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Results for “Candidate pathways”

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PubMed1992

Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats.

Many visceral afferent neurons contain peptides, which have been proposed as histochemical markers for nerve pathways of particular targets or as transmitter candidates. The former possibility was investigated in the present study. Primary afferent neurons which project to the urinary bladder, distal colon or penis of rats, and the colon of cats were labelled with retrogradely transported fluorescent dyes (Fast Blue, True Blue, or Fluoro Gold). One to six weeks after dye injection into the organs, lumbosacral dorsal root ganglia were removed, treated with colchicine, and processed for immunohistochemical identification of five peptides. Dye-labelled neurons were distributed in an organ-specific manner in the lower lumbosacral ganglia, where colon afferent neurons were almost exclusively found in S1 ganglia, penis neurons primarily in L6, and bladder neurons at both levels. Substance P- (SP), calcitonin gene-related peptide-(CGRP), vasoactive intestinal peptide- (VIP), enkephalin- (ENK), and somatostatin- (SOM) immunoreactivity (IR) were detected in neurons in all lumbosacral ganglia but only some of these peptides were present in a large percentage of labelled neurons. The numbers of peptide-containing neurons innervating each organ were CGRP greater than SP greater than VIP greater than ENK greater than SOM; however some differences were observed in the relative proportions of these neuronal populations between upper lumbar and lower lumbosacral ganglia and between different organs. The major difference seen at the upper lumbar level was amongst the SP-IR neurons, which were common (25-30%) amongst bladder and colon afferent neurons but absent in penis neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Cellular localization and signaling activity of beta-catenin in migrating neural crest cells.

In the vertebrate embryo, development of the neural crest is accompanied by sequential changes in cellular adhesiveness, allowing cells to delaminate from the neural epithelium, to undergo migration through extracellular matrix material, and to coalesce into ganglia of the peripheral nervous system. Because of its dual role in cell adhesion, as a link between cadherins and the actin cytoskeleton, and in cell signaling, as a key mediator of the Wnt-signaling pathway, beta-catenin is a good candidate to play a central role in the control of neural crest cell development. In the present study, we analyzed, by using an in vitro culture system, whether the cellular localization and the signaling activity of beta-catenin are regulated in conjunction with cell migration during ontogeny of trunk neural crest cells in the avian embryo. beta-Catenin molecules were found primarily in association with N-cadherin in the regions of intercellular contacts in most migrating neural crest cells, and only early-migrating cells situated in proximity with the dorsal side of the neural tube showed detectable beta-catenin in their nuclei. This finding indicates that beta-catenin may be recruited for signaling in neural crest cells only transiently at the onset of migration and that sustained beta-catenin signals are not necessary for the progression of migration. The nuclear distribution of beta-catenin within crest cells was not affected upon modification of the N-cadherin-mediated cell-cell contacts, revealing that recruitment of beta-catenin for signaling is not driven by changes in intercellular cohesion during migration. Overstimulation of beta-catenin signals in neural crest cells at the time of their migration, using LiCl treatment or coculture with Wnt-1-producing cells, induced nuclear translocation of beta-catenin and Lef-1 up-regulation in neural crest cells and provoked a marked inhibition of cell delamination and migration. The effect of LiCl and exogenous Wnt-1 on neural crest cells could be essentially attributed to a dramatic decrease in integrin-mediated cell-matrix adhesion as well as a massive reduction of cell proliferation. In addition, although it apparently did not affect expression of neural crest markers, Wnt-1 exposure dramatically affected signaling events involving Notch-Delta, presumably also accounting for the strong reduction in cell delamination. In conclusion, our data indicate that beta-catenin functions primarily in cell adhesion events during migration and may be recruited transiently for signaling during delamination possibly to regulate the balance between cell proliferation and cell differentiation.

Actins↗

PubMed2003

Detailed gene copy number and RNA expression analysis of the 17q12-23 region in primary breast cancers.

Chromosome region 17q12-23 commonly shows an increase in DNA copy number in breast cancers, suggesting that several oncogenes are located at this site. We performed a high-resolution expression array and comparative genomic hybridization analysis of genes mapped to the entire 17q12-23 region, to identify novel candidate oncogenes. We identified 24 genes that showed significant overexpression in breast cancers with gain of 17q12-23, compared to cancers without gain. These genes included previously identified oncogenes, together with several novel candidate oncogenes. FISH analysis using specific gene probes hybridized to tissue arrays confirmed the underlying amplification of overexpressed genes. This high-resolution analysis of the 17q12-23 region indicates that several established and novel candidate oncogenes, including a Wnt-signaling pathway member, are amplified and overexpressed within individual primary breast cancer samples. We were also able to confirm the presence of two apparently separate and reciprocally amplified groups of genes within this region. Investigation of these genes and their functional interactions will facilitate our understanding of breast oncogenesis and optimal management of this disease.

