastrand crosslink that forms on DNA, although treatment activates a number of signal transduction pathways. Treatment with these agents is characterized by resistance, both acquired and intrinsic. This resistance can be caused by a number of cellular adaptations, including reduced uptake, inactivation by glutathione and other anti-oxidants, and increased levels of DNA repair or DNA tolerance. Here we investigate the pathways that treatment with platinating agents activate, the mechanisms of resistance, potential candidate genes involved in the development of resistance, and associated clinical toxicities. Although the purpose of this review is to provide an overview of cisplatin, carboplatin, and oxaliplatin, we have focused primarily on preclinical data that has clinical relevance generated over the past five years.

Antineoplastic Agents↗