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At least 1,279 records · Page 71Linked to original sources
PubMed2006

Exploiting scents of distress: the prospect of manipulating herbivore-induced plant odours to enhance the control of agricultural pests.

In response to feeding by arthropods, plants actively and systemically emit various volatile substances. It has been proposed that these herbivore-induced volatiles (HIPVs) can be exploited in agricultural pest control because they might repel herbivores and because they serve as attractants for the enemies of the herbivores. Indeed, recent studies with transgenic plants confirm that odour emissions can be manipulated in order to enhance the plants' attractiveness to beneficial arthropods. An additional advantage of manipulating HIPV emissions could be their effects on neighbouring plants, as a rapidly increasing number of studies show that exposure to HIPVs primes plants for augmented defence expression. Targeting the right volatiles for enhanced emission should lead to ecologically and economically sound ways of combating important pests.

Animals↗
PubMed2005

Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease.

Despite our present knowledge of some of the cellular pathways that modulate central nervous system injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. The cellular mechanisms that precipitate these diseases are more involved than initially believed. As a result, identification of novel therapeutic targets for the treatment of cellular injury would be extremely beneficial to reduce or eliminate disability from nervous system disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we discuss novel pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Current work has identified exciting pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and their downstream substrates that include Forkhead transcription factors, glycogen synthase kinase-3beta, mitochondrial dysfunction, Bad, and Bcl-x(L). Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation. New therapeutic avenues that are just open to exploration, such as with brain temperature regulation, nicotinamide adenine dinucleotide modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat a variety of disorders that include stroke, Alzheimer's disease, and traumatic brain injury.

Animals↗
PubMed2006

Role of the AP-1 transcription factor c-Jun in developing, adult and injured brain.

The transcription factor activator protein-1 (AP-1) consists of a variety of dimers composed of members of the Jun and Fos families of proteins. However, it is the up-regulation of c-jun that is a particularly common event in the developing, adult as well as in injured nervous system that serves as a model of transcriptional control of brain function. In view of the long list of excellent in depth overviews on the different members of the Jun family and associated molecules, the primary focus of the current paper is to focus on c-Jun specifically and discuss the evidence on the involvement of this transcription factor in ischaemia and stroke, in seizures, during learning and memory, or following axonal injury and during successful regeneration. Functional studies employing in vivo strategies using gene deletion, targeted expression of dominant negative isoforms and pharmacological inhibitors all suggest a bipotential role of c-Jun, in mediating neurodegeneration and cell death, as well as in plasticity and repair. Phosphorylation of c-Jun, and the activation of its upstream kinases (Jun N-terminal Kinase (JNK) 1-3, JNK kinases (JNKK)) is required in many but not in all forms of these events, with only a partial overlap of the Jun-, JNK- or JNKK(n)-dependent functions. Moreover, a better understanding of the non-overlapping roles could considerably increase the potential of pharmacological agents to improve neurological outcome following trauma, neonatal encephalopathy and stroke, or neurodegenerative disease.

Animals↗
PubMed2025

Network-based drug repurposing for psychiatric disorders using single-cell genomics.

Neuropsychiatric disorders lack effective treatments due to a limited understanding of the underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data and analyzed 23 cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, and autism. Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural networks on those modules to prioritize novel risk genes and leveraged them in a network-based drug repurposing framework to identify 220 drug molecules with the potential for targeting specific cell types. We found evidence for 37 of these drugs in reversing disorder-associated transcriptional phenotypes. Additionally, we discovered 335 drug-cell quantitative trait loci (eQTLs), revealing genetic variation's influence on drug target expression at the cell-type level. Our results provide a single-cell network medicine resource that provides potential mechanistic insights for advancing treatment options for neuropsychiatric disorders.

Drug Repositioning↗
PubMed2004

The activation level of the TNF family receptor, Edar, determines cusp number and tooth number during tooth development.