Breast Neoplasms↗

PubMed1992

Serum independence of low K+ induction of Na,K-ATPase: possible role of c-fos.

Cultured ARL15 cells respond to abnormally low extracellular K+ concentrations by increasing the abundance of Na,K-ATPase (the Na/K pump). This response is preceded by significant increases in the mRNAs of the alpha 1 and beta 1 subunits of this enzyme, implying transcriptional or post-transcriptional regulation in the response. The present study concerned the possible participation of serum factors in low K+ induction of Na,K-ATPase. In normal K+ (4.5 mM) or low K+ (0.68 mM) the presence of 10% calf serum had no effect on Na,K-ATPase activity. The serum independence of the response to low K+ raised the possibility that low K+ may itself elicit a "growth" response. Accordingly, the effect of low K+ on mRNA abundances of four proto-oncogenes (c-fos, c-myc, c-jun and c-ski) was evaluated in the early phase of the response by quantitative Northern blot analysis. The mRNA for c-fos was transiently elevated by low K+, with a peak at 30 min. In contrast, low K+ had no measurable effect on the abundances of c-myc, c-jun and c-ski, for up to 2 hr of exposure. The early elevation of c-fos mRNA makes it a candidate mediator in this signal-transduction pathway. Induction of c-fos mRNA by the phorbol ester, PMA, or by dioctanoyl glycerol, however, had no effect on Na,K-ATPase activity. These results indicate that an increase in c-fos mRNA alone is not sufficient to induce Na,K-ATPase. Whether induction of c-fos is necessary for the response to low K+ remains to be determined in future studies.

Animals↗

PubMed2006

A perennial ryegrass CBF gene cluster is located in a region predicted by conserved synteny between Poaceae species.

CBF/DREB1 proteins are the most important regulators of the cold temperature signaling pathway in many plants. CBF genes are candidates for low-temperature tolerance QTL in wheat and barley. Ten novel putative CBF cDNAs of perennial ryegrass (Lolium perenne L.) have been isolated from cold-treated leaf tissue. Their primary structures contain some conserved motifs, characteristic of the gene class. Phylogenetic analysis revealed that LpCBF genes were attributable to the HvCBF3-, and HvCBF4-subgroups following the previously proposed classification of barley CBF genes. RT-PCR analysis revealed that the expression of LpCBF genes was rapidly induced in response to low temperature and that the expression pattern under the low-temperature conditions for a long period was different between the various LpCBF genes. Five of the ten LpCBF genes were assigned to the genetic linkage map using the p150/112 reference mapping population. LpCBFIb, LpCBFII, LpCBFIIIb and LpCBFIIIc were mapped on LG5 forming a cluster within 2.2 cM, while LpCBFVb was located on LG1. Based on comparative genetic studies, conserved synteny for CBF gene family was observed between the Triticeae cereals and perennial ryegrass. Information on the perennial ryegrass CBF genes at both the molecular and genetic level obtained in this study would be useful for the further study on the role of CBF genes and low-temperature tolerance in grasses.

Amino Acid Sequence↗

PubMed1999

Review: Theileria schizonts induce fundamental alterations in their host cells.

The sporozoites of Theileria annulata and T. parva invade bovine leukocytes, where they differentiate into schizonts. The latter can immortalize and induce fundamental changes in their host cells. T. annulata infects mainly major histocompatibility complex class II cells, whereas T. parva preferentially transforms T-lymphocytes, which proliferate continuously without the need for exogenously added growth factors. Most of the cell lines appear to be independent of a growth factor but may express several cytokines that influence the outcome of the disease. The mechanisms underlying this transformation are not well understood. The infected cells show increased activity of casein kinase II and Jun NH2-terminal kinase (JNK), whereas extracellular signal-related kinase 1 and 2 and P38 are not activated. In addition, several transcriptional factors such as NFkB and AP-1 are activated. It has been postulated that parasite proteins either expressed on the surface of the schizonts or secreted into the host cell cytoplasm may interfere with the signal-transduction pathway of the host cells. A possible candidate may the casein kinase II homologue that was identified in schizonts of both T. annulata and T. parva.

Animals↗

PubMed2006

Effects of TGF-betas and a specific antagonist on apoptosis of immature rat male germ cells in vitro.

Massive apoptosis of pubertal male germ cells is important for the development of functional spermatogenesis in the adult testis. Although the trigger(s) for male germ cell loss at puberty remain undefined, we have hypothesized that transforming growth factor-betas (TGF-betas) play an active role. Here we demonstrate that the three mammalian TGF-beta isoforms, TGF-beta1, TGF-beta2 and TGF-beta3, induce distinct apoptosis of pubertal spermatogonia and spermatocytes in a dose-dependent manner. Induction of male germ cell death by activation of caspase-3 was most pronounced with TGF-beta2 compared to TGF-beta1 and TGF-beta3. Furthermore, we found colocalization of activated caspase-3 with apoptotic protease-activating factor-1 (Apaf-1) in apoptotic germ cells, thus indicating the importance of the intrinsic mitochondrial pathway in TGF-beta-induced apoptosis. The specificity of the TGF-beta effects was proven by addition of recombinant latency-associated peptide against TGF-beta1 (rLAP-TGF-beta1) which completely abolished TGF-beta1-induced and TGF-beta3-induced germ cell apoptosis. Although TGF-beta2-triggered germ cell death also was significantly reduced by rLAP-TGF-beta1, inhibition was not maximal. Our results suggest that the three TGF-beta isoforms induce apoptosis of pubertal male germ cells via the mitochondrial pathway in vitro and are thus likely candidates involved in the excessive first wave of apoptosis of male germ cells during puberty.

Animals↗

PubMed1990

On the nature of the cytochrome P450scc "ultimate oxidant": characterization of a productive radical intermediate.

The electron paramagnetic (EPR) properties of a transient species detected during a cytochrome P450 (P450)-mediated peroxidative reaction have been compared with those of peroxidases Compound I and model metalloporphyrins. The reaction which was studied with cholesterol-specific P450scc and (20R)-20-hydroperoxycholesterol, occurred without enzyme denaturation. The resulting transient species, which reached its maximum after 50 s reaction, was characterized by a one-line EPR spectrum, g = 2.0035, delta 1/2 = 1.08 mT. The decay of this radical was concomitant with the production of (20R)-20,21-dihydroxycholesterol. The reaction (almost 100% yield) conserved the stereo-specificity of the natural pathway. We suggest this intermediate is a candidate for the in vivo ultimate oxidant in the P450-mediated hydroxylation process. The comparison of the observed EPR spectrum with those of peroxidase Compound I and related synthetic models allows us to propose a FeIV porphyrin II cation radical structure for the intermediate.

Adrenal Cortex↗

PubMed1982

Septal modulation of the population spike in the fascia dentata produced by perforant path stimulation in the rat.

Electrical stimulation of the perforant path, which originates in the entorhinal cortex, produces a characteristic excitatory postsynaptic field potential (extracellular EPSP) which can be recorded in the fascia dentata. This evoked response may include a population spike, if stimulation is sufficient. In the anaesthetized rat, stimulation of the medial septum, when paired with perforant path stimulation, was found to augment the population spike component of the evoked field potential. Stimulation of the septum alone produced no apparent field potential. The augmentation effect was found to have a rapid onset (4 ms), which is sufficient for the participation of interneurons, and a relatively long time course (150 ms). Presynaptic mechanisms of facilitation were ruled out as there was no concurrent alteration of the extracellular EPSP. A change in population spike threshold, compatible with a postsynaptic mechanism, was observed and some possible models of action discussed. Augmentation survived depletion of hippocampal norepinephrine caused by injections of 6-hydroxydopamine into the dorsal noradrenergic bundle, indicating that the facilitation was not due to an activation of the ascending noradrenergic fibres of passage originating from the locus coeruleus. The cholinergic septo-hippocampal pathway was ruled out as a likely candidate for the modulation as the augmentation survived injections of the muscarinic antagonists atropine and scopolamine and the nicotinic antagonists tubocurarine and dihydro-beta-erythroidine. A relationship between the septal modulation and hippocampal theta was suggested.

Animals↗

PubMed1991

Stathmin: a relay phosphoprotein for multiple signal transduction?

Stathmin is a ubiquitous, phylogenetically conserved protein present in the cytoplasm of cells in a variety of unphosphorylated and phosphorylated forms. Its expression and phosphorylation are regulated throughout development and in response to extracellular signals regulating cell proliferation, differentiation and functions. The overall pattern of its molecular forms reflects the activation of corresponding second messenger pathways. This phosphoprotein is therefore a good candidate as a general relay in signal transduction, possibly integrating diverse signals of the cell's environment.