Mutations in members of the ectodysplasin (TNF-related) signalling pathway, EDA, EDAR, and EDARADD in mice and humans produce an ectodermal dysplasia phenotype that includes missing teeth and smaller teeth with reduced cusps. Using the keratin 14 promoter to target expression of an activated form of Edar in transgenic mice, we show that expression of this transgene is able to rescue the tooth phenotype in Tabby (Eda) and Sleek (Edar) mutant mice. High levels of expression of the transgene in wild-type mice result in molar teeth with extra cusps, and in some cases supernumerary teeth, the opposite of the mutant phenotype. The level of activation of Edar thus determines cusp number and tooth number during tooth development.

Animals↗
PubMed2005

Condensation of the central nervous system in embryonic Drosophila is inhibited by blocking hemocyte migration or neural activity.

Condensation is a process whereby a tissue undergoes a coordinated decrease in size and increase in cellular density during development. Although it occurs in many developmental contexts, the mechanisms underlying this process are largely unknown. Here, we investigate condensation in the embryonic Drosophila ventral nerve cord (VNC). Two major events coincide with condensation during embryogenesis: the deposition of extracellular matrix by hemocytes, and the onset of central nervous system activity. We find that preventing hemocyte migration by removing the function of the Drosophila VEGF receptor homologue, Pvr, or by disrupting Rac1 function in these cells, inhibits condensation. In the absence of hemocytes migrating adjacent to the developing VNC, the extracellular matrix components Collagen IV, Viking and Peroxidasin are not deposited around this tissue. Blocking neural activity by targeted expression of tetanus toxin light chain or an inwardly rectifying potassium channel also inhibits condensation. We find that disrupting Rac1 function in either glia or neurons, including those located in the nerve cord, causes a similar phenotype. Our data suggest that condensation of the VNC during Drosophila embryogenesis depends on both hemocyte-deposited extracellular matrix and neural activity, and allow us to propose a mechanism whereby these processes work together to shape the developing central nervous system.

Animals↗
PubMed2026

HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.

Resistance to lenvatinib remains an important limitation in hepatocellular carcinoma treatment. Six patient-derived organoid lines were established and classified as sensitive or resistant according to ex vivo drug responses, retaining histological and immunophenotypic features of matched parental tumors. Resistant organoids showed unchanged ATP activity, whereas sensitive ones exhibited pronounced morphological changes and reduced ATP activity at higher concentrations. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in resistant versus sensitive organoids, with HIF-1 signaling among altered pathways. In resistant organoids, lenvatinib increased HIF-1α, ANGPT2, and HK3 mRNA, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced these transcripts and further decreased ATP activity when combined with lenvatinib. In organoid-derived xenografts, this combination suppressed tumor growth and HIF-1 target expression more than lenvatinib alone, indicating HIF-1 signaling contributes to the resistant phenotype and its inhibition may enhance response.

Drug resistance↗
PubMed2004

Spliced spleen necrosis virus vector RNA is not encapsidated: implications for retroviral replication and vector design.

RNA splicing is a complex event in the retroviral life cycle and can involve multiple steps, as well as cis-acting sequences, to maintain a proper balance of spliced and unspliced viral RNA for translation and encapsidation. The retroviral RNA can be processed by cellular machinery and enables the removal of intronic sequences. We aimed to utilize the removal of a synthetic intron for targeted gene expression. To analyze intron removal and gene expression, we have constructed a novel self-inactivating gene-activating (SIGA) vector for potential universal gene therapy. New vectors for gene therapy are necessary for safe and effective gene delivery in humans. The SIGA vector is derived from spleen necrosis virus (SNV), which is an avian reticuloendotheliosis virus. The vector was designed so that expression of a therapeutic gene is blocked in helper cell lines due to an intervening sequence containing various blocks in transcription and translation. However, after one round of retroviral replication, the intervening sequence should be removed by the cellular machinery and the therapeutic gene will be selectively expressed in target cells. Our studies show that the intervening sequence in SIGA vector RNA is partially spliced. However, spliced vector RNA was not transduced to target cells. Previous studies showed that an infectious SNV vector enabled transduction of spliced RNA. However, yet-undefined differences in infectious and replication-deficient retroviral replication may have an effect on the transduction of spliced RNA. The results of this study present key information on spliced RNA and its encapsidation, as well as data for the construction of a new generation of SNV-derived retroviral vectors.

Animals↗
PubMed2003

Transforming growth factor-beta mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells.

In vitro studies suggest that transforming growth factor (TGF)-beta has potent effects on gastrointestinal mucosal integrity, wound repair, and neoplasia. However, the multiplicity of actions of this peptide on many different cell types confounds efforts to define the role of TGF-beta within the intestinal epithelium in vivo. To delineate these effects selective blockade of intestinal epithelial TGF-beta activity was undertaken through targeted expression of a dominant-negative (DN) TGF-beta RII to intestinal epithelial cells in vitro and in vivo. Stable intestinal epithelial cell (IEC)-6 lines overexpressing TGF-beta RII-DN (nucleotides -7 to 573) were established. Transgenic mice overexpressing TGF-beta RII-DN under the regulation of a modified liver fatty acid-binding promoter (LFABP-PTS4) were constructed. In vitro healing was assessed by wounding of confluent monolayers. Colitis was induced by the addition of dextran sodium sulfate (2.5 to 7.5% w/v) to their drinking water. Overexpression of TGF-beta RII-DN in intestinal epithelial cell-6 cells resulted in a marked reduction in cell migration and TGF-beta-stimulated wound healing in vitro. TGF-beta RII-DN transgenic mice did not exhibit baseline intestinal inflammation or changes in survival, body weight, epithelial cell proliferation, aberrant crypt foci, or tumor formation. TGF-beta RII-DN mice were markedly more susceptible to dextran sodium sulfate-induced colitis and exhibited impaired recovery after colonic injury. TGF-beta is required for intestinal mucosal healing and TGF-beta modulation of the intestinal epithelium plays a central role in determining susceptibility to injury.

Animals↗
PubMed2000

Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas.

Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice </=28 weeks of age or p53-/- mice </= 17 weeks of age; however, an older (170-day-old) male p53-/- mouse used to maintain the colony developed anaplastic thyroid carcinoma with liver metastases. These findings demonstrate that the lack of functional p53 in ret/PTC1 mice promotes anaplasia and invasiveness of thyroid carcinomas.

Anaplasia↗
PubMed2002

Retinal ablation and altered lens differentiation induced by ocular overexpression of BMP7.

The alphaA-crystallin promoter was used to target expression of bone morphogenetic protein 7 (BMP7) to lens fiber cells in transgenic mice. Surprisingly, lens-specific expression of BMP7 induced widespread apoptosis and rapid ablation of the neural retina in multiple families. Subsequent to retinal ablation, the lens bow region shifted posteriorly until lens epithelial cells completely enveloped the lens. Lens-specific expression of FGF3 was found to rescue the loss of fiber cell differentiation. Our results show that elevated BMP7 levels can induce rapid retinal degeneration accompanied by disruption of the endogenous ocular system for fiber cell induction.

Animals↗
PubMed2005

ESR techniques for the detection of nitric oxide in vivo and in tissues.