Amino Acid Sequence↗

PubMed2006

From motivation to behaviour: a model of reward sensitivity, overeating, and food preferences in the risk profile for obesity.

The reinforcing effects of addictive drugs and palatable foods are regulated, at least in part, by a common biological mechanism. The reactivity or sensitivity of these brain reward regions have been found to correlate significantly with the risk for a variety of drug addictions. Sensitivity to Reward (STR) is conceptualised as a psycho-biological personality trait rooted firmly in the availability of dopamine in the mesocorticolimbic ('common reward') pathways, and as such is a good candidate for studying motivational factors and eating behaviours. The purpose of the present study was to examine whether STR was related to behaviours that contribute to excess body weight. Structural equation modelling procedures were used with a sample of healthy adult women (n=151). We hypothesised that STR would positively predict overeating and a preference for foods high in fat and sugar; and that these two behaviour would, in turn, predict a higher Body Mass Index. Results provided an excellent fit of the model to our data confirming our view that a personality trait like STR can only influence a physical condition like body weight indirectly by the way it co-varies with behaviours that contribute directly to variation in the outcome variable.

Adult↗

PubMed2005

Thioredoxin reductase as a novel molecular target for cancer therapy.

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers. We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities.

Animals↗

PubMed2026

Ossicle occurrence characteristics and related molecular mechanisms in the sea cucumber Apostichopus japonicus.

To investigate the morphogenetic pattern and molecular mechanism of ossicle formation in the sea cucumber Apostichopus japonicus, this study systematically examined the morphological development and temporal sequence of spicules using the NaClO maceration method, in-situ squash preparation and microscopic observation. Comparative transcriptome sequencing was performed between doliolaria and pentactula larvae to screen differentially expressed genes (DEGs) related to ossicles formation, followed by pathway enrichment analysis. The function of the candidate key gene papilin-like was verified using siRNA-mediated gene silencing. The results were as follows: 1) Ossicles of A. japonicus first appeared at the late auricularia stage, initiating as X-shaped ossicles at the base of the oral tentacles. The number of X-shaped ossicles increased dramatically during the doliolaria stage. X-shaped ossicles were gradually replaced by table-shaped and rosette-shaped ossicles at the pentactula stage, suggesting that X-shaped ossicles may differentiate into these two ossicle types. The morphology of table-shaped ossicles showed a "simple-complex-simple" pattern with development. 2) Key genes related to ossicles formation, including CA1, COL1A2, and papilin-like, were identified by transcriptome analysis. After papilin-like knockdown, abnormal morphologies were observed in table-shaped ossicles of 1-year-old A. japonicus, such as spine-like protrusions on the outer margin of the disc and loss of table legs, confirming its crucial roles in maintaining ossicle morphology. This study clarified the morphological development pattern of ossicles in A. japonicus and identified a key regulatory gene (papilin-like) involved in ossicle morphogenesis, providing preliminary insights into the underlying molecular regulatory mechanism. These findings enrich our understanding on ossicles formation in echinoderms, and provide important morphological and molecular biological information for further studies on the developmental mechanism of ossicles in A. japonicus.

Animals↗

PubMed2026

Genome-wide epigenomic atlas and multi-omics responses of Eriocheir sinensis to natural extreme heat.

BACKGROUND: Global climate warming has led to increasingly frequent and prolonged extreme summer heat events, posing severe environmental challenges to aquaculture systems. Extreme summer heat can disrupt the performance of pond-cultured ectotherms. The Chinese mitten crab (Eriocheir sinensis) is an economically important freshwater crustacean, but coordinated molecular differences following contrasting natural summers remain incompletely characterized. RESULTS: We performed a comprehensive multi-omics analysis integrating meteorological monitoring, mRNA/lncRNA transcriptomics, small-RNA profiling of miRNAs, DNA methylomics, and LC-MS metabolomics in E. sinensis populations collected from Yancheng, China, between 2020 and 2024. Across the ten farms, survival was significantly lower in 2024, whereas yield and the proportion of large individuals showed nonsignificant downward trends. Gene-set analyses showed negative enrichment of cellular heat-response, protein-folding, oxidative-phosphorylation, and mitochondrial ATP-production terms in the 2024 cohort at the time of sampling. The integrated transcript annotation contained 72,240 lncRNAs and 63,833 mRNAs, and CpG was the predominant methylation context. Differential methylation analysis identified 73 regions and 185 cytosines, with hypomethylated events predominating within the significant subset. Metabolomic profiles differed between annual cohorts and mapped to carbohydrate, lipid, and amino-acid pathways. Cross-omics integration prioritized eight candidate genes-ADCY9, UNC79, UBN1, IFT52, ACO2, LOC126986070, LOC127001126, and LOC126997895-and qPCR reproduced the reported directions of expression for selected RNAs. CONCLUSION: This study provides the first integrative multi-omics framework for understanding chronic heat adaptation in E. sinensis. By linking transcriptomic, epigenomic, and metabolic remodeling, we elucidate the molecular mechanisms underlying energy imbalance, epigenetic reprogramming, and immune dysregulation during prolonged thermal stress. These findings offer valuable insights and genomic resources for breeding heat-tolerant crab strains and improving aquaculture resilience under ongoing climate change.