Plasma levels of nitrite/nitrate may not accurately reflect endothelial nitric oxide synthase (eNOS) function because of interference by dietary nitrates. Nitrosyl hemoglobin (HbNO), a metabolic product of nitric oxide (NO*), may better correlate with bioavailable NO*, but it may depend on the activity of different NOS isoforms and may be affected by dietary nitrite/nitrate. This work examined the correlation between vascular endothelial NO* release and blood levels of HbNO. We measured HbNO in mouse blood using electron spin resonance (ESR) spectrometry, and we quantified vascular production of NO* using colloid Fe(DETC)2 and ESR. C57Blk/6 mice who were fed a high-nitrate diet had levels of plasma HbNO increased 10-fold, whereas those fed a low-nitrate diet had decreased HbNO levels from 0.58 +/- 0.02 to 0.48 +/- 0.01 microM. Therefore, a low-nitrate diet is essential when using HbNO as a marker of eNOS activity. Treatment with L-NAME and the eNOS-specific inhibitor L-NIO halved HbNO formation, which reflects the complete inhibition of NO* release by aorta endothelium. Treatment of mice with the selective inducible NOS (iNOS) inhibitor, 1400W, or the selective neuronal NOS (nNOS) inhibitor N-AANG did not alter either blood HbNO levels or vascular NO*. The relationship between HbNO and NO* production by the endothelium (0.23 microM HbNO to 5.27 microM/h of NO*/mg of dry weight aorta) was found to be identical for both C57Blk/6 mice and mice with vascular smooth muscle-targeted expression of p22phox associated with strong increase in eNOS activity. These results support the important role of eNOS in the formation of circulating HbNO, whereas iNOS and nNOS do not contribute to HbNO formation under normal conditions. These data suggest that HbNO can be used as a noninvasive marker of endothelial NO* production in vivo.

Animals↗
PubMed2006

Development and implementation of three mitogen-activated protein kinase (MAPK) signaling pathway imaging assays to provide MAPK module selectivity profiling for kinase inhibitors: MK2-EGFP translocation, c-Jun, and ERK activation.

This chapter describes the development and implementation of three independent imaging assays for the major mitogen-activated protein kinase (MAPK) signaling modules: p38, JNK, and ERK. There are more than 500 protein kinases encoded in the human genome that share an ATP-binding site and catalytic domain conserved in both sequence and structure. The majority of kinase inhibitors have been found to be competitive with ATP, raising concerns regarding kinase selectivity and potency in an environment of millimolar intracellular concentrations of ATP, as well as the potential for off-target effects via the many other cellular proteins that bind and/or utilize ATP. The apparent redundancy of the kinase isoforms and functions in the MAPK signaling modules present additional challenges for kinase inhibitor selectivity and potency. Imaging assays provide a method to address many of these concerns. Cellular imaging approaches facilitate analysis of the targets expressed in the context of their endogenous substrates and scaffolding proteins and in a complex environment for which subcellular localization, cross talk between pathways, phosphatase regulatory control, and intracellular ATP concentrations are relevant to the functions of the kinase. The assays described herein provide a strategy to profile kinase inhibitors for MAPK pathway selectivity while simultaneously providing information on cell morphology or toxicity. Results suggest that the MAPK pathways are indeed susceptible to nonselective kinase inhibitors such as staurosporin and inhibitors that inhibit upstream MAPK Kinase Kinases (MKKKs) and MAPK Kinases (MKKs) in the MAPK signaling pathway, especially those involved in cross talk between the pathways. However, selective MAPK inhibitors were identified that exhibited pathway selectivity as evidenced by significantly lower IC(50) values for their respective p38, JNK, or ERK signaling pathway assays.

Biochemistry↗
PubMed2002

Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock.

Electrical silencing of Drosophila circadian pacemaker neurons through targeted expression of K+ channels causes severe deficits in free-running circadian locomotor rhythmicity in complete darkness. Pacemaker electrical silencing also stops the free-running oscillation of PERIOD (PER) and TIMELESS (TIM) proteins that constitutes the core of the cell-autonomous molecular clock. In contrast, electrical silencing fails to abolish PER and TIM oscillation in light-dark cycles, although it does impair rhythmic behavior. On the basis of these findings, we propose that electrical activity is an essential element of the free-running molecular clock of pacemaker neurons along with the transcription factors and regulatory enzymes that have been previously identified as required for clock function.

Action Potentials↗
PubMed2002

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection.

The appearance of non-cytolytic T cells that suppressed feline immunodeficiency virus (FIV) replication in vitro, and FIV-specific cytotoxic T cell (CTL) responses was compared in a group of seven, specific pathogen free (SPF) domestic cats following primary infection with the Glasgow(8) isolate of FIV (FIV(GL-8)). FIV proviral burdens were quantified in the blood and lymphoid tissues by real-time PCR. Non-cytolytic T cell suppression of FIV replication was measured by co-cultivating lymphoblasts prepared from the cats at different time-points during infection with FIV-infected MYA-1 cells in vitro. Non-cytolytic suppressor activity was detected as early as 1 week after infection, and was evident in all the lymphoid tissues examined. Further, this activity was present in subpopulations of T cells in the blood with normal (CD8(hi)) or reduced (CD8(lo)) expression of the CD8 molecule, and temporal modulations in non-cytolytic suppressor activity were unrelated to the circulating CD8(+) T cell numbers. Virus-specific CTL responses, measured by (51)Cr release assays, were not detected until 4 weeks after infection, with the emergence of FIV-specific effector CTLs in the blood. Throughout infection the response was predominantly directed towards FIV Gag-expressing target cells, and by 47 weeks after infection CTL responses had become localised in the lymph nodes and spleen. The results suggest that both non-cytolytic T cell suppression of FIV replication and FIV-specific CTL responses are important cellular immune mechanisms in the control of FIV replication in infected asymptomatic cats.

Animals↗
PubMed1997

Potential deleterious effect of anti-viral cytotoxic lymphocyte through the CD95 (FAS/APO-1)-mediated pathway during chronic HIV infection.

The potential deleterious effect through a CD95-based pathway of anti-viral cytotoxic lymphocyte (CTL) during HIV-infection was studied. The present paper reports that a Nef specific CTL line derived from an HIV-infected person is able to kill not only Nef-expressing target cells but also CD95+ compliant Jurkat cells. The two mechanisms of cytotoxicity, i.e. perforin-vs-CD95-dependent were differentiated according to their respective Ca(2+)-dependence. The existence of the dual killing machinery in the anti-HIV CTL line was correlated with the coexpression in these cells of perforin and CD95-L molecules. A model of AIDS pathogenesis involving the deleterious effect through the CD95 pathway of the viral specific CTL response is discussed.

Antigen-Presenting Cells↗
PubMed2000

Rice transformation for crop improvement and functional genomics.

Although several japonica and some indica varieties of rice have already been transformed, there is significant scope for improvement in the technology for transformation of economically important indica varieties. Successful transformation of rice employing Agrobacterium and recent advances in direct gene transfer by biolistics, evidenced by transfer of multiple genes, have removed some of the serious impediments in the area of gene engineering. The transfer of genes for nutritionally important biosynthetic pathway has provided many opportunities for performing metabolic engineering. Other useful genes for resistance against pests, diseases and abiotic stresses have also been transferred to rice. But the limited knowledge about important target genes requires rapid progress in the field of functional genomics. Transgenic rice system can be applied to isolate new genes, promoters, and enhancers and their functions could be unravelled. The combination of novel regulatory systems for targeted expression and useful new genes should pave the way for improvement of rice and other cereals.

Journal Article↗
PubMed2000

Modeling human neurodegenerative diseases in Drosophila: on a wing and a prayer.

The ability of Drosophila genetics to reveal new insights into human neurodegenerative disease is highlighted not only by mutants in flies that show neuronal cell loss, but also by targeted expression of human disease genes in the fly. Moreover, study of Drosophila homologs of various human disease genes provides new insight into fundamental aspects of protein function. These recent findings confirm the remarkable homology of gene function in flies when compared with humans. With the advent of complete genomic sequencing on the horizon, Drosophila will continue to be an outstanding model system in which to unravel the complexities, causes and treatments for human neural degeneration.

Animals↗