DNA methylation↗

PubMed2005

A functional genomics approach to identify new regulators of Wnt signaling.

A recent study by used a genome-wide RNAi screen in Drosophila cells to identify 238 candidate regulators of the Wnt-signaling pathway, most of which had not been previously connected to Wnt signaling. Supporting in vivo studies are in progress. The fact that such an impressive number of potential modulators had eluded detection in genetic screens underscores the potential of applying new, high-throughput approaches to old problems.

Animals↗

PubMed2005

Lack of consensus gene expression changes associated with radiation-induced chromosomal instability.

The relatively high frequency with which ionizing radiation induces genomic instability suggests that a gene mutation occurring after irradiation is an unlikely cause of the phenotype. To search for mechanism(s) of initiation and perpetuation of this instability phenotype, gene expression profiles of clones exhibiting delayed chromosomal instability were analyzed. Microarray analysis using two pools of isogenic radiation-induced chromosomally unstable clones compared to an irradiated but chromosomally stable clone uncovered a set of 68 differentially expressed genes using two methods of analysis. Unexpectedly, all 68 genes were under-expressed relative to the chromosomally stable reference clone. Further analysis of the candidates placed the differentially expressed genes into pathways implicating differential MAP kinase signaling, ubiquitin/proteasome function, DNA repair, cell cycle control, lipid signaling, nucleotide metabolism, and other potentially disrupted pathways. Validation studies using northern and western blotting, and functional assays concluded that although differences in some of these pathways exist, no single gene or molecular pathway was found to be differentially regulated in all of the chromosomally unstable clones tested. Inferred from these data is that there are multiple potential molecular pathways and/or events that maintain the unstable phenotype, and no single expression pattern is linked to instability in the unstable clones analyzed.

Animals↗

PubMed2005

Molecular epidemiology of extraintestinal pathogenic (uropathogenic) Escherichia coli.

Molecular epidemiological analyses of extraintestinal pathogenic Escherichia coli (ExPEC), which are also called "uropathogenic E. coli" since they are the principle pathogens in urinary tract infection, involve structured observations of E. coli as they occur in the wild. Careful selection of subjects and use of appropriate methods for genotyping and statistical analysis are required for optimal results. Molecular epidemiological studies have helped to clarify the host-pathogen relationships, phylogenetic background, reservoirs, and transmission pathways of ExPEC, to assess potential vaccine candidates, and to delineate areas for further study. Ongoing discovery of new putative virulence factors (VFs), increasing awareness of the importance of VF expression and molecular variants of VFs, and growing appreciation of transmission as an important contributor to ExPEC infections provide abundant stimulus for future molecular epidemiological studies. Published by Elsevier GmbH.

Adhesins, Escherichia coli↗

PubMed2006

Therapeutic targeting of pattern-recognition receptors.

Innate immune system could recognize the pathogen-associated molecular patterns by pattern-recognition receptors like Toll-like receptor (TLR) and nucleotide-binding oligomerisation domain (NOD) protein. Information regarding the structure and signalling pathways of TLRs and NODs could provide opportunities for new therapeutic approaches to modulate the innate immunity. Therapeutic targeting could be done by prevention of ligand binding to leucine-rich repeats domains of receptors, blocking the interactions between receptors (like Toll/interleukin-1 receptor domains of TLRs) and adaptors in signalling pathways, blocking the enzymes in signalling pathways, and immunostimulation with vaccine adjuvants. These therapeutic approaches could be useful in the treatment of different human diseases like immunological disorders, infections, and cancers. Further research on these receptors and their signalling pathways could help scientists to identify new candidates for therapeutic targeting.

Adjuvants, Immunologic↗